Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+]>CO>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A mixture of 66 mg (0.129 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]-methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 10 mL of methanol was treated with 0.10 mL of 2 M sodium hydroxide and stirred at reflux for 4 hours. The reaction was cooled to ambient temperature. The product precipitated upon addition of 1 M HCl and was collected by filtration. The solids were dried in vacuo to provide 50 mg (79%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a solid. nmr (300 MHz, dmso-d6) δ0.99 (t, 3H), 2.36 (s, 3H), 2.82 (q, 2H), 4.86 (s, 2H), 5.62 (s, 2H), 6.48 (d, 1H), 7.51 (m, 2H), 7.64 (s, 1H), 7.84 (d 1H), 8.05 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:15][C:14]=2[F:29])[CH:6]=1)[CH3:2].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([O:11][C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[CH:8]=[C:7]([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:15][C:14]=2[F:29])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2c(F)cc(CNC(=O)OC(C)(C)C)cc2F)c1
Reactant: N#Cc1ccc(F)cc1
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2c(F)cc(CNC(=O)OC(C)(C)C)cc2F)c1
Yield: 48.5 %

Procedure:
Using 0.5 g (1.18 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy-benzoic acid ethyl ester and 4-fluorobenzonitrile (0.21 g, 1.77 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, t), 1.42 (9H, s), 4.2 (2H, d), 4.28 (2H, q), 7.22 (6H, m), 7.32 (1H, s), 7.54 (1H, t), 7.90 (2H, d).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1>O1CCCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[N:5]1[N:4]=[C:3]([CH2:2][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([C:26]([F:43])([F:42])[F:25])[CH:32]=2)[C:7]([CH3:8])=[N:6]1
Reactant: Cc1nn(-c2ccc(F)cc2F)nc1CBr
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2F)nc1Cc1ccnc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
To a solution of 4-(bromomethyl)-2-(2,4-difluorophenyl)-5-methyl-2H-1,2,3-triazole (i.e. the product of Step C, 0.30 g, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.31 g, 1.15 mmol). The mixture was heated to 70° C. and stirred for 96 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by twice by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes, and then was purified by reverse-phase chromatography on C18 silica gel to afford the title compound (0.18 g) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:27]([O:31][C:32](=O)[O-:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[C:27]([O:31][C:32]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([Cl:2])=[N:4][CH:5]=[CH:6]3)[CH2:15][CH2:16]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1nccc2cc(OC3CCNCC3)ccc12
Reactant: CC(C)(C)OC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
1.23 g (4.11 mmol) of 1-Chloro-6-(piperidin-4-yloxy)-isoquinoline hydrochloride (161) were dissolved in 50 ml of dichloromethane and 0.85 ml (6.15 mmol) of triethylamine were added. At 0° C. a solution of 1.09 g (5.0 mmol) of tert-butyl-carbonate in 10 ml dichloromethane was added dropwise and the mixture was allowed to stand at room temperature overnight. For working up, the mixture was washed twice with H2O, dried over magnesium sulfate and evaporated, to yield 1.1 g of the desired product, which could be used without further purification. Rt=1.86 min (Method #4). Detected mass: 363.1/365.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:17]1[S:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:13](=O)[CH2:14][CH3:15])[C:6]#[N:7].[NH2:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][C:26]#[N:27].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:13]([CH2:14][CH3:15])[NH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[C:25]2[C:26]#[N:27])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.480 mmol) of the compound from example 20A, 65 mg (0.480 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 8.1 mg (0.072 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude material is purified initially by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5) and then by MPLC (Biotage 12M cartridge, eluent: isohexane/ethyl acetate 80:20). 25 mg (12% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[N:36]#[C:37]Br>C(O)C>[NH2:36][C:37]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Solvent: CCO
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N)nc4ccccc43)nc21
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (220 mg, 0.46 mmol) and cyanogen bromide (150 mg, 1.4 mmol) in ethanol (2 mL) was stirred at 95° C. for 15 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 167 (18.1 mg, 7.8%). LCMS: M+H+=506.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1H), 7.70 (s, br, 2H), 7.24 (d, 1H), 7.12 (t, 1H), 7.03 (t, 1H), 4.26 (s, br, 4H), 4.10 (s, 1H), 3.84 (s, 3H), 3.80 (m, 4H), 1.73 (m, 2H), 1.27 (m, 3H), 1.03 (s, 6H)
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>ClC(Cl)C>[CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:32]([C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[O:33])[C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2C(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2.0 ml) was added triethylamine (0.057 ml, 0.406 mmol) and 5-methylisoxazole-3-carbonyl chloride (32.5 mg, 0.223 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (ethyl acetate/methanol:98/2) of the crude residue gave the desired compound (53 mg, 74%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C@H:6]1[CH2:23][O:24][Si](C(C)(C)C)(C)C)(=[O:4])=[O:3].[OH:32]O.Cl.O>CO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:32])[CH2:7][C@H:6]1[CH2:23][OH:24])(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Reactant: OO
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1C[C@@H](P(=O)(c2ccccc2)c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 180 ml of methanol was dissolved 8.39 g (0.0176 mol) of 2S,4S)-N-methanesulfonyl-2 -tert-butyldimethlysilyloxymethyl-4-di-phosphinopyrrolidine [VI], and 11.85 g (0.0348 mol) of 10% hydrogen peroxide was added dropwise to the solution under ice-cooling. The mixture was stirred at 0° C. for one hour and then at room temperature for one hour. To the mixture was then slowly added dropwise a liquid mixture of 8.6 g of 35% hydrochloric acid, 52.7 g of water and 38.7 g of methanol, and the mixture was stirred for 2 hours at room temperature. Any insoluble matter was removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 50 ml of water and the aqueous solution was extracted three times with 100 ml of methylene chloride in each case. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure whereby white crystals were obtained which were then recrystallized from a mixture of ethanol and isopropyl alcohol. Yield 5.3 g (80%), melting point: 138°-139° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Product: Brc1ccc(COc2ccc(Cc3ncc[nH]3)cc2)cc1

Procedure:
This substance is prepared analogously to Example 1 from 4-(1-imidazolylmethyl)-phenol and 4-bromobenzyl bromide.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19]1(=[O:33])[N:23]([CH2:24][C:25](Cl)=[O:26])[C:22](=[O:28])[C:21]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]12>C(Cl)Cl>[CH2:5]([N:4]1[C@H:3]([CH2:2][Cl:1])[C@H:24]([N:23]2[C:22](=[O:28])[C:21]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]3[C:19]2=[O:33])[C:25]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC=NCc1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](CCl)N1Cc1ccccc1
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
A solution of 3.34 g of the product of Step A in 20 ml of methylene chloride was cooled to -50° C. and 2.8 ml of triethylamine were added all at once. A solution of 4 g of phthalimidoacetic acid chloride in 20 ml of methylene chloride was added thereto over 20 minutes. The mixture was stirred for one hour at 0° to -5° C. and was then poured into a decanting flask. The decanted organic phase was washed with 50 ml of demineralized water and 5 ml of a molar aqueous solution of sodium bicarbonate, and then twice with 30 ml of demineralized water. The wash water was re-extracted with 20 ml of methylene chloride and the combined organic phases were dried, rinsed and evaporated to dryness under vacuum. The 6 g of residue were chromatographed over silica gel and eluted with methylene chloride containing 5% ether. The fraction with an Rf=0.45 was evaporated to dryness and the residue was triturated with 10 ml of ether. The separated product was rinsed three times with 2 ml of ether and dried under vacuum to obtain 1.25 g of cis N-benzyl-3-phthalimido-4-chloromethyl-2-azetidinone melting at 149° C.
Reaction SMILES: [CH:1]1([CH:7]([N:18]2[CH2:23][CH2:22][C:21]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)([CH2:24][CH2:25][N:26]3[C@H:31]4[CH2:32][CH2:33][C@@H:27]3[CH2:28][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:30]4)[CH2:20][CH2:19]2)[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH:7]([N:18]2[CH2:23][CH2:22][C:21]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)([CH2:24][CH2:25][N:26]3[C@H:27]4[CH2:33][CH2:32][C@@H:31]3[CH2:30][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:28]4)[CH2:20][CH2:19]2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)OCc2ccccc2)C2CCCCC2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)O)C2CCCCC2)CC1
Yield: 85.2 %

Procedure:
A solution of benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (23.8 mg, 0.035 mmol) in 3 mL MeOH was stirred for 3 h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (17.5 mg, 85%). ESI-MS 585 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[CH2:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccoc1
Reactant: CC1(C)CCC(c2ccccc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg, 0.11 mmol) produced in Example (3c), furan-3-carbaldehyde (21 mg, 0.22 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid was dried to give 31 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([Cl:5])Cl.[Na].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].C(OCCO)C>C(Cl)Cl>[Cl:5][C:3]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[CH:2][Cl:1]
Reactant: COC(=O)c1cccc(O)c1
Reactant: ClC=C(Cl)Cl
Agent: [Na]
Solvent: CCOCCO
Solvent: ClCCl
Product: COC(=O)c1cccc(OC(Cl)=CCl)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
185 parts of trichloroethylene are introduced into a suspension of 180 parts of the sodium salt of methyl 3-hydroxybenzoate in 200 parts of ethylene glycol monoethyl ether in an autoclave, and the mixture is stirred for 2 hours at 150° C. The solvent is then stripped off under reduced pressure, the viscous residue is taken up in 300 parts of methylene chloride and the solution is filtered in the presence of active charcoal and is chromatographed over neutral alumina. After removing the methylene chloride under reduced pressure from the whole eluate, the residue is distilled through a Vigreux column at 125°-131° C./0.6 mbar, giving methyl 3-(1',2'-dichlorovinyloxy)-benzoate, of nD25 =1.5419.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10](Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(Br)cc1F
Yield: 99.3 %

Procedure:
100 g (0.524 mol) of 4-bromo-2-fluorophenol and 66.7 g (0.612 mol) of ethyl bromide were dissolved in 2 1 of ethyl methyl ketone and refluxed for 24 hours in the presence of 185 g (1.34 mol) of potassium carbonate. The solution was subsequently filtered, the filtrate was evaporated, and the crude product was filtered through silica gel with n-hexane, giving 114 g (99% of theory) of 4-bromo-1-ethoxy-2-fluorobenzene as a colourless liquid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:31])[C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:34]>O1CCOCC1>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:31])[C:23]4[CH:28]=[CH:27][C:26]([CH2:29][Cl:34])=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(NC(=O)c2ccc(CO)cc2)cc1Nc1nccc(-c2ccccc2)n1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.3 %

Procedure:
To the solution of Example K (410 mg, 0.99 mmol) in 1,4-dioxane (40 mL) was slowly added SOCl2 (650 mg, 5.50 mmol) at RT. After being stirred at RT for 3 h, the solvent and excessive SOCl2 was removed in vacuo to yield N-(3-(4-phenylpyrimidin-2-ylamino)-4-methylphenyl)-4-(chloromethyl)benzamide as a yellow solid (460 mg), which was used without further purification. 1H NMR (CDCl3-d6) δ: 8.42 (s, 1H), 8.22 (d, J=6.0 Hz, 3H), 8.05 (m, 1H), 7.94 (d, J=1.0 Hz, 2H) 7.53-7.62 (m, 5H), 7.26 (s, 2H), 4.63 (d, J=5.4 Hz, 2H), 2.44 (s, 3H); MS (ESI) m/e: 429.20 (M++1)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][O:29][N:28]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:32]>ClCCl.C(OCC)(=O)C>[ClH:32].[ClH:32].[O:29]1[CH:30]=[N:31][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:22][CH:23]=2)=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(-c3ncon3)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1nc(-c2ccc(C3CNCCN3)cc2)no1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 1,4-di(t-butoxycarbonyl)-2-(4-(1,2,4-oxadiazol-3-yl) phenyl)piperazine (464 mg, 1.08 mmol) in dichloromethane (2 mL) was added 4 N hydrogen chloride in ethyl acetate (3 mL) at room temperature. After stirring for 1.5 h, the precipitate was collected and dried in vacuo to afford 2-(4-(1,2,4-oxadiazol-3-yl)phenyl)piperazine dihydrochloride (321 mg, 98%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH:38]C(OC(C)(C)C)=O)[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH2:38])[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(N)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C

Procedure:
A solution of 209 mg of 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino) -piperidin-1-yl]-xanthine in 4 ml methylene chloride is combined with 1 ml of trifluoroacetic acid and stirred for half an hour at ambient temperature. For working up the reaction mixture is diluted with methylene chloride and washed with saturated potassium carbonate solution. The organic phase is dried, evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (1:0 to 4:1) as eluant.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[N:15][CH:14]=[CH:13][CH:12]=2)=O.Cl.C([O:27][NH2:28])C1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C)C>[N:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[N:28]3[O:27][CH2:2][CH2:3][CH2:4][C:5]3=[N:7][C:8]=1[CH:9]=[N:10]2
Reactant: O=C(CCCCl)Nc1cnc2cccnc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Product: c1cnc2c(c1)ncc1nc3n(c12)OCCC3
Reaction time: 72 h
Yield: 5.2 %

Procedure:
A mixture of 4-chloro-N-(4-chloro[1,5]naphthyridin-3-yl)butanamide (3.1 g, 11 mmol) and O-benzylhydroxylamine hydrochloride (2.1 g, 13 mmol) in isopropanol (75 mL) was heated at reflux for 24 hours, then pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol) was added and reflux continued for 48 more hours. The reaction mixture was then concentrated under reduced pressure and dichloromethane (50 mL) and saturated aqueous sodium carbonate (25 mL) were added and the mixture was stirred for 72 hours. The dichloromethane layer was then separated, concentrated under reduced pressure, and the residue purified by chromatography (silica gel eluted with 10% methanol in dichloromethane containing 5 mL of ammonium hydroxide solution per liter) to provide 0.13 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine.