Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:61])[CH2:59][CH3:60])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:61][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH2:59][CH3:60])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.209 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), 1-(4-chlorophenyl)propan-1-amine (0.085 g) and DIPEA (0.262 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.138 g, 66.8
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Yield: 88.5 %

Procedure:
1.56 g (4.5 mmol) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate are dissolved in 300 ml of a 1:1 ethanol:ethyl acetate mixture. The solution was mixed with H2 was passed through a cartridge containing Pd/C in a H-cube apparatus, then was evaporated to provide 1.26 g (88% yield) of tert-butyl 4-(2,3-diaminopyridin-4-yloxy)phenylcarbamate as a white foamy solid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl.C([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=[O:36])C1C=CC=CC=1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]([O:37][CH2:2][C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: O=C(O)[C@@H]1CCCCN1Cc1ccccc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Product: COc1ccccc1C1(N2CCCC[C@H]2C(=O)OCc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Yield: 202.9 %

Procedure:
With 2.19 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 2.00 g of benzyl(2S)piperidine-2-carboxylic acid hydrochloride, which is the compound described in Example X of the brochure Publication No. WO98/42342, as starting materials, 3.54 g of the title compound (amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][CH2:37][CH2:38][OH:39]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:36]([CH2:37][CH2:38][OH:39])[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:28])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: OCCNCc1ccccn1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccn2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].Cl>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: Oc1ccccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2ccccc2Cl)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 20.5 g. (0.16 mole) of o-chlorophenol and 3 drops concentrated hydrochloric acid was heated on a steam both overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.9 g. (25%) of an oil as residue. The oil was converted to the hydrochloride and recrystallized from ethyl acetate-acetonitrile to yield white powder, m.p. 108°-110° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Yield: 68.6 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 85 mg crude, 0.29 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (52 mg, 0.29 mmol) and sodium triacetoxy borohydride (190 mg, 0.88 mmol) were reacted as described according to Example 69 to give 90 mg (69%) of the free base of the product.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:35][CH3:36])=[CH:22][C:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32]([CH3:34])=[O:33])=[CH:24][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].CCOC(C)=O>C(O)(=O)C>[Br:1][C:24]1[C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]=2[C:21]([O:35][CH3:36])=[CH:22][C:23]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([CH3:34])=[O:33]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3S(C)=O)cc(OC)c21
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 501.7 %

Procedure:
53 μl (0.122 mmol) bromine are added to a solution of 496 mg (1.03 mmol) 2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 22 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. Then 25 ml EtOAc are added and this solution is washed with 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:4) to afford 340 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1ccc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound: Rf =0.35 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.68 mmol) is dissolved in DMF (7 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction mixture is heated to 100° C. in the microwave for 30 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane ethyl acetate) as yellow oil in a yield of 62%; HPLC (method C): 1.93 min; LC-MS (method A): 1.80 min, 291.15 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:22](=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:22])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.12 g (30 mmol) of tyrosine-tert-butyl ester is dissolved in 28 ml of anhydrous N,N-dimethylformamide and mixed at 5° C. under argon with 1.21 g (31 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 4.4 g (31 mmol) of methyl iodide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another hour. For working-up, the batch is taken up in ethyl acetate and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]([CH:11]=O)[CH2:9][CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=O.C(O)(=O)C.[CH3:31][NH2:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:20]([C:5]12[C:3](=[O:2])[N:32]([CH3:31])[CH2:11][CH:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Temperature: 70 °C

Procedure:
To a solution of the compound of Example 200, Step C (0.210 g, 0.60 mmol) in dichloroethane (5 mL) in a resealable tube was added acetic acid (0.188 mL, 3.28 mmol), methyl amine (2.0 M in MeOH, 1.64 mL, 3.28 mmol) and NaB(OAc)3H (0.951 g, 4.48 mmol), the tube was sealed and the reaction mixture was heated to 70° C. for 30 h. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate solution. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 5-20% EtOAc/CH2Cl2 as the eluant afforded the less polar isomer of Example 200, Step D (0.034 g) as well as the more polar isomer (0.046 g). Example 200, Step D less polar isomer. +APcl MS (M+1)+ 355; 1H NMR (400 MHz, CDCl3) δ: 7.03-7.37 (arom, series of m, 10 H), 3.54 (m, 2H), 3.24 (m, 1H), 2.70 (s, 3H). More polar isomer: +APcl MS (M+1)+ 355; 1H NMR (400 MHz, CDCl3) δ: 7.15-7.33 (arom, series of m, 10 H), 3.59 (d, 1H), 3.43 (d, 1H), 2.74 (s, 3H).
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)#[N:6].Cl>C(O)C>[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)(=[O:1])[NH2:6]
Reactant: OO
Reactant: CCOc1ccccc1-c1nc2c(C#N)ccnc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)ccnc2c(=O)[nH]1
Yield: 72 %

Procedure:
30% Aqueous hydrogen peroxide solution (0.5 ml) was added to a stirred aqueous sodium hydroxide solution (1M, 40 ml), followed by 8-cyano-2-(2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 14; 0.2 g, 0.00068 mol) and ethanol (2 ml). The mixture was heated under reflux for 2 hours, allowed to cool, acidified with 1N hydrochloric acid, and then extracted with a mixture of dichloromethane and methanol (10:1, 5×50 ml). The combined organic fractions were evaporated under vacuum and the resulting residue triturated with ethanol to give the title compound as a colourless solid (0.152 g, 72%), m.p. 295-297° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([C:12]([F:15])([CH3:14])[CH3:13])[CH2:10]I)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([O:5][C:6]([NH:8][CH:9]([C:12]([F:15])([CH3:13])[CH3:14])[CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC(CI)C(C)(C)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)NC(C)C(C)(C)F
Reaction time: 20 h
Yield: 89.5 %

Procedure:
A Parr bottle was charged with palladium (II) hydroxide (800 mg), a solution of N-butoxycarbonyl-1-iodo-2-amino-3-fluoro-3-methyl-n-butane (3.26 g, 9.8 mmol) in ethanol (80 mL) and triethylamine (0.99 g, 9.8 mmol). The reaction mixture was placed under hydrogen gas (50 psig) and shaken for 20 hours. The mixture was filtered through Celite® and evaporated. The residue was dissolved in diethyl ether (100 mL) and washed with 1N aqueous HCl (2×50 mL), water (2×50 mL), and then dried (MgSO4). Filtration and evaporation gave a residue that was chromatographed (silica gel, diethyl ether/hexane (3/1)) to afford 1.80 g of N-butoxycarbonyl-2-amino-3-fluoro-3-methyl-n-butane: 1H NMR (CDCl3) δ4.65 (br, 1H), 3.70 (br m, 1H), 1.45 (s, 9H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H) ppm.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>C1(C)C=CC=CC=1.CO>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 0.177 g. (7.7 g.-atom) of sodium dissolved in 25 ml. of dry methanol was added a solution of 2.4 g. (7.3 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran in 75 ml. of toluene and 10 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation. A solution of 1.15 g. (7.7 mmol.) of 3-diethylaminopropyl chloride in 25 ml. of toluene was then added and the resulting mixture was refluxed for 6 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.Cl.[C:15]1([N:21]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(O)(=O)C(O)=O>CC(=O)CC.CC(C)=O>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:31]([N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:32][CH2:33]2)[CH2:5][CH2:6]1
Reactant: O=C(c1ccc(F)cc1)N(c1ccccc1)C1CCNCC1
Reactant: BrCCC1CCOc2ccccc21
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: O=C(c1ccc(F)cc1)N(c1ccccc1)C1CCN(CCC2CCOc3ccccc32)CC1
Yield: 89.2 %

Procedure:
The procedure is as in Example 4, but starting with 4-(2-bromoethyl)-3,4-dihydro-2H-benzopyran (1.6 g), N-phenyl-N(4-piperidyl)-4-fluorobenzamide hydrochloride (2.21 g), dry potassium carbonate (1.8 g) and potassium iodide (0.8 g) in 2-butanone (50 cc). The oil obtained is taken up in the minimum amount of acetone and oxalic acid (0.6 g), dissolved in acetone, is added. The white precipitate formed is filtered off on sintered glass and then recrystallized in ethanol (50 cc). N-{1-[2-(3,4-Dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidyl}-N-phenyl-4-fluorobenzamide acid oxalate (2.7 g) is thereby obtained in the form of a white solid, m.p. 161° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>C1COCC1>[NH2:3][C:4]1[CH:5]=[C:6]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: Nc1cc(NC(=O)CCCCl)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(N2CCCC2=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Add sodium hydride (60%, 65 mg, 1.64 mmol) portionwise to the solution of N-(3-amino-5-(trifluoromethyl)phenyl)-4-chlorobutanamide (230 mg, 0.82 mmol) in THF (5 mL), stir the resulting mixture for 2 hrs at ambient temperature. Quench the reaction with water, extract the mixture with ethyl acetate, wash the organic layer with water and brine sequentially, and dry over anhydrous sodium sulfate, concentrate to give brownish oil. Purify by flash chromatography (silica gel, PE:EtOAc=1:1) to yield white solid as the title compound (180 mg, 90%). MS: (M+1): 245.1.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2C(=O)C(C)(C)NC2=O)=CC=1.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[C:68]([CH3:70])([CH3:69])[C:67](=[O:71])[N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[C:68]([CH3:69])([CH3:70])[C:67](=[O:71])[NH:66][C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2C(=O)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C(C)(C)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4(C)C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (149 mg) described in Preparation Example 53 and by the reaction and treatment in the same manner as in Example 508, the title compound (120 mg) was obtained via 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[ClH:10].[N:11]1([CH2:17][C:18]([OH:20])=O)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]1[CH:35]=[CH:36][C:37]2[N:43]3[CH:44]=[N:45][C:46]([C:47](=[N:49]O)[NH2:48])=[C:42]3[CH2:41][N:40]([CH3:51])[C:39](=[O:52])[C:38]=2[CH:53]=1>CN(C=O)C>[ClH:10].[F:33][C:34]1[CH:35]=[CH:36][C:37]2[N:43]3[CH:44]=[N:45][C:46]([C:47]4[N:48]=[C:18]([CH2:17][N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)[O:20][N:49]=4)=[C:42]3[CH2:41][N:40]([CH3:51])[C:39](=[O:52])[C:38]=2[CH:53]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)cc2C1=O
Reactant: O=C(O)CN1CCOCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3noc(CN4CCOCC4)n3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
0.38 ml (2.2 mmol) of N-ethyldiisopropylamine was added to a suspension of 0.4 g (2.2 mmol) of morpholin-4-yl-acetic acid hydrochloride in 4 ml of DMF. 390 mg (2.4 mmol) of 1,1'- carbonyldiimidazole were added portionwise at room temperature, whereupon the solution was stirred at 50° for 30 min. and then treated at room temperature with 0.58 g (2.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime. The reaction mixture was heated to 90° for 20 hrs. The solvent was removed in a vacuum, the residue was taken up in 15 ml of water and the solution was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel (methylene chloride/methanol 19:1). The solvent was removed in a vacuum, the residue was dissolved in 5 ml of acetonitrile and the solution was made acid by the addition of ethereal HCl solution. The white crystals were filtered off under suction and recrystallized from acetonitrile. There was obtained 0.5 g (54%) of 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (3:5) of m.p. 198°-205° (dec.).