Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[C:17]3[C:22]([CH:23]=[C:24]4[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([C:16]2[C:17]3[C:22]([C:23]([Br:32])=[C:24]4[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In a stream of nitrogen, 11.2 g (30 mmol) of 9-[N,N-bis(4-methylphenyl)amino]anthracene was dissolved in 100 ml of dioxane, and the whole was stirred at room temperature. Then, 1.68 g (30 mmol) of potassium hydroxide dissolved in 3 ml of water was added to the mixture dropwise. 5.75 g of bromine was added thereto, and the whole was stirred for 30 minutes. A 5% aqueous solution of sodium thiosulfate was added to the mixture, and the whole was stirred for 1 hour. The product was filtrated and washed with methanol. The product was recrystallized by using toluene, to thereby obtain 11.3 g of 9-[N,N-bis(4-methylphenyl)amino]-10-bromoanthracene.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: BrBr
Reactant: CCCCOC(=O)C(=O)CCCC
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C(=O)C(Br)CCC
Yield: 121.2 %

Procedure:
The same operation as in Example (106a) was performed using butyl 2-oxohexanoate (Lapkin, I. I.; Dvinskikh, V. V.; J. Gen. Chem. USSR (Engl. Transl.); 48; 1978; 2278-2280; Zh. Obshch. Khim.; 48; 1978; 2509-2511, 3.41 g, 18.3 mmol), bromine (2.55 g, 16 mmol) and chloroform (30 mL), to obtain 5.14 g of the title compound as a colorless liquid (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 110 °C
Yield: 4.6 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), 4-ethoxyphenylboronic acid (63.2 mg, 0.38 mmol), and 2N aqueous potassium carbonate solution (1.10 mL, 2.18 mmol) in toluene (1.6 mL) and EtOH (2.4 mL) was degassed with N2 and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29.4 mg, 0.036 mmol) under N2. The reaction mixture was sealed in a pressure tube and heated to 110° C. for 1 hour. The cooled reaction mixture was acidified to pH 5 and concentrated in vacuo. The resulting solid was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 80.0% H2O/20.0% MeCN linear to 40.0% H2O/60.0% MeCN in 10.5 min, 40.0% H2O/60.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (5.3 mg, 5% yield). MS (ES+) 317.1 (M+H)+. Retention time=2.91 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:21][CH3:22])[CH:14]=[CH:13]1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[N:12]([CH:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][OH:2])[CH:13]=[CH:14]2
Reactant: COC(=O)CC(c1cccnc1)n1ccc2cccc(OC)c21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2ccn(C(CCO)c3cccnc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of 3-(7-methoxy-indol-1-yl)-3-pyridin-3-yl-propionic acid methyl ester (0.290 g) in THF (10 ml) was added a solution of lithium aluminum hydride (1 M in THF, 1 ml) at 0° C. The reaction mixture was stirred for 2 hours at room temperature. To the solution was added sodium sulfate decahydrate (1 g) and stirring was continued until no more bubbling was observed. The suspension was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel eluting with ethyl acetate to give 3-(7-methoxy-indol-1-yl)-3-pyridin-3-yl-propan-1-ol (0.178 g) as an oil, (M+H=283).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC=O)C[C@@H]1C
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC=O)C[C@@H]1C
Reaction time: 2 h

Procedure:
To a solution of [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 43) (82 g, 0.263 mol) in DME (2 L) are added (4-formylphenyl)boronic acid (51.4 g, 0.34 mol) at room temperature. A 2N solution of Na2CO3 (527 mL, 1.05 mol) and tetrakis(triphenylphosphine)palladium(0) (8.2 g, 10% w/w) are added and the mixture is heated to reflux under a nitrogen atmosphere. After 2 hours, the reaction is complete and the mixture is concentrated under reduced pressure. The residue is taken up in water (1 L) and the darkened mixture is diluted with EtOAC (1 L) and transferred to a separatory funnel. A dark precipitate has formed and is isolated by filtration after separation of the organic phase. The organic layer is dried over Na2SO4 and delivers the title compound (37.5 g) as a yellow solid after concentration under reduced pressure and precipitation of the organic residue in a DCM/hexane mixture. The dark solid is taken up in a DCM/MeOH mixture and purified by flash chromatography on silica gel eluting with a 80/2 ratio of DCM/MeOH to afford the title compound (45 g) as a yellow brown solid. Mp: 85.6° C.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Referring to Scheme 4, to a solution of 1.74 g (10 mmol) of tert-butyl hydrogen succinate (Buchi, G.; Roberts, C. J. Org Chem., 33:460, 1968) and 1.15 g (10 mmol) of N-hydroxy-succinimide in anhydrous tetrahydrofuran (20 ml) was added 2.06 g (10 mmol) of 1,3-dicyclohexylcarbodiimide. After stirring at room temperature overnight, the reaction was filtered to remove the dicyclohexylurea by-product. The filtrate was concentrated in vacuo to give a residue. Chromatography on silica gel using ethyl acetate-hexane (1:1), provided 2.3 g (84% yield) of tert-butyl succinimidyl succinate (4a) as a white solid. TLC: Rf 0.50 (ethyl acetate-hexane 1:1); NMR(d6 -DMSO) δ 1.39(s,9H), 2.56(m,2H), 2.80(bs,4H), 2.86 (m,2H).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[O:20][CH:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])=[C:21]([F:22])[C:17]3[N:18]=[CH:19][O:20][C:16]=3[CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4ncoc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3ocnc3c(F)c2Nc2ccc(Br)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (120 mg, 0.23 mmol) in THF (5 mL) was added potassium trimethylsilanolate (32 mg, 0.23 mmol). The mixture was stirred at room temperature for 1 h and treated with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the product as a white solid (100 mg, 87.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.42 (d, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCCCCCCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and dodecyl bromide (0.719 mL) as starting materials, 5-benzyloxy-N-[(1-dodecylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.29 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.54 g) was obtained. MS (ESI) m/z: 559[MH]+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[S:26][C:27]([F:34])([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[Br:1][C:25]1[N:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[C:22]([S:26][C:27]([F:34])([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(F)(F)Sc1nccn1-c1ccc(C#N)c2ccccc12
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Sc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-bromosuccinimide (1 eq) was added in three portions to a solution of ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate (1 eq) in dichloromethane at 0° C. and then stirred at room temperature for 18 h. The mixture was washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate/hexanes) provided ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:18][CH2:19][CH:20]([OH:35])[CH:21]([NH:31][C:32](=[O:34])[CH3:33])[CH2:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:18][CH2:19][CH:20]([OH:35])[CH:21]([NH:31][C:32](=[O:34])[CH3:33])[CH2:22][C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC(=O)CC1
Temperature: 100 °C
Yield: 100.7 %

Procedure:
Compound 18 (0.4 g, 0.78 mmol), p-Toluenesulfonic acid monohydrate (TsOH) (0.16 g, 0.84 mmol), and poly(Ethylene glycol) (8.9 g, 143.4 mmol) were added to 25 mL benzene. The reaction was heated to 100° C. for 30 min. The benzene was removed under reduced pressure and fresh benzene was added. The resulting mixture was treated with saturated NaHCO3 and extracted CH2Cl2. The organic layer was washed with brine and dried with MgSO4, filtered and concentrated under reduced pressure providing 0.4 g of Compound 19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14](Cl)[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)C>[OH:16][CH2:15][CH2:14][N:11]1[CH2:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: OCCN1CC=C(c2ccc(F)cc2)CC1

Procedure:
1.77 g of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 0.8 g. of ethylene chlorohydrin, 1.2 g. of sodium carbonate and a few crystals of sodium iodide are heated under reflux conditions in 10 ml. of ethanol for 24 hours and filtered hot and the filtrate is evaporated to dryness. The residual oil is purified by column chromatography on silica gel with acetic acid ethyl ester-ethanol (1:1) as eluting agent. The 1-(2-hydroxyethyl)-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine obtained from the eluate melts at 96°-98°C. after recrystallization from cyclohexane.
Reaction SMILES: FC1C=C(OC2C=CC(OC)=CC=2)C=C(F)C=1C(OCC)C(O)=O.Cl.Cl.[CH2:27]([O:34][C:35](=[O:47])[NH:36]C(C1C=CC(CN)=CC=1)=N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[CH2:27]([O:34][C:35](=[O:47])[NH2:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(C(=O)O)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
(RS)-[2,6-Difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid (398 mg) was dissolved in DMF (15 ml). [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (367 mg) and 1-hydroxybenzotriazole (254 mg) were added and the mixture was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (254 mg) and triethylamine (1.38 ml) were added and it was stirred 1 h at 0° C. and 5.5 h at rt. The solvent was evaporated and the residue was taken up in H2O (40 ml) and CH2Cl2 (30 ml). The organic layer was separated, washed with brine and dried (MgSO4). The aqueous layers were extracted with two more portions CH2Cl2. After evaporation of the solvent CC(CH2Cl2 to CH2Cl2/MeOH 98:2) afforded 228 mg (32%) of (RS)-[4-(12-[2,6-difluoro-4-(4-methoxy-phenoxy)-phenyl]-2-ethoxy-acetylamino)-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester. White foam. MS 602.0 ([M−H]−).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)(=O)=O.[C:21]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22]>CN(C)C=O>[C:21]([CH:23]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C#N)C(=O)OC(C)(C)C)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-ml eggplant-shaped flask equipped with a magnetic stirrer and a reflux condenser were added 6.08 g (44 mmol) of potassium carbonate, 4.36 g (20 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine, 3.11 g (22 mmol) of tert-butyl cyanoacetate and 10 ml of N,N-dimethylformamide. The system inside was purged with nitrogen and stirred for 2 hours at 60° C. and for 4 hours at 70° C. The reaction slurry was cooled to room temperature and poured into 30 ml of a 5% aqueous hydrochloric acid solution. Thereto was added 50 ml of water, and concentrated hydrochloric acid was dropped until the system became acidic, followed by sufficient stirring. Then, filtration and washing with 30 ml of water were conducted. The crystals obtained were dried to obtain tert-butyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate as white crystal of 5.4 g. HPLC purity: 99.3% Yield: 97%
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:27])[CH:14]3[NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:28]([O:30]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:29])=[CH:8][N:9]=1)(=[O:3])[CH3:2]>C(O)=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:27])[CH:14]3[NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:28]([OH:30])=[O:29])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Solvent: O=CO
Product: CC(=O)Nc1ncc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A solution of 3-(2-acetamidothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.85 g) in formic acid (20 cc) is stirred for 30 minutes at 50° C. and then concentrated to dryness under reduced pressure (10 mm Hg; 1.3 kPa) at 40° C. The residue is taken up in ethanol (50 cc), the mixture is stirred for 5 minutes at 50° C. and the solvent is then evaporated off to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up in ethanol (100 cc); the mixture is stirred for 10 minutes at 50° C. and the solid is then filtered off and washed with ethanol (3×15 cc) and ethyl ether (3×10 cc). After drying, 3-(2-acetamidothiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo [4.2.0]oct-2-ene (0.53 g) is obtained in the form of a light yellow powder.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH:15]=[O:16])[CH2:12][CH:13]=[CH2:14])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][OH:16])[CH2:12][CH:13]=[CH2:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=CCC(C=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCC(CO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Sodium borohydride (2.2 g) was added in four portions, over 10 minutes, to an ice-cooled solution of 4-(3,4-dichlorophenyl)-4-formylbut-1-ene (13 g) (see Preparation 21) in ethanol (100 ml). The mixture was stirred for a further 30 minutes before removing the solvent under reduced pressure to give a residue. This was suspended in water (50 ml), cooled to 0° C. and the mixture acidified (pH<6) with 2N aqueous hydrochloric acid solution. The mixture was extracted three times with dichloromethane, the organic phases combined and the solvent removed under reduced pressure. Dichloromethane (200 ml) was then added, the mixture stirred and filtered and the solvent removed from the filtrate under reduced pressure to give an oil. This was chromatographed on silica gel eluting with dichloromethane to give 4-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (7 g) as a orange oil.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccnc(-c2nc(C)c(C)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cc(C)ccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,4′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (157 mg), and cesium carbonate (229 mg), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (42 mg, yield 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[Cl:23][C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: Clc1cccnc1N1CCNCC1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Product: CC(C)S(=O)(=O)N1CC(C(=O)N2CCN(c3ncccc3Cl)CC2)N(c2ccccc2Cl)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 85, step 2) was coupled with 1-(3-chloropyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 526.3 ([M+H]+)