Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20]O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:20])=[O:14])=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
Thionyl chloride (9.5 mL) was added dropwise to a solution of 4-chloro-2-(trifluoromethyl)phenylacetic acid (CAS #601513-31-9, 10.5 g) in methanol (50 mL) under ice-cooling. Then, the reaction solution was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 10.96 g of the title compound. 1H-NMR (CDCl3) δ (ppm): 3.71 (s, 3H), 3.80 (s, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].Cl[C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[C:17]=1[CH3:27].O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][C:17]1[C:18](=[O:26])[N:19]([CH2:24][CH3:25])[C:20]([S:22][CH3:23])=[N:21][C:16]=1[S:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=1
Reactant: CCn1c(SC)nc(Cl)c(C)c1=O
Reactant: CCCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCOc1ccc(CSc2nc(SC)n(CC)c(=O)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Sodium hydride (55% in mineral oil) (0.70 g) was suspended in 20 ml of hexamethyl phosphoric triamide, and then 3.0 g of 4-propyloxybenzyl mercaptan was added thereto. The mixture was stirred for one hour at room temperature and then incorporated with 3.0 g of 6-chloro-5-methyl-2-methylthio-3-ethyl-4(3H)-pyrimidinone. After stirring at room temperature, resulting mixture was heated to 80° C. under stirring for 3 hours. The resulting solution was poured into water and then extracted with benzene. The extract was washed with an aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate and freed of solvent by distillation udner reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with chloroform) to give 2.6 g of the intended product.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:25][OH:26].OS(O)(=O)=O>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[C:11]([CH2:25][OH:26])[CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CO
Reactant: CCN(CC)Cc1ccncc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CCN(CC)Cc1ccnc(CO)c1
Yield: 29 %

Procedure:
Treatment of 4-(N,N-diethylaminomethyl)pyridine (2.0 g, 12.20 mmol) with ammonium persulfate (5.56 g, 24.4 g, 2.0 equiv.), methanol (22 ml), water (11 ml) and concentrated H2SO4 (2.76 g, 28.18 mmol, 2.31 equiv.) as described for Cpd #214 gave 0.697 g (29%) of 4-(N,N-diethylaminomethyl)-2-hydroxymethylpyridine.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:10]([OH:14])[C:11]([OH:13])=[O:12].O>C(O)(=O)C>[Cl:4][C:15]1[CH:16]=[C:17]([OH:18])[C:7]([OH:6])=[CH:8][C:9]=1[CH:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(O)c1cc(O)c(O)cc1Cl
Reaction time: 2 h

Procedure:
Sulphuryl chloride (0.8 ml) was added to a solution of 3,4-dihydroxymandelic acid (1.84 g, 10 mmol) in warm acetic acid (20 ml). The mixture was stirred for two hours then poured into water and extracted with ethyl acetate (6×40 ml). The extracts were washed with saturated brine (50 ml), dried and evaporated to a crystalline mass (2.36 g) which was recrystallised from ethyl acetate-cyclohexane, 0.97 g, 44%, mp 177°, δ[(CD3)2SO] 5.15(1H, s, CH), 6.71 and 6.85(2H, 2×s, Ar), 8.4-9.8(3H, m, 2×OH, CO2H).
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][OH:5].[OH-].[K+].[CH2:40]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][O:5][CH3:40]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide (81 mg, 0.152 mmol) was dissolved in THF (1.5 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (86 mg, 1.52 mmol), 18-crown-6 (40 mg, 0.152 mmol), and iodomethane (10 μl, 0.152 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-60% EtOAc) to afford 30 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.66 (s, 1H), 8.14 (d, J=9.4 Hz, 1H), 7.67 (dd, J=9.8, 2.3 Hz, 1H), 7.17 (td, J=9.2, 2.1 Hz, 1H), 5.75 (s, 2H), 5.21 (d, J=4.2 Hz, 1H), 4.22-4.34 (m, 1H), 4.17 (s, 3H), 3.97-4.12 (m, 1H), 3.61 (app t, J=8.2 Hz, 3H), 3.52 (dd, J=9.8, 6.4 Hz, 1H), 3.28 (s, 3H), 1.14 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.9 Hz, 2H), −0.07 (s, 9H).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[CH3:13][Mg]Br.Cl.C([O:19][CH2:20][CH3:21])C>C1COCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([Cl:11])=[C:4]([C:20]([OH:19])([CH3:21])[CH3:13])[CH:9]=1
Reactant: COC(=O)c1cc(Br)ccc1Cl
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Br)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloro-benzoic acid methyl ester (5 g) in diethyl ether (200 mL) cooled to −70° C. is added 3 M methylmagnesium bromide in THF (20 mL) dropwisely. The solution is stirred at −78° C. for 2 h and allowed to warm to room temperature for 16 hours. The solution is cooled to 0° C. and 1 N HCl (100 mL) is added dropwisely. The mixture is extracted with EtOAc (2×150 mL). The combined organic layer is washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel eluting with 20% EtOAc in heptane to afford 2-(5 bromo-2-chloro-phenyl)-propan-2-ol (4.56 g). MS: 250 (M+H); 1H NMR (300 MHz, CDCl3) □7.8 (m, 1H); 7.5 (m, 1H); 7.2 (m, 1H); 4.4 (s, 1H); 1.6 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[C:6]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[N:5]=[C:4]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.C([CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:31]#[N:32])#N.[H-].[Na+].CN(C=[O:43])C>>[C:8]([C:7]1[C:2]([C:27]([C:28]2[CH:29]=[C:30]([CH:33]=[C:34]([CH3:36])[CH:35]=2)[C:31]#[N:32])=[O:43])=[N:3][C:4]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:5][C:6]=1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])=[CH2:9]
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: CN(C)C=O
Reactant: C=C(C)c1c(Cl)nc(OCC[Si](C)(C)C)nc1OCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Product: C=C(C)c1c(OCC[Si](C)(C)C)nc(OCC[Si](C)(C)C)nc1C(=O)c1cc(C)cc(C#N)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
4-Chloro-5-isopropenyl-2,6-bis-(2-trimethylsilanyl-ethoxy)-pyrimidine (2.12 g, 5.49 mmol, prepared according to Pews et al. J. Fluorine. Chem. 1989, 42, 179-186) and 3-cyanomethyl-5-methyl-benzonitrile (0.8166 g, 5.23 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. 60% Sodium hydride (0.157 g, 3.92 mmol, 2.0 eq.) was added portionwise and the reaction was stirred at 0° C. for 6 h, then rt for 1 h. Oxygen was bubbled into reaction mixture overnight. The reaction was quenched with 1N HCl and saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 5% ethyl acetate/hexane) to give a yellow solid (1.568 g, 58%). 1H NMR (300 MHz, CDCl3): δ 7.87 (s, 1H), 7.84 (s, 1H), 7.60 (s, 1H), 4.96 (s, 1H), 4.96 (s, 1H), 4.66 (s, 1H), 4.6-4.4 (m, 2H), 4.4-4.3 (m, 1H) 2.39 (s, 3H), 1.91 (s, 1H), 1.20-1.00 (m, 4H), 0.03 (br s, 9H), 0.027 (br s, 9H). Mass spectrum: 495.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) in tetrahydrofuran (45 mL) was added 2-methylpropyl chlorocarbonate (2.84 mL) at 10° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 7 days. Ethyl acetate (50 mL) and aqueous sodium hydrogen carbonate (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (50 mL) was added 2M aqueous sodium hydroxide solution (24.8 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was neutralized with 6M hydrochloric acid (8.5 mL) under ice-cooling, and water (10 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (3.03 g) as a pale-yellow solid. The optical purity was 73.8% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.Cl[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1cccnc1CCl
Agent: Cl
Product: Cc1cccnc1Cn1cc(C#Cc2cccc(C#N)c2)nc1C

Procedure:
The title compound, MS: m/e=313.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=1.[Li+].[OH-].Cl>O1CCOCC1.O.CCOC(C)=O>[CH3:15][O:14][C:12]([C:8]1[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:16])=[O:2])=[CH:11][NH:10][CH:9]=1)=[O:13]
Reactant: COC(=O)CCCc1c[nH]cc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]cc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methyl 4-(4-methoxy-4-oxobutyl)-1H-pyrrole-3-carboxylate (50 mg, 0.220 mmol) was suspended in anhydrous dioxane (2 mL) and H2O (0.5 mL) and LiOH (5.3 mg, 0.220 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Reaction solution was acidified with 1N HCl and AcOEt (50 mL) and H2O (20 mL) were added. Acqueous layer was extracted with AcOEt and the combined organic layers anidrified on Na2SO4, filtered and concentrated to give 46 mg (quantitative yield) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cccc2C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (0.58 g, 6.1 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.0 mL, 7.3 mmol) in DMF (15 mL) was added K2CO3 (3.4 g, 24.5 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.45 g (˜100%) of crude 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde. This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Temperature: 160 °C

Procedure:
A mixture of 2-trifluoromethylbenzyl chloride (2.0 g, 10.0 mmol) and triethyl phosphite (2.13 g, 13 mmol) was heated at 160° C. under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 87°-90° C. (0.05 mm Hg) and isolated as a colorless oil; yield, 1.68 g, 56.8%; D.C.I.M.S.[MH+,297].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:35][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1ccc2ccccc2c1
Yield: 79.8 %

Procedure:
The (2S)-(2-Amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.400 g, 0.972 mmol) was made according to the procedure for Example 282 and this was subjected to reductive amination with naphthalene-2-carbaldehyde (0.227 g, 1.45 mmol) and sodium triacetoxyborohydride (0.515 g, 2.43 mmol) as per general procedure E to yield the 3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (0.428 g, 80%).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:11]([N:10]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
N-benzoyl-N'-t-butyl hydrazine (0.8 g) was stirred in pyridine (2 ml) at room temperature. Benzenesulfonyl chloride (0.8 g) was added slowly dropwise, stirred about 1 hour, diluted with diethyl ether (10 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate. The mixture was filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:12](=O)[C:10]2=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:1]1([CH2:7][CH2:8][N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)/[C:12](=[N:31]/[NH:30][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:10]2=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)N(CCC1CCCCC1)C(=O)C2=O
Product: COc1ccc2c(c1)N(CCC1CCCCC1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-(2-cyclohexylethyl)-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.96-1.04 (m, 2H), 1.15-1.38 (m, 4H), 1.59 (dd, 2H), 1.65-1.75 (m, 3H), 1.81 (d, 2H), 3.74 (t, 2H), 3.87 (s, 3H), 6.43 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.96 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].[BrH:19]>CC(C)=O.O>[Br:19][CH:14]([CH2:15][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])[C:13]([O:17][CH3:18])=[O:16]
Reactant: Br
Reactant: C=CC(=O)OC
Reactant: Nc1ccccc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccccc1Cl
Temperature: 25 °C

Procedure:
6.35 g. of 2-chloroaniline (0.05 mole) in acetone (100 ml.) and concentrated hydrobromic acid (16 ml.) was stirred at -5° C. and treated with a solution of 4.2 g. of sodium nitrite (0.06 mole) in water (10 ml.). Methyl acrylate (0.5 mole) (43 g.) and cuprous bromide (100 mg.) were then added at 0° C. The reaction temperature was kept below 15° C. until nitrogen evolution ceased and then stirred at 25° C. for thirty minutes. The reaction mixture was poured into water and extracted with benzene which was dried over sodium sulfate and evaporated to give methyl 2-bromo-3-(2-chlorophenyl)propionate.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2cccc(F)c2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 3-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(3-fluorophenoxy)ethyl)benzoate (400 mg, 29%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][N:6]4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: ClCc1cn2ccccc2n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: Clc1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Yield: 51 %

Procedure:
Following the general procedure of Example 38, Step 2, and making non-critical variations, 2-(chloromethyl)imidazo[1,2-a]pyridine (Example 2, Step 1; 0.25 g) and 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.45 g) give 0.25 g of the title compound after chromatography on silica gel using methanol/dichloromethane (4/96), pooling of the appropriate fractions, and crystallization from dichloromethane/ethyl ether; mp 138-139° C.; IR (mineral oil) 1339, 1498, 765, 814, 1223 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.20, 3.79, 6.79, 7.17, 7.56, 7.57, 8.08.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:36]=[CH:37][C:23]([NH:22][C:2]3[N:12]=[C:11]4[C:5](=[CH:4][N:3]=3)[N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]4[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:24]([O:38][CH3:39])[CH:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COc1cc(C(=O)NC2CCCCC2)ccc1N
Reactant: CN1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NC2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCN(C)CC1)CCC(=O)N2C
Temperature: 100 °C

Procedure:
10-chloro-6-methyl-2-(1-methyl-4-piperidyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 118; 39 mg, 0.13 mmol), 4-amino-N-cyclohexyl-3-methoxy-benzamide (Intermediate 119; 31 mg, 0.13 mmol) and p-toluenesulphonic acid monohydrate (60 mg, 0.31 mmol) were combined in 4-Methyl-2-pentanol (2 mL) and heated at 100° C. for 16 hrs. The reaction mixture was cooled to room temperature and dissolved in Methanol and added to a 5 g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant material was dissolved in DCM and purified on silica eluting with a shallow (25 column volumes) gradient of 0-10% MeOH/DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid. (15 mg, 23%).