Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:40])[NH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])=[CH:36][CH:37]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.Br.[NH2:9][CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][C:11]2=[O:12])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCOC1=O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCCC1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Triethylamine (20.0 ml, 143.9 mmol) was added to a suspension of α-amino-γ-butyrolactone hydrobromide (7.28 g, 40.0 mmol) in dichloromethane (80 ml), and then 20 minutes were spent in adding dropwise a solution of 4-phenoxybenzenesulfonyl chloride (11.0 g, 40.9 mmol) in dichloromethane (40 ml) to the mixture with ice-cooling. After this mixture was stirred at room temperature for 2 hours, the solvent of the reaction mixture was evaporated under reduced pressure. The residue was acidified with water and hydrochloric acid (1N), and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to give the title compound (8.74 g, yield 73%) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=2.ClC1C=NC2C(=CC=C(C(Cl)=O)C=2)N=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([N:4]([O:3][CH3:2])[CH3:5])=[O:27])=[CH:21][CH:20]=2
Reactant: O=C(Cl)c1ccc2ncc(Cl)nc2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)c1ccc2nc(Cl)cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of O,N-dimethyl-hydroxylamine hydrochloride salt (29 g, 0.30 mol, 1.1 eq) and DIEA (182 mL, 1.08 mol, 4.0 eq) in DCM (300 mL) was added the mixture of 3-chloro-quinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (52 g, 0.27 mol, 1.0 eq) at 0° C. The mixture was stirred at rt overnight, then concentrated. The residue was washed with water (300 mL×2) and extracted with EA (300 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was triturated with EA/PE=1/1 (300 mL) to afford 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (16.5 g, 24.3%).
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[F:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](B(O)O)=[CH:34][C:33]=2[CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C@@H:1]([NH:5][C:6]1[C:7]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:40][C:33]=3[CH:34]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc2cc(F)ccc2o1
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: O
Solvent: C1COCCO1
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (390 mg, crude) in dioxane (6 mL) was added 5-fluorobenzofuran-2-ylboronic acid (353 mg, 1.96 mmol), K3PO4 (416 mg, 1.96 mmol), Pd(PPh3)4 (64 mg, 0.06 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of dichloromethane (100 mL). The resulting mixture washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate as a red solid (130.0 mg, 30% 2 steps).
Reaction SMILES: [O:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)([Cl:11])=[O:10].C(Cl)Cl>CN(C)C=O>[Cl:11][C:9]([O:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: OOc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)OOc1ccccc1

Procedure:
The intermediate phenoxy chloroformates are prepared by reaction of the appropriate phenoxyalcohol with excess phosgene in an inert solvent such as methylene chloride in the presence of a catalytic quantity of dimethyl formamide. The reaction is carried out at 20°-80° C. The solvent and excess phosgene is then removed under vacuo to give the desired intermediate phenoxy chloroformate.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]=[C:10]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11]1.CI>C1COCC1>[CH3:2][C:12]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:10](=[CH2:9])[CH2:11]1
Reactant: CC(C)[N-]C(C)C
Reactant: C=C1CC(C(=O)OCC)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C=C1CC(C)(C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To a stirred solution of LDA (60 mL, 54 mmol, 1.0 M in THF (150 mL) at −78° C., was added ethyl 3-methylenecyclobutanecarboxylate (5.0 g, 35.7 mmol) and the reaction mixture was slowly allowed to warm to 0° C. and stir for 20 min. The reaction mixture was again cooled to −78° C. and MeI (8.92 mL, 143 mmol) was added and the reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and the aqueous layer was extracted with diethyl ether (3×5 mL). The combined organic layer was washed with an aqueous solution of 1.5N HCl, brine, then dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 1% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 258A as a pale yellow liquid (3.5 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83-4.93 (m, 2H), 4.18 (q, J=7.18 Hz, 3.12-3.24 (m, 2H), 2.41-2.55 (m, 2H), 1.45 (s, 3H), 1.23-1.36 (m, 3H).
Reaction SMILES: C([S:4][CH2:5][N:6]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([O:16]C)=[O:15])[N:8]2[C:7]1=[O:20])(=O)C>C(OCC)(=O)C.CCCCCC>[SH:4][CH2:5][N:6]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:20]
Reactant: COC(=O)C1CCCn2c(=O)n(CSC(C)=O)c(=O)n21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)C1CCCn2c(=O)n(CS)c(=O)n21
Yield: 29 %

Procedure:
In a manner analogous to that described in Example 32, from methyl 2-acetylthiomethyl-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate there was obtained in 29% yield 2,3,5,6,7,8-hexahydro-2-mercaptomethyl-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 157.5°-158.5° C. (from ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.[H-].[Na+].[Br:34]Br.Cl>CN(C)C=O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:11]([C:17]([NH:18][CH:19]([CH:21]3[CH2:23][CH2:22]3)[CH3:20])=[O:24])=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=2[Br:34])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: BrBr
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 0.42 h
Yield: 72.4 %

Procedure:
A mixed solution comprising 0.24 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide and 5 ml of dimethylformamide was cooled with ice, 46 mg of 60% sodium hydride was added, and the temperature was returned to room temperature, followed by stirring for 25 minutes. The reaction liquid was cooled with ice again, and a mixed solution comprising 0.15 g of bromine and 1 ml of dimethylformamide was dropwise added over a period of 1 minute, followed by reaction at room temperature for 2 hours and 45 minutes. After completion of the reaction, the reaction liquid was slowly added to 60 ml of diluted hydrochloric acid. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 0/1) to obtain 0.20 g of the desired product (melting point: 244 to 247° C.) in the form of white crystals.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)[C:6]=2[CH:5]=1.[C:29](Cl)(=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([O:26][C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22]3)[C:6]=2[CH:5]=1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1
Agent: Cl
Product: CCCCCCCCCCC(=O)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1

Procedure:
According to the procedure of Example 5, 10.8 g of 2-trifluoromethyl-10-[3-(3-hydroxypyrrolidino)-propyl]-phenothiazine.hydrochloride and 6.2 g of undecanoylchloride were subjected to the reaction, to object the object as the free base. (Yield: 11.2 g)
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:15]([C:22]([OH:24])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:29]1([NH:31][C:22]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.7 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(3-methylbutyl)-1H-1,2,3-triazole-4-carboxylic acid (462 mg, 1.40 mmol) obtained in Example 97b), HOBt (95.4 mg, 0.700 mmol, 0.5 eq.) and cyclopropylamine (0.130 ml, 1.82 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (328 mg, 1.68 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a grayish white powder (481 mg, 1.30 mmol, 93.0%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[CH2:19][CH2:20]Cl.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([N:27]2[C:2]3[N:7]4[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]4[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=3[CH2:19][CH2:20]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc2c([N+](=O)[O-])cnn2c(Cl)c1CCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c([N+](=O)[O-])cnn2c2c1CCN2C1CCCC1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
In 12 ml of anhydrous dimethylformamide were dissolved 1.16 g (3.48 mmol) of ethyl 7-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine-5-carboxylate, and 2.4 ml (d=0.863, 24.32 mmol) of cyclopentylamine were added to the solution, and the resultant mixture was stirred for 4 hours at room temperature. The reaction mixture was then poured into ice water. Insoluble solids were collected by filtration, washed with water and air-dried to obtain 1.15 g (yield: 95.7%) of the intended product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6](CC1C=CC=CC=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15](CC1C=CC=CC=1)[CH2:16][CH2:17][CH2:18][CH2:19][OH:20].[H][H]>[Pd]=O.CC(O)=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: OCCCCN(CCCCCCCCN(CCCCO)Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CC(=O)O
Product: OCCCCNCCCCCCCCNCCCCO

Procedure:
Hydrogenate a mixture containing 3.0 gm of the product of Step D, 30 ml of AcOH and 0.6 gm of palladium oxide at 45 lbs./sq.in. until no further hydrogen is taken up. Filter and remove the solvent (in vacuo) to yield 1.77 gm of the desired product, Rf is 0.37 (eluted from silica gel with 10% conc. NH3 /CH3OH).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH3:15])[C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH2:18])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:18][C:4]=2[CH:3]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Yield: 87.1 %

Procedure:
Suspending 7.8 g (26 mmol) of 4′-bromo-N-methyl-2′-amino-benzanilide obtained in the above step (3) into 50 milliliter of xylene, and adding 1.5 g (7.7 mmol) of p-toluenesulfonic acid 1 hydrate, the resultant solution was refluxed with heating for 7 hours. After completing the reaction, the resultant solution was filtered. Dissolving the resultant solids into methylene chloride, the resultant solution was washed with 10% K2CO3 aqueous solution and with a saturated solution of sodium chloride, and then, after drying with the use of magnesium sulfate, the solvent was removed by distillation. Washing the filtrate with 10% K2CO3 aqueous solution and with saturated solution of sodium chloride, and then, after drying with the use of magnesium sulfate, the solvent was removed by distillation. Combining the above two kinds of residues after removing by distillation, the resultant product was refined with silicagel column chromatography, 6.50 g of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole was obtained as white solids (yield: 89%).
Reaction SMILES: [OH:1][C:2]1(/[CH:29]=[CH:30]/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][O:10][CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH3:26])(=[O:16])=[O:15])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][C:2]1([CH2:29][CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:3][CH2:4][N:5]([C:8](=[O:28])[CH2:9][O:10][CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH3:26])(=[O:15])=[O:16])[CH2:6][CH2:7]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(/C=C/c3cccnc3)CC2)c(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(CCc3cccnc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (E)-N-(2-(2-(4-hydroxy-4-(2-(pyridin-3-yl)vinyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide (0.9 mmol) in methanol (10 ml) was degassed for 15 min with argon, and 10% Pd/C (200 mg) was added. The resulting mixture was stirred for 16 h at 25° C. under a hydrogen atmosphere (conversion monitored by TLC). The reaction mixture was filtered through Celite, the filter cake was washed thoroughly with methanol, and the filtrate was concentrated completely. The residue was purified by column chromatography on silica gel (methylene chloride/methanol).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccn3)nc12

Procedure:
From 2-pyridylacetic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+26.8° (c=0.51, CHCl3), ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Mg]Br.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[S:3][C:4]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1
Reactant: Brc1cnc(Br)s1
Reactant: Br[Mg]c1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: c1csc(-c2cnc(-c3cccs3)s2)c1
Yield: 5.8 %

Procedure:
When a three-neck 50-ml flask fitted with a reflux condenser, a stirrer, and a calcium chloride tube was charged with 6.45 g (40 m.mols) of 2-bromothiophene and 29 ml of dehydrated ether and then 1.06 g (44 m.mols) of a magnesium metal was added thereto, the resultant reaction mixture produced 2-thienyl magnesium bromide with evolution of heat. Under an atmosphere of nitrogen, 4.0 g (16 m.mols) of 2,5-dibromothiazole, 0.179 g (0.33 m.mol) of dichloro[1,3-bis(diphenylphosphino)propane]nickel, and 29 ml of dehydrated ether were added to the 2-thienyl magnesium bromide. The resultant mixture was placed and refluxed for 16 hours in a three-necked 100-ml flask fitted with a reflux condenser, a stirrer, and a calcium chloride tube. The reaction mixture was treated with 1N hydrochloric acid and the water layer separated from the organic layer was extracted with ether. The organic layer was added to the water layer extracted with ether. The resultant liquid was washed with water, cleaned with a saturated aqueous sodium hydrogen carbonate solution, and then washed again with water. The washed liquid layer was dried with anhydrous sodium sulfate, treated with activated carbon, and recrystallized twice with n-hexane, to produce 237 mg (5.8%) of yellow leaflike crystals of 2,5-di(2-thienyl)thiazole having a melting point of 93.0° to 93.8° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A dry 25 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.880 g, 5.15 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.01 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 5-Acetyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.275 g, 3.05 mmol, 77%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].O.[CH:15]([NH2:17])=O>>[CH3:12][C:5]1[C:6]2[C:7]([OH:8])=[N:17][CH:15]=[N:1][C:2]=2[S:3][C:4]=1[CH3:13]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: NC=O
Solvent: O
Product: Cc1sc2ncnc(O)c2c1C
Temperature: 180 °C
Yield: 85 %

Procedure:
The mixture of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (30 g, 0.15 mol) in 150 mL of formamide was heated at 180° C. for 4 h and cooled down. The mixture was poured into 200 mL of water and filtered. The solid was collected and recrystallized from ethanol to afford 5,6-dimethylthieno[2,3-d]pyrimidin-4-ol as yellow solid (23 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O[C@@H]1CCN(Cc2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
4-bromo-2-fluorobenzaldehyde (203.0 mg, 1.0 mmol) was mixed with (3R)-pyrrolidin-3-ol (87.1 mg, 1.0 mmol) in 1,2-dichloroethane (10 mL). The mixture was stirred at RT for 5 min, and then was treated with sodium triacetoxyborohydride (318 mg, 1.5 mmol). The mixture was stirred at RT for 2 h, and quenched by adding 1N NaOH. The organic phase was separated. The aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (252 mg, 91.9%) which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9.