Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]([N:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)[C:8]1[CH2:12][N:11]([C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][C:9]=1[C:19]([O:21]CC)=O)=[O:6].C[O-].[Na+]>CO>[OH:21][C:19]1[C:9]2[CH2:10][N:11]([C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:12][C:8]=2[N:7]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)[C:5](=[O:6])[C:4]=1[C:3]([O:2][CH3:1])=[O:35]
Reactant: C=CCCC(=O)N1CC(C(=O)OCC)=C(N(Cc2ccc(C(F)(F)F)cc2)C(=O)CC(=O)OC)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCCC(=O)N1Cc2c(O)c(C(=O)OC)c(=O)n(Cc3ccc(C(F)(F)F)cc3)c2C1

Procedure:
To the product of Step B, 4-b, (6.30 g, 12.7 mmol) in MeOH (50 mL) was added NaOMe (4.35 mL, 19.0 mmol, 25 wt % in MeOH) at rt. After about 15 min the reaction was concentrated and the residue was diluted with EtOAc and washed with aq HCl (2 M) and brine. The material was crystallized from EtOAc and hexane to afford the title compound, 4-1. HPLC/MS: 451.0 (M+1); Rt=3.33 min.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C1COCC1>[C:13]1([S:19]([CH2:22][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCC1CCCCC1
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(CCCC1CCCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
A solution of 2.5M nBuLi in hexanes (1.9 mL, 4.7 mmol) was added to a solution of diisopropylamine (660 μL, 4.7 mmol) in THF (9.0 mL) at ambient temperature. After 10 min, the mixture was cooled to −78° C. and methyl phenyl sulfone (700 mg, 4.5 mmol) was added to the reaction vessel. The cold bath was removed and after stirring for 30 min, 1-bromo-2-cyclohexylethane (1.3 g, 6.7 mmol) was added to the reaction mixture. The mixture was allowed to warm to ambient temperature and stir for 18 hours. A solution of 2N HCl was added to the reaction mixture followed by extraction with EtOAc (2×). The organic phases were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:8) to afford a clear oil (620 mg, 52%). 1H NMR (CDCl3, MHz) δ 0.75-0.91 (m, 2H), 1.07-1.26 (m, 6H), 1.58-1.76 (m, 7H), 3.06 (t, J=8 Hz, 2H), 7.55-7.70 (m, 3H), 7.92 (m, 2H); MS (CI/NH3) m/z: (M+NH4)+ 284.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1.O=C1C(CC(OC)=O)CC2C=CC(OCCCN(C3C=CC=CN=3)C(OC(C)(C)C)=O)=CC=2CN1CC1C=CC(C(F)(F)F)=CC=1>>[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:39][CH:38]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCN(C(=O)OC(C)(C)C)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCCN(C(=O)OC(C)(C)C)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Product: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)[C@H](CC(=O)O)C2)c1ccccn1
Yield: 60 %

Procedure:
According to the procedure of Example 24(c) except substituting methyl (S)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the methyl (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound (0.8 g, 60%) was prepared: MS (ES) m/e 628.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.C([Li])CCC.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.Cl.CCOC(C)=O>[Cl:27][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[C:3]2[O:2][CH3:1])=[CH:8][C:9]=1[O:13][CH3:14]
Reactant: COc1ccc2c(OC)cccc2c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc2cccc(OC)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 0.5 L round bottom flask equipped with magnetic stirring bar and thermometer was charged with 1,6-dimethoxynaphtalene (14.56 g, 77.36 mmol), THF (50 ml) and resultant solution was cooled to −78° C. (acetone/dry ice bath). Solution of butyl lithium (1.6 M in hexane, 53.18 ml, 85.09 mmol) was added through a syringe during 10 min. Mixture was allowed to warm to room temperature and stirred for 20 h. Then reaction mixture was cooled again to −78° C. and solution of hexachloroethane (20.144 g, 85.09 mmol) in THF (50 ml) was added through a syringe during 10 min. Reaction mixture was allowed to warm to room temperature, diluted with 1N HCl (150 ml), EtOAc (200 ml) and transferred into separation funnel. Organic phase was washed with saturated NaCl solution (2×30 ml), dried over MgSO4 and concentrated in vacuum. Residue was purified by vacuum flash chromatography (SiO2, 150 g, 35-65 m, eluent 10% EtOAc in hexane) to give a mixture (˜3:2) of 47 and 46. Pure desired product (47) was obtained by multiple crystallizations from ether (5.0 g, 22.5 mmol, yield=29%) as white solid. 1H NMR (CDCl3): δ 8.38 (s, 1H), 7.49-7.37 (m, 3H), 6.82 (dd, J=7.2, 1.0 Hz; 1H), 4.11 (s, 3H), 4.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 46.9 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and thiomorpholine (0.018 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (32 mg, 0.075 mmol, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([O:14]C)=[O:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 81.2 %

Procedure:
To a solution of 13.0 g of methyl 2-(2,6-dichloroanilino)-phenylglycolate in 150 ml of ethanol were added 10 ml of a 5 N aqueous sodium hydroxide solution and the reaction was effected at 80° C. under a nitrogen stream for 1 hour. The ethanol was distilled off under reduced pressure and the residual liquid was diluted with 100 ml of cold water and acidified with a 10% aqueous hydrochloric acid solution. The solid thus deposited was extracted with ether, and the ether extract was washed with water, dried over anhydrous sodium sulfate and then the ether was distilled off at room temperature under reduced pressure. The residue was recrystallized from ether-petroleum ether to give 10.1 g of 2-(2,6-dichloroanilino)phenylglycolic acid. m.p. 140°-142° C. Yield: 81% of theoretical amount.
Reaction SMILES: [N:1]([C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37])=[N+]=[N-].C(O)(=O)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N)c(F)cc2c1=O
Yield: 68.1 %

Procedure:
Ethyl 7-azido-8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (650 mg) was dissolved in methanol (20 ml). An acetic acid suspension (3 ml) of 20% palladium hydroxide (100 mg) was added to this solution, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After palladium hydroxide was removed by filtration, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (423 mg) as a liver-colored amorphous substance.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH2:22][CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:33]=[O:34])C.P(Cl)(Cl)(Cl)=O.C1(C)C=CC=CC=1>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1.C(OCC)(=O)C>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH2:22][CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][C:17]([CH:33]=[O:34])=[CH:16][CH:15]=4)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCn1c2ccccc2c2cc(C=C(c3ccccc3)c3ccccc3)ccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCn1c2ccc(C=O)cc2c2cc(C=C(c3ccccc3)c3ccccc3)ccc21
Yield: 29.8 %

Procedure:
35.4 g (87.87 mmol) of 3-(2',2'-diphenylvinyl)-9-ethylcarbazole (6a), 46.2 g (631.8 mmol) of DMF, 23.9 g (175.5 mmol) of zinc chloride, 80.7 g (526.6 mmol) of phosphorus oxychloride and 354 g of toluene were allowed to react and after treated in the same manner as with Example 1 (1). The crude product was treated by silica gel column chromatography (eluent; benzene/ethyl acetate=9/1 by volume), and recrystallized from a mixed solvent of toluene and heptane (3/2 by weight), thus obtaining 10.5 g of 3-(2',2'-diphenylvinyl)-6-formyl-9-ethylcarbazole.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Product: COC(=O)c1c(Cl)ccc(C(=O)Cl)c1Cl
Reaction time: 3 h

Procedure:
2,4-Dichloro-3-methoxycarbonylbenzoic acid (32.37 g) and thionyl chloride (100 ml) was heated under reflux with stirring for 3 hours. The mixture was cooled and evaporated in vacuo, then re-evaporated after addition of toluene to give 2,4-dichloro-3-methoxycarbonylbenzoyl chloride (34.76 g) as a dark brown oil. This was used in the next stage without purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:13])=[C:9]([F:16])[CH:8]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)nc1C
Yield: 63.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (205 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (282 mg) was obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])C1N=C(C2C=CC(C(O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=CN=1)[CH2:2][CH2:3][CH3:4].Cl[C:38]1[N:43]=[C:42]([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50]C)=[O:49])=[CH:46][C:45]=2[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:41]=[CH:40][N:39]=1>>[C:57]([O:56][C:54]([C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][C:44]=1[C:42]1[CH:41]=[CH:40][N:39]=[C:38]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:1][CH2:2][CH2:3][CH3:4])[N:43]=1)[C:48]([OH:50])=[O:49])=[O:55])([CH3:58])([CH3:59])[CH3:60]
Reactant: COC(=O)c1ccc(-c2ccnc(Cl)n2)c(C(=O)OC(C)(C)C)c1
Reactant: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Product: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)O)cc2C(=O)OC(C)(C)C)n1
Yield: 70 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 291B, 3-tert-butyl 1-methyl 4-(2-chloropyrimidin-4-yl)isophthalate (244 mg, 0.70 mmol) was converted to the title compound (210 mg, 70% for two steps). MS(ESI+) m/z 428.2 (M+H)+.
Reaction SMILES: C(OC(=O)[C:5](=[O:27])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][C:8]=1[N+:24]([O-:26])=[O:25])C.[OH-:29].[Li+]>CO>[CH2:17]([O:16][CH2:15][CH2:14][O:13][C:11]1[CH:10]=[CH:9][C:8]([N+:24]([O-:26])=[O:25])=[C:7]([CH2:6][C:5]([OH:27])=[O:29])[CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(=O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 3-[5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-2-oxo-propionic acid ethyl ester(37.77 g, 97.50 mmol) in methanol (370 ml) was added 1 N lithium hydroxide solution (230 ml, 0.23 mol). The deep red reaction mixture was stirred at 55° C. for 30 min and worked up to give [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-acetic acid (22.42 g, 69%) as an off-white solid. Analysis calculated for C17H17NO6 : C, 61.63; H, 5.17; N, 4.23. Found: C, 61.66; H, 5.08; N, 4.18.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][N:21]1[C:25](=[O:26])[C:24](Br)=[C:23]([Br:28])[C:22]1=[O:29].Cl>O1CCCC1>[Br:28][C:23]1[C:22](=[O:29])[N:21]([CH3:20])[C:25](=[O:26])[C:24]=1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Reaction time: 0.75 h

Procedure:
A solution of 1.445 g of indole dissolved in 29 ml of dry tetrahydrofliran is brought to from −20 to −10° C. under argon, and then 26 ml of LiHMDS (1M in hexane) are added dropwise in the course of 15 minutes. After 45 minutes at −10° C., the solution is diluted with an additional 15 ml of tetrahydrofuran and a solution of 2 g of N-methyl-2,3-dibromomaleimide dissolved in 17 ml of tetrahydrofuran is added dropwise in the course of 30 minutes. After 15 minutes at −10° C. and 15 minutes at 0° C., the reaction is stopped by the addition, at 0° C., of 50 ml of a 0.3N hydrochloric acid solution. The reaction mixture is extracted with ethyl acetate, and the organic phases are washed with a saturated NaCl solution, dried over MgSO4 and then evaporated under reduced pressure. The desired product is precipitated using methanol.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][CH2:14][C:13](=[O:15])[C:5](=[N:4][O:3][CH:2]([F:16])[F:1])[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: O=C(O)C(=NOC(F)F)C(=O)CCl
Reaction time: 7 h

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (5.0 g) in acetic acid (5 ml) was added sulfuryl chloride (8.5 ml). The mixture was stirred at 60°-63° C. for 7 hours. The solvent was evaporated in vacuo to give 4-chloro-2-difluoromethoxyimino-3-oxobutyric acid (4.5 g) as a glassy mass.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:4][CH2:3][CH2:2][N:43]2[CH2:44][CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42]2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: FC(F)(F)C1CCCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCCC(C(F)(F)F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-(trifluoromethyl)piperidine were converted to the title compound.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>O>[OH:16][CH2:15][CH2:14][N:13]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[CH3:12]
Reactant: CNCCO
Reactant: COc1ccc([N+](=O)[O-])cn1
Solvent: O
Product: CN(CCO)c1ccc([N+](=O)[O-])cn1
Yield: 78 %

Procedure:
A mixture of 154 g (1 mole) of 2-methoxy-5-nitropyridine, 90 g (1.2 mole) of N-methylethanolamine and 200 ml of water is heated to reflux for 8 hours with stirring. After cooling, the solid substance is filtered off with suction, washed with water and is then dried in the vacuum. An intensively yellow dyed product is obtained with a melting point of 83°-4° C. and in a yield of 78% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[OH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[C:42](=[S:55])[C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37]>C1(C)C=CC=CC=1>[OH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[C:42](=[S:55])[C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[CH:47][CH:48]=1)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:25][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)=[O:37]
Reactant: O=C(O)CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Solvent: Cc1ccccc1
Product: O=C(CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
The title compound is prepared by reacting equimolar amounts of the alcohol compound of Example 7 and the acid compound of Example 16 in refluxing toluene in the presence of AMBERLYST® 15 strong acid resin.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.[CH3:33][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]([OH:27])[CH3:33])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C=O)[nH]c2c1=O
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
To a solution of Example 278a (0.20 g, 0.44 mmol) in tetrahydrofuran (6 mL) at 0° C. was added methylmagnesium bromide (1.0 M in tetrahydrofuran, 0.873 mL, 0.873 mmol). The reaction mixture was stirred at 0° C. for one hour, and then 1M aqueous HCl (2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10 mL) and ethyl acetate (2×30 mL). The combined organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/methanol, 15/1) to provide the title compound (51 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.50 (m, 1H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.15 (d, J=2 Hz, 1H), 5.13 (d, J=5.2 Hz, 1H), 4.80-4.77 (m, 1H), 3.57 (s, 3H), 3.25 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). MS (ESI+) m/z 475.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:34][CH:35]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: CN(C)Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetate (0.005 g, 0.010 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction stirred for 1 hour at ambient temperature. The reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetic acid (0.005 g). MS−465.1 [M−1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11](O)([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:33])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:33])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 2.1 mmol) in CH2Cl2 (60 mL) under nitrogen at −78° C. was added DAST (550 μL, 4.16 mmol) and the solution was slowly allowed to reach RT and stirred for 1 h. The reaction mixture was poured into cold aqueous saturated NaHCO3 solution and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the desired material which was used in the next step without further purification. TLC, Rf (EtOAc)=0.75; MS (UPLC/MS): 389.3/391.3 [M+H]+, 411.3/413.2 [M+Na]+, 333.2/335. [MH−tBu]+, 289.2/291.2 [MH−Boc]+, 387.2/389.4 [M−H]−, 433./435.2 [M+HCOO]−; tR (HPLC conditions f): 2.2 min.