Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26][C@@H]5CCCN5C[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.C(OC([N:43]1[CH2:50][CH:49]2[CH:45](CNC2)[CH2:44]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:22][CH:49]5[CH:45]([CH2:44][NH:43][CH2:50]5)[CH2:26]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC5CNCC5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (34 mg, 47%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:46])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:42][CH2:43][CH2:44]O)[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[O:31])=[CH:24][CH:23]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:47]([N:49](CC)[CH2:50]C)[CH3:48].C(NC)C>ClCCl.O>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:46])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:42][CH2:43][CH2:44][N:49]([CH2:47][CH3:48])[CH3:50])[C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[CH3:41])=[CH:37][CH:38]=2)=[O:31])=[CH:24][CH:23]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)c1ccc(NC(=O)N(CCCO)Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCN(CC)CC
Agent: CCNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1ccc(N(C)C)cc1
Reaction time: 7 h
Yield: 4 %

Procedure:
Under ice cooling, methanesulfonyl chloride (0.30 mL, 3.9 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(4-dimethylamino phenyl)-1-(3-hydroxypropyl)ureidomethyl]benzamide (Reference Compound No. 13-79, 200 mg, 0.36 mmol) and triethylamine (0.68 mL, 4.9 mmol) in anhydrous dichloromethane (5.0 mL), and then the reaction mixture was stirred for 7 hours. Water (100 mL) was added thereto, the whole was extracted with ethyl acetate (100 mL), and then the organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. Anhydrous dichloromethane (1.0 mL) and ethylmethylamine (0.03 mL, 0.35 mmol) were added to the residue, and then the mixture was stirred at room temperature for 5 hours. Water (50 mL) was added thereto, the whole was extracted with ethyl acetate (50 mL) and then the organic layer was washed with brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 9.0 mg of the title reference compound as colorless oil. (Yield 4%)
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][NH:16]2
Reactant: Clc1ccccc1-c1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1-c1cccc2c1CCN2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
558 g of sodium cyanoborohydride are added in portions to a suspension of 960 mg of 4-(2-chlorophenyl)-1H-indole in 11 ml of trifluoroacetic acid cooled to 0° C. The reaction medium is stirred for 16 hours while allowing it to rise to ambient temperature and then the pH is brought to neutrality with a sodium hydroxide solution. The reaction mixture is diluted with 300 ml of water then extracted with ethyl acetate (2×250 ml). The organic phases are combined and then concentrated to dryness under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (80/20), 395 mg of 4-(2-chlorophenyl)-2,3-dihydro-1H-indole are obtained in the form of a colorless viscous oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[NH2:27][CH2:28][CH:29]([C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[C:33]([Cl:39])[CH:32]=1)[OH:30]>C(OCC)(=O)C.C(N(CC)CC)C>[NH2:38][C:34]1[C:33]([Cl:39])=[CH:32][C:31]([CH:29]([OH:30])[CH2:28][NH:27][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:36][C:35]=1[Cl:37].[C:3]([O-:4])(=[O:30])/[CH:16]=[CH:15]\[C:14]([O-:26])=[O:13]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CN(C)C=O
Reactant: COc1ccc(CCCC(=O)OCCCCCCBr)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CCCC(=O)OCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)cc1
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
According to method I (dimethylformamide, 2 hours at 90° C.) from (6-bromo-1-hexyl)4-(4-methoxyphenyl)butanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/triethylamine 5:1). Recrystallized as the maleate from diethyl ether. Melting point: 66°-67° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:9][C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].Cl>N1C=CC=CC=1.CO>[CH:6]([N:9]([C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)[S:2]([CH3:1])(=[O:4])=[O:3])([CH3:8])[CH3:7]
Reactant: Cc1c(NC(C)C)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)cccc1N(C(C)C)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.3 L, 0.016 mmol) was added to a stirred solution of 4-(3-(isopropylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, TFA salt (Example 9-1, 13 mg, 0.016 mmol) in pyridine (0.2 mL) at rt. After 30 min, additional methanesulfonyl chloride (2.4 μL) was added and the mixture was stirred overnight. The mixture was treated with 1 M hydrochloric acid (0.56 mL), dissolved in methanol and purified by preparative HPLC to provide two rotational isomers of 4-(3-(N-isopropylmethylsulfonamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, isolated separately as TFA salts after lyophilization. Isomer A (3.3 mg, 31%) 1H NMR (400 MHz, chloroform-d) δ 9.58 (1H, s), 7.81 (1H, d, J=7.70 Hz), 7.68 (1H, s), 7.41-7.47 (1H, m), 7.32-7.37 (2H, m), 7.11 (1H, d, J=7.70 Hz), 7.05 (1H, d, J=8.14 Hz), 6.86 (1H, d, J=8.14 Hz), 4.60-4.72 (1H, m), 3.66 (3H, br. s.), 3.05 (8H, br. s.), 2.90 (3H, s), 1.91 (3H, s), 1.40 (3H, d, J=6.60 Hz), 1.12 (3H, d, J=6.82 Hz). Mass spectrum m/z 562.1 (M+H)+. Isomer B (2.9 mg, 27%) 1H NMR (400 MHz, chloroform-d) δ 9.41 (1H, br. s.), 7.84 (1H, d, J=7.70 Hz), 7.69 (1H, s), 7.46 (1H, t, J=7.81 Hz), 7.36 (2H, t, J=8.25 Hz), 7.13 (1H, d, J=7.70 Hz), 7.05 (1H, dd, J=8.25, 1.21 Hz), 6.92 (1H, d, J=8.36 Hz), 4.71-4.82 (1H, m), 3.67 (3H, br. s.), 2.59-3.07 (11H, m), 1.90 (3H, s), 1.43 (3H, d, J=6.60 Hz), 1.10 (3H, d, J=6.60 Hz). Mass spectrum m/z 562.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[C:28](C2C=CC(OC)=CC=2)[CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15][CH2:14]1>>[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[C:28]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15][CH2:14]1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1

Procedure:
This compound has been synthesized from 4-ethoxy-phenyl-boronic acid analogously to the method described in the synthesis of 178 (see example 141).
Reaction SMILES: Cl[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[O:5][CH2:4]1.[C:14]([OH:17])(=[O:16])[CH3:15].[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>O>[C:14]([O:17][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])([OH:5])[CH2:4][O:21][C:18](=[O:20])[CH3:19])(=[O:16])[CH3:15]
Reactant: Fc1ccc(C2(CCl)CO2)c(F)c1
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Agent: [K+]
Solvent: O
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 105 g of 1-chloro-2-(2, 4-difluorophenyl)-2,3-epoxypropane were added 525 ml of acetic acid and 126 g of potassium acetate and the resulting mixture was stirred at 115° C. for 15 hours. The reaction mixture was allowed to cool to room temperature. Then, to this reaction liquid was added 700 ml of water and a solid matter was dissolved and the resulting solution was extracted three times with 500 ml of ethyl acetate. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with water and dried over anhydrous sodium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 100 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CC1(c2ccccc2)CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(C)(c2ccccc2)C1=O
Yield: 101.9 %

Procedure:
A mixture 2-methyl-2-phenylcyclohexanone (94 mg, 0.5 mmol) and tert.-butoxy-bis-(dimethylamino)-methane (0.16 mL, 0.77 mmol) was stirred at 110° C. for 1.5 h, whereupon it was cooled and evaporated under reduced pressure. Toluene (3 mL) was added to the residue and the solution was evaporated again to give the title compound (124 mg) as red oil which was used without further purification. MS ISP (m/e): 244.4 [(M+H)+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]1[C:16](=[O:28])[C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH3:19])=[O:4].[OH-].[Na+].ClCCl>CO.O>[C:24]([O:23][C:21]([NH:20][C@@H:17]([CH2:18][CH3:19])[C:16]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:28])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)O
Temperature: 7.5 °C
Reaction time: 4 h

Procedure:
To the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-methoxyindoline-2(R/S)-carboxylic acid methyl ester (1.3 g, 3.3 mmol) in methanol (20 ml), was added sodium hydroxide(0.265 g, 6.6 mmol) in water (10 ml). The solution was stirred at 5 to 10° C. for 4 hours. The mixture was poured into dichloromethane (40 ml), and washed with cold potassium hydrogen sulphate (3×20 ml), and water (20 ml). The organic layer was dried over sodium sulphate, and evaporated to provide a white foam which was pure enough for the next step.
Reaction SMILES: CO[CH:3]([C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:4][NH2:5].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](Cl)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH3:15][O:14][C:8]1[C:7]([O:14][CH:8]([CH3:9])[CH3:7])=[C:6]([CH2:3][CH2:4][NH:5][C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C(CN)OC)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1ccc(CC(=O)NCCc2cccc(OC)c2OC(C)C)cc1OC

Procedure:
prepared by reaction of 2,3,4-trimethoxyphenylethylamine with 3,4-dimethoxyphenyl acetyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:41]1COCC1.CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:29]=[C:30]([F:37])[CH:31]=1)[CH3:41]
Reactant: C1CCOC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 15.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2 M ethanamine in THF (210 ul, 0.42 mmol) for methanamine to afford 6.5 mg of the title compound (15.5%).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO>[F:1][CH:2]([F:6])[C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)C(F)F
Solvent: CCO
Product: CCOC(=O)c1csc(C(F)F)n1
Temperature: 50 °C

Procedure:
A mixture of 2,2-difluoroethanethioamide (1.023 g, 9.21 mmol) and ethyl bromopyruvate (1.150 mL, 9.21 mmol) in EtOH (20 mL) was heated to 50° C. for 2 h.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30][CH:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:17](=[O:19])[C@@H:16]([N:15]2[CH2:14][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=4[O:7][C:6]=3[C:12]2=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23])=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4cccc(Cl)c4C3)C2=O)nc1
Yield: 28.4 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1), commercially available 6-amino-nicotinic acid methyl ester (163 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester (143 mg, 3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.36 (s, 1H), 8.87 (s, 1H), 8.29 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.18-7.39 (m, 2H), 7.09 (dd, J=6.8, 2.0 Hz, 1H), 5.09 (dd, J=10.8, 4.4 Hz, 1H), 4.43 (d, J=19.1 Hz, 1H), 4.08 (d, J=19.1 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.47 (br. s., 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19])=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)[CH2:2][P+:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(CBr)cc(-c2ccccc2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(-c2ccccc2)c1
Product: [Br-]
Yield: 76 %

Procedure:
A solution of methyl 3-bromomethyl-5-phenylbenzoate (3.78 g; 1.23 mmol) and triphenyl phosphine (3.26 g; 1.23 mmol) in toluene (40 ml) was heated at reflux under argon atmosphere for 9 hours. The resulting solid was filtered, washed with ether and pentane to give 3-methoxycarbonyl-5-phenylbenzyl triphenylphosphonium bromide. Yield=76%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21](=[O:22])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH3:19]
Reactant: CCN=C=O
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with ethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained having the following characteristics (12.4 mg, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 72 %

Procedure:
As described for Example 46, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (97 mg, 0.4 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (105 mg, 72%) which was obtained as a light yellow solid. MS: m/e=365.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>C(OCC)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:23])=[O:22])[CH:20]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a stirred suspension of piperazine (28.4 g, 288 mmol) in triethylamine (42 mL, 300 mmol) and diethyl ether (500 mL) that was cooled to 0° C. was added dropwise a solution of 5-fluoro-2-methylbenzene sulfonylchloride (30 g, 144 mmol) dissolved in diethyl ether (50 mL). The resulting mixture was stirred at room temp for 2 h then diluted with EtOAc and saturated aqueous NaHCO3. The organic phase was washed with water, brine and dried (Na2SO4). Concentration gave the title compound as a white solid (20.6 g, 55% yield). 1H NMR (300 MHz, CDCl3) δ: 7.57 (1H, dd, J=8.6, 2.7 Hz), 7.25 (1H, dd, J=8.4, 5.1 Hz), 7.12 (1H, td, J=8.1,2.8 Hz), 3.13-3.10 (4H, m), 2.98-2.85 (4H, m), 2.55 (3H, s), 1.69 (1H, bs). LCMS (M+H) calcd for C11H16FN2O2S: 259.09; found: 259.18.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CCCCc1ccc(N2CCNCC2)cc1
Product: CCCCc1ccc(N2CCN(C(=O)Nc3cc(CC)c(C)nc3OC)CC2)cc1
Yield: 57 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-normalbutylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.