Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.[C:13]1([S:19]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:13]1([S:19][C:9]2[S:8][C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClSc1ccccc1
Reactant: Cc1ccc(-c2cccs2)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(Sc3ccccc3)s2)cc1
Reaction time: 96 h
Yield: 28.3 %

Procedure:
Into 500 ml of reagent carbon tetrachloride were added 61 g (0.35 mole) of 2-p-tolylthiophene, 41 ml (51 g, 0.35 mole) of benzenesulfenyl chloride and 0.05 g of powdered iron. The reaction mixture was allowed to stand four days at room temperature after which the carbon tetrachloride was distilled off and the 45-gram residue washed with a mixture of 80 ml of ether and 250 ml of petroleum ether. Recrystallization of the washed solid from 300 ml of ethanol gave 28 g (29%) of 2-phenylthio-5-p-tolylthiophene, m.p. 85°-86° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:29])=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:29])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc(C(=O)Cl)cc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-t-butyl-4-methoxy-5-methylsulfonyl benzoic acid (200 mg), toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (80 μL) were added to the solution, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc2c1N(C)C(=O)C(N)N=C2c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3cccc(C)c3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,9-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo, dissolution of the residue in CH2Cl2 and flash chromatography on silica gel (12% Et2O in CH2Cl2) gave the title compound which was crystallized as a white fluffy solid from Et2O: m.p. 215°-217° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8])=[O:3].[C:15]([O-:18])([CH3:17])=[CH2:16].[K+]>O1CCCC1>[C:2](=[O:3])([O:18][C:15]([CH3:17])=[CH2:16])[O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: C=C(C)[O-]
Reactant: CC(C)=CCCC(C)CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)OCCC(C)CCC=C(C)C
Yield: 56.8 %

Procedure:
To a solution of 20.78 g (0.095 mole) of citronellyl chloroformate in 150 ml of tetrahydrofuran was added under a nitrogen atmosphere with cooling and stirring an aliquot (215 ml, 0.101 mole) of the solution of potassium isopropenolate described in EXAMPLE XVIII. The reaction temperature did not rise above 10° C. during addition. After addition was complete the cooling bath was removed and the mixture was poured into 400 ml of diethyl ether, and washed successively with one 300-ml portion and three 400-ml portions of water. The ether layer was separated and dried over magnesium sulfate. Removal of solvent under reduced pressure left a red, slightly viscous residue weighing 20.83 g, which on distillation through a rotary thin-film molecular still at 75° C. skin temperature and 0.10-0.13 mm pressure yielded 12.97 g (56.8%) of citronellyl isopropenyl carbonate as a colorless liquid. The identity of the compound was confirmed by spectral data.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(S(C)(=O)=O)c12
Yield: 95 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and methylsulfonyl chloride as starting materials, the title compound was obtained in a yield of 95% as an oil.
Reaction SMILES: O1CCCC1.[OH-].[Li+].C([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[Br:23])=[O:12])C>O>[Br:23][C:16]1[CH:17]=[C:18]([F:22])[CH:19]=[C:20]2[C:15]=1[NH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:21]2
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)cc(Br)c2[nH]1

Procedure:
Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.11 g, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:38]=2)[CH2:33][CH2:32]1>>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])=[CH:3][C:2]([C:40]3[CH:39]=[N:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[CH:10][C:9]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.218 mmol) and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (0.086 g, 0.283 mmol). The title compound was collected as a white solid (0.105 g, 84%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.50-1.63 (m, 2H), 2.12 (s, 3H), 2.22 (s, 3H), 2.38-2.45 (m, 7H), 2.52-2.59 (m, 2H), 3.51-3.60 (m, 4H), 4.37 (d, J=5.05 Hz, 2H), 4.96-5.10 (m, 1H), 5.90 (s, 1H), 6.94 (d, J=8.84 Hz, 1H), 7.32 (d, J=1.26 Hz, 1H), 7.89 (d, J=1.26 Hz, 1H), 7.98 (dd, J=8.84, 2.53 Hz, 1H), 8.40 (t, J=5.05 Hz, 1H), 8.56 (d, J=2.27 Hz, 1H), 11.50 (s, 1H); LCMS (ES+) m/z: 556.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[N:15]1.[Cl:24]Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:24])[C:16]([C:20]([F:21])([F:22])[F:23])=[N:15]1
Reactant: Cc1cc(C(F)(F)F)nn1-c1cc(OS(C)(=O)=O)c(Cl)cc1F
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)c(C(F)(F)F)nn1-c1cc(OS(C)(=O)=O)c(Cl)cc1F
Yield: 98.7 %

Procedure:
Into a solution of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3-trifluoromethyl-5-methylpyrazole (37.3 g) in chloroform (200 ml) was introduced chlorine gas (7.1 g) at 60° C. for 20 minutes. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (40.2 g) as a pale yellow oil which soon crystallized on standing at room temperature. Recrystallization from a mixture of n-hexane/benzene yielded a white crystalline solid. m.p. 72°-74.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([O:20][CH2:21][O:22][CH3:23])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].[CH3:25][NH:26][CH3:27]>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:26]([CH3:27])[CH3:25])=[CH:4][C:5]([O:20][CH2:21][O:22][CH3:23])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: CNC
Reactant: COCOc1cc(F)c(Cl)cc1C(=O)c1ncccc1OCOC
Solvent: CN(C)C=O
Product: COCOc1cc(N(C)C)c(Cl)cc1C(=O)c1ncccc1OCOC

Procedure:
A mixture of 2-(5-chloro-4-fluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (1.98 g), a 50% aqueous solution of dimethylamine (20 ml) and DMF (50 ml) was stirred overnight at room temperature. The reaction mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate). The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (ethyl acetate/hexane) to afford 2-(5-chloro-4-dimethylamino-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (1.82 g) (Compound F-3).
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:16]
Reactant: O=C(O)C1NCCc2c1[nH]c1ccccc21
Reactant: CO
Agent: Cl
Product: COC(=O)C1NCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tetrahydro-beta-carboline-1-carboxylic acid (7.4 g) in MeOH (250 ml) was saturated with HCl gas for 20 min. The reaction mixture was gently stirred at room temperature for 18 h. and ca. 80% conversion was observed. The reaction mixture was re-treated with HCl gas and allowed to stir for another 18 h. Upon completion of the reaction the mixture was concentrated in vacuo to yield 2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid methyl ester (building block C), LCMS purity 95%, m/z 231 [M++H]+. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[N:3]=1.BrC1C=CC([N+:30]([O-:32])=[O:31])=CN=1>CN(C)C(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:30]([O-:32])=[O:31])=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#CC=C2CCN(c3ccc([N+](=O)[O-])cn3)CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 59, but substituting NMP with N,N-dimethylacetamide and substituting 2-fluoropyridine with 2-bromo-5-nitropyridine. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-1.4 N MeOH NH3 100:0.5.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O>C(Cl)(Cl)Cl>[F:23][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][S:15]([C:16]1[CH2:20][C:19]([CH3:21])([CH3:22])[O:18][N:17]=1)=[O:32]
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CS(=O)C2=NOC(C)(C)C2)c1OC(F)F
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 6.2 g (17.3 mmol) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline in 40 ml of chloroform was added 3.4 g (purity: 70%, 13.8 mmol) of m-chloroperbenzoic acid under ice-cooling, followed by 1 hour of stirring. Thereafter, the whole was further stirred at room temperature for 3 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogen sulfite solution, an aqueous sodium hydrogen carbonate, water, and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting solid was washed with n-hexane to obtain 4.1 g (yield: 63.2%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethanesulfinyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 112 to 114° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Yield: 87.7 %

Procedure:
A solution of 4,6-dichloropyrimidine (10.05 g), tert-butoxycarbonylpiperazine (11.94 g) and triethylamine (28.20 ml) in ethanol (150 ml) was heated at reflux for 18 hours. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, saturated aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(tert-butoxycarbonyl)-4-(6-chloro-pyrimidin-4-yl)piperazine (16.80 g).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[CH:6][C:7](=[O:18])[N:8]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:9]=1)=[O:3]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:1][C:2]([C:4]1[C:5]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[CH:6][C:7](=[O:18])[N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cn(CC(=O)O)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
tert-Butyl (5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl)acetate (225 mg, 0.46 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and trifluoroacetic acid (10 mL) and stirred at R.T. for 2 h. All solvent was evaporated under a stream of nitrogen and the resulting oil was redissolved in MeOH (10 mL) to which was added sat. NaHCO3 (10 mL). This mixture was stirred at R.T for 1 h. then 1 M HCl (50 mL) added and the resulting white precipitate collected by filtration. Purification was carried out by recrystallisation from EtOAc/MeOH to afford (5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl)acetic acid as a white solid (76 mg, 38%), m.p. (EtOAc/MeOH) 296-300° C. 1H NMR [(CD3)2SO, 400 MHz] δ 13.10 (v br s, 1H), 10.42 (s, 1H), 8.32 (s, 1H), 7.86 (br s, 1H), 7.75 (dd, J=10.2, 1.9 Hz, 1H), 7.58 (dd, J=8.4, 0.8 Hz, 1H), 7.52 (br s, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.53 (d, J=1.0 Hz, 1H), 4.49 (s, 2H). Anal. Calcd for C14H11FIN3O4.0.5H2O: C, 38.2; H, 2.7; N, 9.5. Found: C, 38.0; H, 2.4; N, 9.1.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:12][NH2:13]>C(O)C>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[NH:13][N:12]=[C:4]([NH2:5])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: N#CCC(=O)c1ccncc1
Reactant: NN
Solvent: CCO
Product: Nc1cc(-c2ccncc2)[nH]n1
Yield: 21 %

Procedure:
To 3-oxo-3-(pyridin-4-yl)propanenitrile (3.40 g; Example 7, Step 1) suspended in 230 mL ethanol was added 2.92 mL hydrazine. The mixture refluxed for 3 hours and concentrated to dryness. The residue was purified by chromatography, eluting with a mixture of 10% methanol in dichloromethane to yield 0.80 g (21% yield) product as a light yellow solid. MS showed a M+1 molecular ion of m/z 161.3 by positive APCI.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(OC)CC1
Temperature: 3 °C

Procedure:
1-ethoxycarbonyl-4-hydroxypiperidine (30.3 g) and triethylamine (23 g) were dissolved in ethyl acetate (182 mL) and the obtained mixture was cooled to 3° C. Methanesulfonyl chloride (22.05 g) was added thereto under stirring while taking caution such that the temperature did not exceed 20° C., and the mixture was continuously stirred under ice cooling for 1 hour. The obtained reaction mixture was washed with water (90 mL×3). The organic layer was isolated and concentrated to obtain a target compound as a light yellow oily substance. The yield amount was 43.09 g (98%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:19])=[O:12])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cc(C)ccc2[nH]1

Procedure:
5-Methylindole-2-carboxylic acid (0.9 g, 5.13 mmol) was dissolved in methanol (25 ml) and treated with sulphuric acid (0.5 ml). The mixture was refluxed for 4 h. The volume of solvent was reduced and the residue treated with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic fractions were dried and concentrated to give the desired ester.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>C(O)(C)C>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C=CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
Diphenylacetaldehyde (25.6 g), acrylonitrile (12.5 ml), and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU:2.5 g) were stirred in isopropyl alcohol (250 ml) with warming at 70° C. for 6 hours. The reaction mixture was concentrated to dryness and the group was purified by silica gel column chromatography. The crude crystal crop obtained was washed with isopropyl ether to provide the title compound (19.8 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24](=[S:26])[NH2:25])[N:6]2[CH2:21][O:22][CH3:23].Br[CH2:28][CH:29](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]1[S:26][CH:28]=[CH:29][N:25]=1)[N:6]2[CH2:21][O:22][CH3:23]
Reactant: CCOC(CBr)OCC
Reactant: COCn1c(C(N)=S)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCn1c(-c2nccs2)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Yield: 62 %

Procedure:
A mixed solution of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.25 g), 1-bromo-2,2-diethoxyethane (0.24 mL) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85-30:70) to give the title compound (165 mg, yield 62%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]1=[O:62]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]1=[O:62])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CC=CCN(c2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (30 mg, 0.053 mmol) and Intermediate 52 (20 mg, 0.064 mmol) to give a white solid (26 mg, 65% yield). Anal. Calcd. for C43H50N4O6S m/z 750.4. found: 751.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (dd, J=36.0, 7.3 Hz, 2H), 7.34 (t, J=7.8 Hz, 2H), 7.26-7.06 (m, 11H), 6.02-5.84 (m, 1H), 5.79-5.66 (m, 1H), 5.65-5.56 (m, 1H), 5.28-5.12 (m, 1H), 5.01 (d, J=4.4 Hz, 2H), 4.82 (d, J=17.7 Hz, 1H), 3.78 (dd, J=17.8, 7.9 Hz, 1H), 3.17-2.93 (m, 2H), 2.93-2.36 (m, 11H), 2.25-2.04 (m, 2H), 2.04-1.87 (m, 2H), 1.87-1.73 (m, 1H), 1.72-1.38 (m, 7H), 1.32 (d, J=6.2 Hz, 2H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1>C(O)(=O)C>[Br:1][C:10]1[C:6]2[CH:5]=[C:4]([Cl:3])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1
Reactant: BrBr
Reactant: Clc1ccc2sccc2c1
Solvent: CC(=O)O
Product: Clc1ccc2scc(Br)c2c1
Temperature: 50 °C
Yield: 76.5 %

Procedure:
A solution of bromine (0.31 g, 1.95 mmol) in 1.0 ml glacial acetic acid was added to a stirred solution of 5-chlorobenzo[b]thiophene (0.300 g, 1.77 mmol) in glacial acetic acid (1.0 ml) under nitrogen atmosphere. The reaction was heated to 50° C. for 4 hours, the volatiles removed under reduced pressure, the residue diluted in methylene chloride, washed with aq. sodium bicarbonate and with brine and dried over sodium sulfate. Evaporation gave 0.335 g (76%) of a tan solid. mp 85-86 C., FDMS m/e=249 (M+2).