Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
The synthesis was performed with reference to the known literature (Heterocycles, Vol. 30, p. 627, 1990). A solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (0.21 g, 1.4 mmol) obtained in Example A46, Step 2 in methylene chloride (10 mL) was successively added with sodium hydroxide (0.17 g, 4.2 mmol), and tetrabutylammonium hydrogensulfate (0.14 g, 0.42 mmol), and the mixture was stirred at room temperature. Then, the reaction mixture was added dropwise with a solution of tosyl chloride (0.32 g, 1.7 mmol) in methylene chloride (5 mL), and then the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, and then the resulting organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with a mixed solvent of ethyl acetate and hexane to obtain 6-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.39 g, 93%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].C(N(CC)CC)C.[CH2:14]([S:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:24][CH2:23][CH2:22][S:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: OCCSCc1ccccc1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCSCc1ccccc1

Procedure:
A solution of 21.6 g of 2-bromopropionyl bromide in 30 ml of toluene was added dropwise to a solution of 10.1 g of triethylamine and 16.8 g of 2-benzylthioethanol in 150 ml of toluene at room temperature whilst stirring. After the addition was completed, the reaction mixture was stirred for a further 2 hours at room temperature. The mixture was then washed successively with 1% strength by weight aqueous solution of sodium hydroxide and water. After drying the organic phase over anhydrous sodium sulphate, the toluene was distilled off under reduced pressure, and the end product of 2-benzylthioethyl 2-bromopropionate was obtained in a yield of 28.8 g as a colorless product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[C:11](O)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:14])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.3 %

Procedure:
7 ml of a 1.0M tetrahydrofuran solution of diborane-tetrahydrofuran complex were added, at 0° C. under a stream of nitrogen, to a solution of 0.5 g of crude 4-nitrophenylglyoxylic acid in tetrahydrofuran, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 0.56 g (quantitative yield) of 1-(4-nitrophenyl)-1,2-ethanediol as a crude product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14]O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14][Br:35])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCO)nc2cc(C(F)(F)F)ccn12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCBr)nc2cc(C(F)(F)F)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of compound 17-G (0.031 g, 0.062 mmol) and carbon tetrabromide (0.025 g, 0.075 mmol) in methylene chloride (1.5 mL) at 0° C. was added triphenylphosphine (0.020 g, 0.075 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 17-H as a white solid (0.010 g, 29%); MS m/z (M+H+) 560.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.Br[CH2:16][Cl:17]>>[Cl:17][CH2:16][S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: ClCBr
Reactant: Cn1ccnc1S
Solvent: CCN(CC)CC
Product: Cn1ccnc1SCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (40 mmol) was added to a mixture of 2-mercapto-1-methylimidazole (40 mmol) and bromochloromethane (0.8 mol). The mixture was stirred for 1 hour at room temperature, washed with water and the dried (MgSO4) solution evaporated. Yield: 5.85 g (90%). 1H NMR (CDCl3, δ): 3.77 (CH3), 5.00 (CH2), 6.7-7.2 (H-4 and H-5). The product was used in the succeeding step without further purification.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1)[CH3:20]>O1CCCC1>[CH2:19]([N:21]1[C:25]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:24][CH:23]=[N:22]1)[CH3:20]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: CCn1nccc1N
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCn1nccc1NC=C1C(=O)Nc2ccccc21

Procedure:
The named compound is prepared by substituting 2-ethyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1632 gms. 2-ethyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: Brc1ccccn1
Product: c1ccc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)nc1
Yield: 31 %

Procedure:
The title compound (25 mg, 31%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 2-bromopyridine similarly to the procedure used for example 152. 1H NMR (400 MHz, CDCl3) δ 1.68-1.72 (m, 2H), 1.84-1.94 (m, 6H), 2.00-2.16 (m, 8H), 2.63-2.67 (m, 2H), 2.74 (m, 1H), 3.49 (d, 2H), 3.56-3.62 (m, 2H), 3.80-3.85 (m, 2H), 4.02 (m, 1H), 4.31 (m, 1H), 6.22 (d, 1H), 6.51 (t, 1H), 6.91 (d, 2H), 7.24 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). HRMS ESI+ m/z 422.2792 [MH]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][CH3:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)(=[O:3])[NH2:2].[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:40]([O:16][CH2:15][CH2:14][CH2:13][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:17][C@H:18]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH3:19])=[CH:5][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:9][CH2:10]1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCOC(=O)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (6.24 g) was dissolved in dry pyridine (9.4 ml), and pivaloyl chloride (1.54 ml) was added to the solution. The mixture was stirred overnight at room temperature, and a saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent:hexane/ethyl acetate=1/1) to give colorless amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]-propyl]-7-carbamoyl-2,3-dihydro-1H-indol-1-yl]propyl pivalate (4.30 g).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=433.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.CC(C)([O-])C.[K+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:11]2[C:10]3[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=3[C:4]3[C:12]2=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=3)=[CH:29][CH:28]=1
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.6 %

Procedure:
A solution of 11.1 g of acid from Step II in 100 cc of THF was added portionwise 10.3 g of potassium tert-butoxide. The resulting mixture was stirred for 45 min at room temperature and 10.3 g p-chlorobenzyl bromide was added portionwise. The reaction mixture was stirred 18 hours at room temperature. The resulting mixture was diluted with 100 cc of water and washed with hexane. The aqueous layer was acidified with HCl (1N) and the resulting precipitate filtered, washed with water and air-dried to afford 9.4 g of 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][N:9]2[CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C#N)c2ccc(OC)cc21
Reaction time: 0.25 h

Procedure:
To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[N:35]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][N:37]=[CH:36]1>O1CCCC1.O>[N:35]1([CH2:40][CH2:41][CH2:42][NH:43][CH:5]=[O:7])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCn1ccnc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: O=CNCCCn1ccnc1
Reaction time: 2 h

Procedure:
12.3 ml of acetic anhydride was cooled below 0° C. and treated dropwise with 6.1 ml of 98% formic acid, keeping the reaction temperature below 0° C. by external cooling. The mixture was then slowly warmed, and kept at 50° C.-60° C. for two hours. 10 ml of tetrahydrofuran was added, and the solution of acetic formic anhydric cooled to -20° C. A solution of 6.2 g of 3-(1H-imidazol-l-yl)propanamine in 20 ml of tetrahydrofuran was then added dropwise, keeping the temperature below -10° C. The reaction mixture was allowed to come to room temperature, 10 ml of water was added, and the mixture taken to dryness in vacuo. Distillation of the viscous residue at 195° C.-200° C. gave 6.2 g of N-(3-(1H-imidazol-l-yl)propyl)formamide. This was reduced to N-methyl-3-(1H-imidazol-l-yl)propylamine by the use of borane dimethylsulfide in refluxing tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]2(Br)[CH2:13][C:12]2(Br)Br)=[CH:4][CH:3]=1.C[Li].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][C:11]2[CH2:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(SCCC2(Br)CC2(Br)Br)cc1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(SCCC2=CC2)cc1
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
A solution of 0.500 g (0.0011 mol) of 2-(2-(4-chlorophenylthio)ethyl)-1,1,2-tribromocyclopropane in 6 ml of diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling in an ice water bath, 2.38 ml (0.00334 mol) of 1.4 M methyl lithium in diethyl ether was added slowly via syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.100 g of 1-(2-(4-chlorophenylthio)ethyl)cyclopropene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][C:21]([CH3:27])([CH3:26])[C:20]=3[CH:28]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:29]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][C:21]([CH3:26])([CH3:27])[C:20]=3[CH:28]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[5-(3,4-dichlorophenylmercapto)-pentoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35])(=[O:27])[CH3:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:35])[CH:37]=[CH:38][CH:39]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cccc(C=CC(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(OC(C)=O)c1
Yield: 98.2 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-acetoxycinnamic acid (2.9 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.7 g, 98%) as an amorphous solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=O)[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>N1C=CC=CC=1>[N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[S:26])[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2CCCC2)c2ncccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=C(CN1CCCC1)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13]C)[CH:9]=2)[C:4]1=[O:15].[BrH:16]>>[BrH:16].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[C:4]1=[O:15]
Reactant: COc1ccc2c(c1)CCC(N)C2=O
Agent: Br
Agent: Cl
Product: NC1CCc2cc(O)ccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 2-amino-6-methoxy-1-tetralone hydrochloride (2 g, 8.79 mmol) and 48% hydrobromic acid (60 mL) was stirred at 100° C. for 2 hours and then increased to 130° C. for additional 100 minutes. The resulting solution was concentrated. The crude product was subjected to re-evaporation with dry toluene and hexane. Upon adding a small amount of ethanol and hexane, a white salt precipitated which was removed. Upon concentrating the filtrate, a purple solid (1.43 g, 63%) resulted.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[N:15]=1>CN(C=O)C>[Cl:20][C:19]1[C:14]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[CH:6]=[N:7]2)=[N:15][C:16]([NH2:21])=[N:17][CH:18]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: Nc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)c(-n2ncc3ccc(I)cc32)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 32 mg, 0.82 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 10 min before addition of 4,5-dichloropyrimidin-2-amine (134.4 mg, 0.82 mmol). The mixture was stirred at 50° C. for 2 hr, then quenched with water and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. LC-MS (Method B) indicated a mixture of title compound [67%, Retention time=2.11 min, m/z=+371.9/373.9 (M+H)+] and an isomeric by-product [10%, Retention time=2.07 min, m/z=+371.9/373.9 (M+H)+]. Purification by flash chromatography (Isolute column, 50% EtOAc in heptane) afforded the title compound: 1H NMR (500 MHz, DMSO) δ 7.31 (2H, br. s.), 7.65 (1H, dd, J=8.51, 1.26 Hz), 7.71 (1H, d, J=8.20 Hz), 8.45-8.48 (1H, m), 8.56-8.71 (1H, m), 8.61 (1H, s); LC-MS: m/z=+371.9 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:23])[CH:10]([NH:22][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCCc1cccs1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCc1cccs1)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg,1.73 mmol) and 4-(2-thienyl)butyric acid (323 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide (445 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20]2[C:21]3[CH:35]=[CH:34][S:33][C:22]=3[C:23](=[O:32])[NH:24][C:25]=2[C:26]([CH3:31])=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH3:31])[C:25]2[NH:24][C:23](=[O:32])[C:22]3[S:33][CH:34]=[CH:35][C:21]=3[C:20]=2[C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 56 %

Procedure:
Following General Procedure E, (S)-tert-butyl 1-(4-bromophenyl)ethylcarbamate (60 mg, 0.20 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (60 mg, 0.20 mmol) to afford the desired product (52 mg, 62%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH2:32][CH:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH:25]2[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:28][C:27](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:26]2)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C

Procedure:
0.54 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester are added dropwise to a suspension of 108 mg of NaH (55% in mineral oil) in 5 ml of THF at 0°. The mixture obtained is stirred and 650 mg of 3-oxo-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 5 ml of THF are slowly added. The mixture obtained is stirred at 60° C. for 3 days, diluted with c-HEX and washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3-Ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C-NMR: 171.79, 154.45, 154.27, 133.38, 132.77, 127.11, 126.30, 79.64, 79.54, 61.03, 61.00, 48.59, 47.20, 46.81, 45.22, 42.72, 33.61, 33.42, 32.59, 32.17, 30.73, 30.07, 28.87, 28.57, 28.13, 16.48, 14.59.