Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(Nc2ccccc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(C(C)(C)C)cc4)cc3)cc2)cc1
Yield: 41.6 %

Procedure:
8.1 g (0.036 mol) of N-phenyl-p-tertiarybutylaniline, 7.3 g (0.018 mol) of 4,4'-diiodobiphenyl, 7.5 g (0.054 mol) of anhydrous potassium carbonate, and 0.53 g (0.008 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 210° to 225° C. for 12 hours. The reaction product was then extracted with 70 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/4 mixture of toluene and n-hexane) to obtain 4.5 g (yield: 41.7%) of N,N'-bis(p-tertiarybutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 232.2° C. to 232.6° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[C:40]([NH:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cn2ccnc12
Temperature: 0 °C

Procedure:
To N-[3-(8-Amino-imidazo[1,2-a]pyridin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (185 mg, 0.414 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.24 mL, 3 eq). The resulting mixture was cooled to 0° C. and with stirring was added acetyl chloride (31 μL, 0.95 eq) and the resulting mixture was stirred from 0° C. to room temperature overnight. The next day the solvent was removed under reduced pressure at 55° C. and ethyl acetate (35 mL) and water (25 mL) were added to the residue. The organic layer was concentrated. Then added THF (5 mL) and 1N NaOH (5 mL) and stirred vigorously at room temperature overnight to hydrolize significant bis-amide. The next day added ethyl acetate (150 mL) and water (50 mL) and added 1N HCl to pH=2 and stirred vigorously for 10 minutes. The layers were separated, and the organic layer was washed with brine (1×50 mL), and then dried over magnesium sulfated, filtered and concentrated. The crude product was purified by Thin Layer Chromatography, eluting with 5% methanol in dichloromethane to give the title compound as an off-white powder (31 mg), ((M+H)+=441).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].CN(C1C=CC=CN=1)C.[NH2:21][C:22]1[C:39]([OH:40])=[CH:38][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30][C:24]=2[CH:23]=1>C(Cl)Cl>[OH:40][C:39]1[C:22]([NH:21][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:23][C:24]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26][C:25]=2[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(NS(C)(=O)=O)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (0.17 ml), methanesulfonyl chloride (0.16 ml) and dimethylaminopyridine (catalytic quantity) were added at 0° C. to a solution in DCM (10 ml) of 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.5 g). The solution was stirred at room temperature overnight. Volatiles were evaporated under reduced pressure and the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was concentrated and submitted to column chromatography to provide the title compound (0.53 g) as a yellow oil. MS (m/z): 357 [MH]+.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[C:8]1=[O:17]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[C:8]1=[O:17]
Reactant: Cn1c(=O)n(CCCCl)c2ccccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1c(=O)n(CCCI)c2ccccc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Sodium iodide (3.43 g, 22.89 mmol, 2 equiv) was added to a solution of 1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (2.57 g, 11.44 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure to remove all the acetone. The residue was worked up using ethyl acetate and water, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a red oil (3.62 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.12-2.19 (m, 2H); 3.24 (t, 2H, J=7.2 and 6.8 u Hz); 3.28 (s, 3H); 3.89 (t, 2H, J=6.8 Hz); 7.04-7.09 (m, 2H); 7.13-7.16 (m, 1H); 7.18-7.22 (m, 1H); MS for C11H13IN2O m/z 316.89 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([CH3:10])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([OH:28])=[O:27])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([O:28][CH2:7][S:8][CH3:10])=[O:27])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Reactant: CS(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCOC(=O)c1ccc(C)n1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of oxalyl chloride (0.3 mL, 3.5 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a solution of DMSO (0.34 mL, 4.8 mmol) in CH2Cl2 (1.5 mL) at −65° C. and stirred for 10 min. The resultant solution was added to a suspension of 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (211 mg, 0.8 mmol) in CH2Cl2 (10 mL) at −65° C. The resultant suspension was stirred at −65° C. for 15 min, then triethylamine (1.12 mL, 8.0 mmol) was added drop-wise. Once the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was then quenched by the addition of CH2Cl2 (50 mL) and water (10 mL), the organic layer was separated and the aqueous extracted with further CH2Cl2 (10 mL). The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a brown solid. The solid was purified by flash column chromatography (Biotage SP4, 40 g cartridge, hexane 1 CV, 0-50% EtOAc/hexanes 10 CV) to give (methylsulfanyl)methyl 1-[2-(4-fluorophenyl)-2-oxoethyl]-5-methyl-1H-pyrrole-2-carboxylate as a off-white solid (162 mg, 62%). 1H NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 2.22 (s, 3H), 5.19 (s, 2H), 5.76 (s, 2H), 6.06 (dd, 1H, J 3.9, 0.7 Hz), 7.06 (d, 1H, J 3.9 Hz), 7.13-7.24 (m, 2H), 8.06 (dd, 2H, J 9.0, 5.3 Hz). ESI-MI m/z [M+H]+ 321.80.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[N+](=[CH2:24])=[N-].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([O:20][CH3:24])=[O:19])=[CH:16][C:3]1=2
Reactant: C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 54 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionic acid in ethanol was added 5 ml of diazomethane etherial solution and the mixture was stirred at room temperature for 1 hour. To this was added acetic acid to decompose an excess reagent, then saturated sodium hydrogen-carbonate solution to make the solution alkaline, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 51 mg of oily substance, which was chromatographed over silica gel, eluted with benzene/chloroform (1/1) to obtain the colorless oily substance, which was crystallized from ethanol to give 40 mg of methyl 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-propionate as colorless crystals having a melting point of 98°-99.5° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (50 mg, 0.133 mmol) was dissolved in 0.5 mL of DMF and cooled to 0° C. Lithium bis(trimethylsilyl)amide (0.146 ml, 0.146 mmol) was added dropwise and the reaction was allowed to stir for 10 minutes. (bromomethyl)benzene (0.024 ml, 0.200 mmol) was added to the reaction, and was allowed to stir overnight at room temperature. The reaction showed disappearance of the majority of the starting material. The reaction was quenched with water. It was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution three times and dried over magnesium sulfate, filtered and concentrated. The crude material was purified through silica gel chromatography using 25% EtOAc:DCM. 1H-NMR (400 MHz, DMSO -d6) 7.64-7.55, 7.42-7.15, 7.13-7.06, 6.75-6.68, 5.56-5.47, 4.64, 4.57-3.91, 3.21-2.89, 2.78, 1.92-1.20
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[CH2:8]([NH2:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([NH:20][C:2](=[O:7])[CH2:3][O:4][CH2:5][CH2:6][OH:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1COCCO1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)COCCO
Temperature: 100 °C

Procedure:
In a glass reaction vessel 10.2 grams (0.1 mole) of 2-p-dioxanone was admixed with 18.5 grams (0.1 mole) of dodecyl amine and heated to 100° C. on a steam bath until reaction was completed within the period of 1 hour. The resulting liquid product was then poured on a glass plate and cooled to room temperature whereupon a pale yellow solid was formed. IR=6.06 mu.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[SH:11][CH2:12][C:13]([NH2:15])=[O:14].C[O-].[Na+]>CN(C=O)C.CO>[NH2:6][C:5]1[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=2[S:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: N#Cc1cccc(Br)c1F
Reactant: NC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1sc2c(Br)cccc2c1N
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirred solution of 3-bromo-2-fluoro-benzonitrile (2 g, 10 mmol) in DMF (50 mL) was added 2-mercaptoacetamide (1.2 eq., 12 mL, 100 mg/mL in MeOH-ammonia solution) followed by sodium methoxide (1.2 eq., 24 mL, 0.5 M in MeOH) at room temperature under nitrogen. After 2 h, the resulting homogenous yellow solution was warmed to 70° C. for 17 h. Upon cooling to room temperature, the resulting dark green reaction mixture was concentrated to give a green solid. This solid was diluted with MeOH and collected via filtration to give 2.0 g (74%) of 3-amino-7-bromo-benzo[b]thiophene-2-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]([F:38])([F:37])[F:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]([F:38])([F:36])[F:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C(F)(F)F

Procedure:
145 mg (purity 84%, 0.22 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 41 mg (37% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([Cl:27])=[N:24]2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([Cl:27])=[N:24]3)=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: Clc1ccc2ccc(CBr)cc2n1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 7-bromomethyl-2-chloro-quinoline in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated in 20% EtOAc/hexanes and filtered to afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc([N+](=O)[O-])cn2)cc1
Yield: 78.3 %

Procedure:
A mixture of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (250 mg; 0.61 mmol), 2-chloro-5-nitro-pyridine (116 mg; 0.73 mmol) and K2CO3 (126 mg; 0.92 mmol) in 2 ml of dioxane was heated at 220C in a pressure tube under nitrogen for 16 hr. Upon cooling, the mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (2–30% gradient) afforded the title compound (254 mg; 78% yield).
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][C@@H:9]1[CH2:13][N:12]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@@H:11]([C:26]([OH:28])=O)[CH2:10]1.ClC(OCC)=O>CC(C)=O>[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:11]([C:26]([NH2:3])=[O:28])[CH2:10]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)N2C[C@@H](O)C[C@@H]2C(=O)O)cc1OC
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)N2CC(O)CC2C(N)=O)cc1OC
Reaction time: 0.33 h

Procedure:
1.1 equivalents of triethylamine are added to 3 g (0.01 mole) of the trans-4-hydroxy- 1-(3,4-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 4 in suspension of 200 ml of acetone at 0° C. The reaction mixture is stirred for 20 minutes and then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° C. and 5° C. After stirring for 20 minutes, the mixture is filtered and ammonia is bubbled through the solution. The precipitate formed is separated, the acetone is removed under vacuum and the product obtained is recrystallized in water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[S:7][C:6]=2[CH:16]=1.FC(F)(F)CO>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[S:7][C:6]=2[CH:16]=1
Reactant: Fc1ccc2cc(C3=CCNCC3)sc2c1
Agent: [Pd]
Solvent: CCO
Solvent: OCC(F)(F)F
Product: Fc1ccc2cc(C3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
Scheme IA, Step C: To a solution of 4-(6-fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.850 g, 3.64 mmol) in a 3:1 mixture of ethanol (30 mL) and 2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C (0.900 g). The black slurry was stirred vigorously at room temperature under hydrogen (balloon pressure) for 1 day. The black slurry was then filtered over a pad of diatomaceous earth and washed with ethanol. The filtrate was concentrated to provide the intermediate title compound as a white solid (0.735 g, 86%). mp 115-120° C. IR (KBr) 3350 (br), 1247 cm1. Ion Spray MS 236 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:10]([NH:12][CH2:13][C:14]([O:16]C)=O)=[O:11].C[O-].[Na+]>C(O)C>[C:10]1(=[O:11])[C@H:2]2[CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]2[C:14](=[O:16])[CH2:13][NH:12]1
Reactant: COC(=O)CNC(=O)[C@H]1Cc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(=O)N2c3ccccc3C[C@H]12
Temperature: 25 °C

Procedure:
methyl {[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate (390 mg) was mixed with 100 mg of NaOMe in 5 mL of Ethanol. The mixture was refluxed for 2 hours and cooled to RT. The crude material was purified by flash chromatography to give the desired (10aR)-2,3,10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4](C)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[CH3:25])(=[O:15])=[O:14].[OH-].[Li+]>O.CO>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH3:25])[C:16]([S:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])(=[O:14])=[O:15])=[C:21]([CH3:22])[CH:20]=1
Reactant: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (1.65 g, 4.3 mmol) was dissolved in water (10 ml) and methanol (35 ml), and lithium hydroxide was added (0.3 g, 12.9 mmol). The mixture was stirred at room temperature for 3 days, the methanol was then distilled off in vacuo and ethyl acetate (50 ml) and HCl solution (1 mol/l, 10 ml) were added to the residue. The phases were then separated, extraction was carried out with ethyl acetate (2×50 ml) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The yield was 1.56 g (98%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>C(O)(C)C>[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:35]4([CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Yield: 79.8 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (14 g, 35 mmol) in isopropanol (210 ml) was added 1-tert-butoxycarbonyl-4-piperidone (35 g, 170 mmol) and the mixture refluxed for about two hours. The solvent was evaporated under reduced pressure. Water (150 ml) was added to the residue followed by 10% NaHCO3 solution until neutral pH and extracted by ethyl acetate (4×50 ml). The combined organic extracts were washed with water (2×50 ml) and dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which solidified on addition of diisopropyl ether (150 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried to afford 13.5 g of the desired product. Melting point: 118-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[CH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1F
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(COc2cc(F)c(CO)c(F)c2)cs1
Yield: 73 %

Procedure:
This compound was prepared from 3,5-difluoro-4-hydroxymethyl-phenol and 4-chlormethyl-2-methylthiazol according to the procedure described in Example 179 to give the product as a colorless oil (369 mg, 73%); MS (ISP): 272.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C>CS(C)=O>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:10]=[C:9]3[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]3[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(F)cc21
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.432 mmol) in DMSO (10 ml), morpholine (1.248 ml, 14.32 mmol) was added drop wise at room temperature. The resulting orange mixture was stirred at room temperature for 24 hours. Ethyl acetate (50 ml) was added and the solution was washed with brine (3×30 ml); the organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH=98:2) affording tert-butyl 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.155 mmol, 81% yield 0. MS/ESI+ 347.1 [MH]+.