Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:24]([OH:26])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:24]=[O:26])[C:9]1=[O:16]
Reactant: CCO
Reactant: Cc1cc(O)cc(=O)n1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(O)c(C=O)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1-(2-Chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one obtained in Step A (9.25 g) was added to a solution of sodium hydroxide′ (54.9 g) in water/ethanol (1:2, 157 mL) at room temperature, and the mixture was heated at 70° C. Chloroform (34.8 mL) was slowly added to the reaction mixture at 70° C., and the mixture was stirred for 2 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from diethyl ether to give the title compound (3.95 g).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([N:13]([CH3:36])[CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)=O)=[C:21](F)[CH:20]=1)[CH:11]=[CH2:12]>CC(N(C)C)=O>[CH2:10]([N:13]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)=[N:3][N:2]2[CH3:1])=[CH:23][C:24]=1[F:25])[CH3:36])[CH:11]=[CH2:12]
Reactant: C=CCN(C)C/C=C/COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/COc1cc2c(cc1F)c(-c1ccc(Br)cc1)nn2C

Procedure:
A mixture of 0.53 ml of methyl hydrazine and 0.17 g of potassium carbonate is stirred in 5 ml of DMA at room temperature. After the addition of 0.44 g of (E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,5-difluoro-phenyl]-(4-bromo-phenyl)-methanone in 5 ml of DMA the mixture is boiled at 120° C. After filtration the filtrate is concentrated at 80° C./0.3 Torr, taken up in methylene chloride, filtered over sodium sulphate and concentrated. The residue consisting of the title compound is dissolved in ether/hexane, treated with 0.11 g of fumaric acid and stirred. After filtration and drying there is obtained 0.41 g of (E)-allyl-[4-[3-(4-bromo-phenyl)-5-fluoro-1-methyl-1H-indazol-6-yloxy]-but-2-enyl]-methyl-amine.fumarate, m.p. 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C-:10]#[N:11].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:10]#[N:11])[CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#N
Reactant: Clc1cccc(CBr)c1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
The experimental procedure was followed by the method of Bruno P. Imbimbo et al [J. Med. Chem. 2005, 48, 5707-7520]. A solution of 3-chlorobenzylbromide (5 g, 24.3 mmol) and sodium cyanide (1.3 g, 26.8 mmol) in ethanol (50 ml) was heated to 80° C. for 2 hours. After resulting solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water and organic layer was extracted with ethyl acetate. The solution was evaporated and crude compound was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to yield 2-(3-chlorophenyl)acetonitrile (3.2 g, 87% yield) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Reactant: NCCCCCN
Solvent: Cc1ccccc1
Product: N=C(NCCCCCN)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol), toluene (3.5 mL) and 1,5-diaminopentane (0.50, 5.0 mmol) was stirred at 40° C. and for 48 h. The reaction mixture was concentrated under vacuum (35° C., 0.3 mbar) to give a crude product which was crystallized by addition of toluene followed by additon of heptane. The yield of N-(5-aminopentyl)-N'-benzyloxycarbonyl guanidine (IIId) was 0.3 g (60% in theory).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CCOCC>[CH:13]1([NH:16][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CCOCC
Product: COC(=O)C=C(CC(=O)OC)NC1CC1
Yield: 83.5 %

Procedure:
This compound was prepared as described in Step A of Example 94: 190.6 g (1.09 mol) of dimethyl acetonedicarboxylate and 75 g (1.3 mol) of cyclopropyl-amine in 200 ml of ether were reacted affording 194 g of clear oil. Trituration with petroleum ether gave 171.5 g (74%) of the enamine diester as a white solid: mp 64°-70° C. Crystallization from cyclohexane afforded an analytical sample; mp 73°-75° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc(-c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of (4′-chlorobiphenyl-3-yl)methanamine HCl salt (Chem-Impex International, Inc., 0.6 g, 2.36 mmol) in CH2Cl2 (6 mL) and 2-propanol (6.00 mL) was added 4-fluorobenzaldehyde (0.28 mL, 2.60 mmol). The resulting reaction mixture was stirred at rt for 1 h. and sodium triacetoxyborohydride (0.75 g, 3.54 mmol) was added under N2. After stirring at rt for 3 h, the reaction mixture was quenched with saturated aqueous NaHCO3, stirred for 10 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the filtrate solution was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with 0-10% ethyl acetate in CH2Cl2 to afford the desired compound (0.63 g, 73%) as a colorless oil. 1H NMR (CDCl3) δ 7.62-7.41 (m, 6H), 7.37-7.32 (m, 3H), 7.09-7.01 (m, 3H), 3.92 (s, 2H), 3.83 (s, 2H). MS (ESI): 326.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH:22]=[C:23]([C:29](=[O:36])[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[CH:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][C:29](=[O:36])[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22]2)=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC=CC(=O)C(=CNCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)C(=O)OCC
Solvent: CN(C)C=O
Product: CCCCC1CC(=O)C(C(=O)OCC)=CN1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 76.2 %

Procedure:
A solution of ethyl 2-[(2'-t-butoxycarbonylbiphenyl-4-yl)methylaminomethylene]-3-oxo-4-nonenate (1.59 g, 3.23 mmol) in DMF (20 ml) and was heated under reflux for 4 hours. After cooling, the reaction solution was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel. The column was eluted with ethyl acetate-hexane (7:3 to 8:2) to give 1.21 g (76.2%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54])=[O:13]
Reactant: Nc1c(C(=O)O)sc2nccnc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A solution of 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid 8 (32 mg, 0.164 mmol), HATU (74.8 mg, 0.197 mmol) and DIPEA (0.054 mL, 0.328 mmol) in DMF (2 mL) was stirred for 15 at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (48.2 mg, 0.164 mmol) was added and stirred overnight at 80° C. The reaction mixture was poured in cold citric acid solution and the resulting precipitate was collected. Purification by HPLC gave the title compound 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 70 (14 mg, 18%). NMR (400 MHz, DMSO-d6) 2.23 (s, 3H), 7.07 (s, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.31 (s, 1H), 8.78 (dd, J=5.1 Hz and 2.3 Hz, 2H), 9.48 (s, 1H), 10.49 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][CH:36]=[C:37]2[CH2:40]O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[N:15]([CH2:40][C:37]1[C:38]2[C:33](=[CH:32][CH:31]=[C:30]([Cl:29])[CH:39]=2)[CH:34]=[CH:35][CH:36]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc2ccc(Cl)cc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cccc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.52 ml of Diphenylphosphoryl azide and 1.10 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to 1.3 g of (7-Chloro-naphthalen-1-yl)-methanol in 18 ml of toluene. The mixture obtained is stirred at rt for 1 hour, washed with brine, the organic phase is dried and solvent is evaporated. The residue obtained is purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 99/1) to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCC(OC)OC)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (10 g, 53 mmol), aminoacetaldehyde dimethylacetal (5.6 g, 6.2 ml, 53 mmol) and potassium carbonate (7.4 g, 53 mmol) in acetonitrile (100 mL) and DMF (10 mL) was heated at 40° C. for 30 minutes. The mixture was filtered and extracted with DCM and brine. The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a yellow solid (12.4 g, 90%).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8](Cl)([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[OH-:25].[Na+]>Cl>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CC)CCNC(=O)C(Cl)(c1ccccc1)C1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCN(CC)CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 55 °C

Procedure:
A mixture of N-[2-(diethylamino)ethyl]-2-chloro-2-cyclohexyl-2-phenylacetamide (6.35 g) and 1N hydrochloric acid (100 ml) was heated at 55° C. for 2 hours. After being cooled, the solution was made alkaline with 6N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated under reduced pressure. And the residue was triturated with a mixture of n-hexane and diisopropyl ether to give N-[2-(diethylamino)ethyl]-2-cyclohexyl-2-hydroxy-2-phenylacetamide (4.98 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:35]([O:34][C:32]([NH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][C:16]([OH:18])=[O:17])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCOCCN(CCOCCNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCN(CCOCCNC(=O)OC(C)(C)C)CC(=O)O
Temperature: 15 °C
Reaction time: 15 h

Procedure:
A solution of benzyl 2-[bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]acetate (2) (2.2 g, 4.1 mmol) in methanol (70 mL) was degassed by bubbling argon through solution for five minutes. Palladium (10%) on activated carbon (220 mg) was added to the solution and the reaction mixture was placed under an atmosphere of hydrogen. The reaction was allowed to stir at 15° C. for 15 h before being filtered through a pad of Celite. The Celite was washed with methanol (2×20 mL) and the combined filtrates were concentrated at reduced pressure to provide a colourless oil (1.69 g, 3.8 mmol, 92%, >95% purity by HPLC). The product (4) was used without further purification. 13C NMR (CD3OD) δ170.1, 158.5, 80.2, 71.5, 65.9, 58.4, 55.8, 41.2, 28.8. ESMS (C20H39N3O8) [M+Na]+ calc. 472.2635. found 472.2623.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Product: CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloropyrimidine (447 mg, 3 mmol) in ethanol (10 mL) was added 1-methylpyperazine (360 mg, 3.6 mmol). The resulting mixture was stirred at room temperature overnight. The resulting white solid was collected by filtration and washed with ethanol, Na2CO3 solution and water and ethanol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:52])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:51]=[CH:50][C:38]([C:39]([NH:41][NH:42]C(OC(C)(C)C)=O)=[O:40])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:42][NH:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:52])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:51][CH:50]=1)=[O:40]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 206 mg of the title compound (87%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:16]3[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[C:9]=2[CH:10]=1)(=[O:4])=[O:3].[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][N:32]2[S:2]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][C:16]4[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=4[C:9]=3[CH:10]=2)(=[O:4])=[O:3])=[CH:28][CH:27]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)n4ccc5ccc(F)cc54)cc3c2C1
Yield: 55 %

Procedure:
The product of Example 41, step B was reacted with 6-fluoroindole following the procedure of Example 41, step C providing tert-butyl 8-(6-fluoro-1H-indol-1-ylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (63 mg, 55%) as a white foamy solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (s, 1H), 7.75 (dd, J=9.6, 2.1 Hz, 2H), 7.58 (d, J=4.0 Hz, 1H), 7.44 (m, 2H), 6.96 (dt, J=4.5, 2.5 Hz, 1H), 6.63 (d, J=4.1 Hz, 1H), 4.55 (br s, 2H), 3.81 (br s, 2H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (9.2 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][C:7]2[S:8][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[Br:22]Br>C(Cl)Cl>[Br:22][CH:13]([CH3:14])[C:12]([C:9]1[S:8][C:7]([CH2:6][N:5]2[C:4](=[O:16])[C:3]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]3[C:1]2=[O:21])=[CH:11][CH:10]=1)=[O:15]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Temperature: 25 °C

Procedure:
2-Phthalimidomethyl-5-propionylthiophene (39.3 g., 0.13 mole) is dissolved in methylene chloride 300 ml.) and bromine (20.8 g., 0.13 mole) is added dropwise with stirring over 3/4 hours at room temperature. The solution is partially evaporated in vacuo to remove the hydrogen bromide. Then it is washed with saturated sodium carbonate solution and with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This affords 5-(2-bromopropionyl)-2-(phthalimidomethyl) thiophene as a pale beige solid (46.7 g.), m.p. 127°-130° C.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:9]([C:10]([NH:12][C:13]2[CH:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[O:11])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:7]([C:6]([OH:26])=[O:5])=[CH:8][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To 45 mg 4-Chloro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-isophthalamic acid tert-butyl ester in 1 ml dichloromethane were added 1 ml trifluoroacetic acid at room temperature. Stirring was continued for 2 hrs and the mixture was evaporated under vacuum to give 28 mg of the title product.
Reaction SMILES: C(O)C.[OH:4][C@@H:5]1[CH2:25][C:24]2[C@:19]([CH3:27])([CH:20]=[CH:21][C:22](=[O:26])[CH:23]=2)[C@@H:18]2[C@@H:6]1[C@H:7]1[C@:15]([CH3:28])([CH2:16][CH2:17]2)[C@@H:10]([C@@H:11]([CH:13]=[O:14])[CH3:12])[CH2:9][CH2:8]1.[BH4-].[Na+].Cl>O>[OH:4][C@@H:5]1[CH2:25][C:24]2[C@:19]([CH3:27])([CH:20]=[CH:21][C:22](=[O:26])[CH:23]=2)[C@@H:18]2[C@@H:6]1[C@H:7]1[C@:15]([CH3:28])([CH2:16][CH2:17]2)[C@@H:10]([C@H:11]([CH3:12])[CH2:13][OH:14])[CH2:9][CH2:8]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.4 %

Procedure:
Ethanol (200 ml) was added to 20.0 g of (7α,20S)-7-hydroxy-3-oxo-pregna-1,4-diene-20-carbaldehyde. To this solution was added 0.61 g of sodium borohydride in several portions with stirring under ice cooling. After completion of the addition, the mixture was further stirred for 1 hour under ice cooling. The reaction mixture was neutralized with 1 N hydrochloric acid, then 200 ml of water was added, and the ethanol was distilled off under reduced pressure. The precipitate was collected by filtration, washed with water, then dehydrated by adding toluene to the precipitate and removing water by azeotropic distillation, and concentrated to give 18.8 g of (7α,20S)-7,21-dihydroxy-20-methyl-pregna-1,4-dien-3-one (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C(N(CC)CC)C.CS([Cl:22])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:22]
Reactant: Cc1c(Cl)cccc1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1CCl
Reaction time: 3 h
Yield: 69 %

Procedure:
910 mg of 3-chloro-2-methylbenzylalcohol was dissolved in 10 mL of methylene chloride, 1.21 mL of triethylamine and 495 μL of methanesulfonyl chloride were added thereto at room temperature, followed by stirring for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 700 mg (yield 69%) of a title compound as a white solid.