Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].Cl[C:7]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:21][C:10]([C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[OH:20])=[O:12])=[CH:9][N:8]=1>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:7]([C:3]#[C:2][CH2:1][O:4][CH3:5])=[N:8][CH:9]=[C:10]([CH:21]=2)[C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[OH:20])=[O:12])=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CCOC
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Yield: 26 %

Procedure:
Bis(triphenylphosphine)palladium (II) dichloride (52 mg, 0.074 mmol), cuprous (I) iodide (14 mg, 0.074 mmol), triphenylphosphine polystyrene resin(146 mg, 1.48 mmol/g) and propargyl methylether (104 mg, 1.48 mmol) were added under argon at room temperature to a solution of 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (450 mg, 1.23 mmol) in N,N-dimethylformamide. The mixture was irradiated for 70 min in a microwave oven at 120° C. The polystyrene resin was filtered off and washed with ethylacetate. The filtrate was treated with 1 N HCl (80 mL); phases were separated and the water phase was extracted with ethyl acetate (2×100 mL). The organic phases were washed with water (100 mL) and saturated sodium bicarbonate solution (100 mL). Organic phases were then combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (heptane/ethyl acetate 1:2 to 1:9) to give 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(3-methoxy-prop-1-ynyl)-nicotinamide as a light yellow solid; 0.13 g (26% yield). m/z (ISP+): 399.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[Cl-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][Zn+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Reactant: Clc1cccc(C[Zn+])c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1nc(Cc2cccc(Cl)c2)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (1.46 g, 3.33 mmol), 3-chlorobenzylzinc chloride (0.5 M in tetrahydrofuran, 6.8 ml, 3.40 mmol), tetrakis(triphenylphoshino)palladium(0) (384 mg, 0.33 mmol), and tetrahydrofuran (10 ml) were combined and stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous ammonium chloride, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 10% ethyl acetate in hexanes) to give 436 mg (30%) of 2,2-dimethyl-propionic acid 5-bromo-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.24-7.18 (m, 4H), 6.41 (s, 2H), 4.25 (s, 2H), 1.18 (s, 9H); MS: m/z 436.1, 438.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:4]1.[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:3]([CH2:2][N:18]3[CH2:19][CH:20]([CH3:22])[CH2:21][CH:16]([CH3:15])[CH2:17]3)[O:4]2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(C2CCC(CBr)O2)cc1
Reactant: CC1CNCC(C)C1
Solvent: CCOC(C)=O
Product: CC1CC(C)CN(CC2CCC(c3ccc(Cl)cc3)O2)C1
Yield: 20 %

Procedure:
20 g (0.073 mole) of 2-bromomethyl-5-(4-chlorophenyl)-tetrahydrofuran and 25 g (0.22 mole) of 3,5-dimethylpiperidine are heated at 120° C. for 16 hours. The cooled reaction mixture is taken up in ethyl acetate and the mixture is washed twice with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60/ligroin-ethyl acetate 2:1/ethyl acetate). 4.5 g (20% of theory) of 2-(4-chlorophenyl)-5-(3,5-dimethylpiperidin-1-ylmethyl)-tetrahydrofuran are obtained as an oil; nD20 =1.5159.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[OH:22]S(O)(=O)=O.N>O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([NH2:17])=[O:22])[CH:14]=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: N#Cc1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: N
Solvent: O
Product: NC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 197.HCl (81 mg, 0.25 mmol) in couc. H2SO4 (9 mL) and water (1 mL) was heated at. 60° C. for 1 h, then poured into cold water. Conc. aqueous NH3 was carefully added until the pH of the mixture was 3, followed by careful addition of solid KHCO3 until the pH of the mixture was 8. The mixture was extracted with cold CH2Cl2 (×3), and the combined organic extracts were washed with water, brine and dried. The solvent was evaporated and the residue was dissolved in CH2Cl2MeOH. The solvents were concentrated until precipitation began. The precipitate was filtered off and washed with MeOH to give crude 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxamide (198) (37 mg, 48%) as red crystals: mp>300° C.; 1H NMR [(CD3)2SO] δ (two H not observed) 8.32 (d, J=1.3 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 7.80 (dd, J=9.1, 1.7 Hz, 1H), 7.72 (s, 1H), 7.53 (br s, 1H), 4.26-4.18 (m, 1H), 3.99 (dd, J=10.9, 3.8 Hz, 1H), 3.83 (t, J=10.1 Hz, 1H), 3.77-3.69 (m, 2H). 1H NMR also showed the presence of an unidentified impurity (ca. 10%) which was not removed by chromatography. HRMS (CI) calcd. for C14H1235ClN3O3 (M+) m/z 305.0567, found 305.0564.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N:14](C(OC(C)(C)C)=O)[NH:15]C(OC(C)(C)C)=O>C(OCC)(=O)C>[ClH:1].[NH:14]([C:10]1[N:9]([CH3:8])[CH:13]=[CH:12][N:11]=1)[NH2:15]
Reactant: Cn1ccnc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1ccnc1NN
Temperature: 22 °C
Reaction time: 20 h

Procedure:
4 M Hydrogen chloride in dioxane (50 mL, 200.00 mmol) was added to di-tert-butyl 1-(1-methyl-1H-imidazol-2-yl)hydrazine-1,2-dicarboxylate (Intermediate AV3) (5.9 g, 18.89 mmol) in ethyl acetate (50 mL) at 22° C. The resulting solution was stirred at 22° C. for 20 hours. The reaction mixture was evaporated to dryness to afford the product (2.80 g) which was used without purification. 1H NMR (400 MHz, DMSO) δ 3.38 (3H, s), 6.90 (1H, d), 6.96 (1H, d).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[SH:5][C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]([CH3:25])=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([S:5][C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]([CH3:25])=[CH:11][CH:12]=2)[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1-n1c(SC(C)C)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 59.4 %

Procedure:
Isopropyl bromide (0.11 mL, 1.25 mmol) was added to a suspension of 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (250 mg, 0.84 mmol) and potassium carbonate (235 mg, 1.68 mmol) in acetone (10 mL) and the mixture was heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and the any solid were filtered and washed with acetone. The filtrate was concentrated to dryness in vacuo and the crude compound was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in pet ether as eluent to afford 2-isopropylsulfanyl-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (170 mg, 59%) as semi solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][NH:3]1.Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>>[CH3:37][N:35]1[CH:36]=[C:32]([CH2:31][N:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=4)=[C:14]([CH:17]=3)[C:15]#[N:16])=[N:7][C:2]2=[O:1])[CH:33]=[N:34]1
Reactant: N#Cc1cc(CCc2cc[nH]c(=O)n2)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(CCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1

Procedure:
The title compound was prepared with a procedure similar to that described for E1 starting form 5-[2-(2-oxo-1,2-dihydro-4-pyrimidinyl)ethyl]-2-{[3-(trifluoromethyl)phenyl]oxy}-benzonitrile and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 480 [M+H]+; 2.90 min (ret time).
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][CH:8](Cl)[CH2:9]Cl>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:7][CH:8]([S:2][CH2:3][CH2:4][OH:5])[CH2:9][S:2][CH2:3][CH2:4][OH:5]
Reactant: ClCC(Cl)CCl
Reactant: OCCS
Agent: [Na]
Solvent: CCO
Product: OCCSCC(CSCCO)SCCO

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 14.7 parts of 1,2,3-trichloropropane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,2,3-tris(2-hydroxyethylthio)propane. This compound was added to 80 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,2,3-tris(2-chloroethylthio)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit 1,2,3-tris(2-chloroethylsulfonyl)propane. The deposited compound was recovered by filtration and dissolved in 100 parts of dimethyl sulfoxide, and the resulting solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and then the dimethyl sulfoxide was removed by distillation to deposit solids. The deposited solids were recrystallized from ethanol to obtain 1,2,3-tris(vinylsulfonyl)propane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and trifluoroethylamine (300 mg, 3 mmol) were dissolved in THE (10 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 60° for 4 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 195-196°, LC MS m/z=465(MH+) Retention time=2.38 min.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:7]=[C:2]([O:22][C:15]2[CH:14]=[CH:13][C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2)[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=NS(=O)(=O)N(C)C(Oc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-chloro-5-methoxy-2-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide (48 g) in methylene chloride (25.5 ml) is added dropwise to a stirred mixture of p-nitrophenol (38 g) and triethylamine (55 g) in methylene chloride (1 l). The mixture is stirred at RT for about 12 hours, refluxed for about 31/2 hours, concentrated in vacuo, the residue is treated with sat'd aq. Na2CO3 solution, and the resulting insoluble solid filtered and washed with water and CH2Cl2. The solid is recrystallized from ethyl acetate/acetonitrile yielding the p-nitrophenoxy compound as a crystalline solid, M.P.=220°-221° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12](Cl)(=[O:14])=[O:13])[CH:3]=[N:2]1.[OH-].[NH4+:17]>O1CCCC1>[O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:17])(=[O:14])=[O:13])[CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1-c1cnoc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1-c1cnoc1

Procedure:
By the procedure of Example 5, 15 g of 2-(isoxazol-4-yl)benzensulfonyl chloride prepared in Example 12 was reacted with 30 ml of concentrated ammonium hydroxide in 150 ml of tetrahydrofuran to give, after recrystallization from 2-propanol, 11 g of the title compound; m.p. 165°-167° C.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:14].[NH2:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]1=2>>[ClH:14].[NH2:8][C@H:9]([C:11]([NH:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]1=2)=[O:12])[CH3:10]
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccc(F)cc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 12), the title compound was prepared.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:21]([CH2:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[CH:22]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccncc2)cc(-c2ccc(F)cc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
4-(Bromomethyl)pyridine hydrobromide (290 mg) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg) and cesium carbonate (998 mg) in DMF (5 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was returned to room temperature and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [chloroform:methanol=10:0->19:1->9:1 (v/v)], and the eluate was concentrated under reduced pressure. The residue was purified by PLC [dichloromethane:methanol=10:1 (v/v)] to give 126 mg of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH2:18]1[C:22]2[CH2:23][NH:24][CH2:25][C:21]=2[CH2:20][N:19]1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][C:21]3[CH2:20][N:19]([C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:35])([F:37])[F:36])=[O:27])[CH2:18][C:22]=3[CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc([N+](=O)[O-])cn1)C2

Procedure:
2-Chloro-5-nitropyridine (510 mg, 3.22 mmol), (3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (1.046 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol) were stirred in 20 ml of DMF at 80° C. for 5 h. After concentrating under reduced pressure, ethyl acetate and water were added, and the precipitated solid was filtered off with suction. The organic phase was removed and concentrated. The two precipitates were combined. Yield: 845 mg (79%), M+H+: 405.04.
Reaction SMILES: C[O-].[Na+].[CH:4]1([NH:7][C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH:16][C:17](=[O:20])[CH2:18][SH:19])[CH:10]=2)[CH2:6][CH2:5]1.C1(S(O[CH:32]=[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:34]#[N:35])(=O)=O)C=CC=CC=1>CO>[NH2:35][C:34]1[C:33]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)=[CH:32][S:19][C:18]=1[C:17]([NH:16][C:11]1[CH:10]=[C:9]([C:8](=[O:21])[NH:7][CH:4]2[CH2:6][CH2:5]2)[CH:14]=[CH:13][C:12]=1[CH3:15])=[O:20]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CS
Reactant: N#CC(=COS(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To MeOH (4 mL) at rt was added a 25% (w/w) solution of NaOMe in MeOH followed by addition of N-cyclopropyl-3-(2-mercaptoacetamido)-4-methylbenzamide a (200 mg, 10.8 mmol). After stirring at rt for 15 min, 200 mg (10.6 mmol) of 2-(4-chlorophenyl)-2-cyanovinyl benzenesulfonate (prepared as described in J. Med. Chem., 6(47): 1448 (2004)) was added and the resulting solution was warmed to 60° C. for 2 h then allowed to cool to rt and stir for an additional 15 h. The mixture was concentrated under vacuum to remove the MeOH then water (20 mL) was added and the solution was extracted with EtOAc (200 mL). The organic extract was washed with water, brine, then dried over anhyd Na2SO4, filtered, and concentrated under vacuum to afford 300 mg of an orange solid as the crude product. This material was purified by reverse-phase preparative HPLC to afford 50 mg of a light yellow solid as the title compound (Example 209). HPLC Ret time=3.57 min. LCMS [M+H]+ 426.17.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: ClCc1ccccc1
Reactant: NC(=O)CCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CCC(=O)OCc1ccccc1

Procedure:
A mixture of 23.4 g. (0.20 mole) of succinamic acid, 25.4 g. (0.20 mole) of benzyl chloride, 20.2 g. (0.20 mole) triethylamine and 250 ml. dimethylformamide is stirred at 95° C. for 20 hours. The reaction mixture is diluted with 500 ml. water the product extracted into two 200 ml. portions of ethyl ether. The combined ether extracts are washed with two 50 ml. portions of saturated sodium bicarbonate solution, then two 50 ml. portions of water and dried over anhydrous magnesium sulfate. After filtering, the solution is concentrated at 15 - 20 mm. and 40° C. to give benzyl succinamate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR(CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB=14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O-2].[Mg+2].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]>C1COCC1.O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:14]([C:12]1[S:13][C:9]([Cl:8])=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CNCCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A suspension of 2-(methylamino)-ethanol (0.29 g, 3.86 mmol) and magnesium oxide (0.77 g, 19.1 mmol) in THF (4 ml) and water (1.4 ml) was allowed to stir at room temperature for 30 min, 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.81 mmol) dissolved in THF (1.6 ml) was added drop wise at room temperature over a period of 1 h and the reaction mixture was allowed to stir for an additional hour. Filtration over Decalite and evaporation yielded the crude product which was further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.4 g, 35%) as a yellow solid. MS (EI) 300.0 [(M)+], mp 62° C.