Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:17]2[CH:16]=[N:15][C:14]([Cl:18])=[CH:13][C:12]=2[N:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:19]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20])[CH2:10]2.O.[Li+].[OH-].CC(O)=O>C1COCC1>[Cl:18][C:14]1[N:15]=[CH:16][C:17]2[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]3[N:11]([C:12]=2[CH:13]=1)[CH2:10][CH:9]([N:19]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20])[CH2:8][CH2:7]3
Reactant: COC(=O)Cc1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CN(C1CCc2c(CC(=O)O)c3cnc(Cl)cc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 4 mg of (±)-{3-chloro-6-[(4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-2,4b-diaza-fluoren-9-yl}-acetic acid methyl ester in 0.2 mL of THF was added 0.1 mL of water, followed by 0.02 mL of 1 N aq. LiOH solution. After stirring for 1 h at room temperature, 0.05 mL of AcOH was added. The reaction mixture was the dried with a jet flow of nitrogen. The residue was suspended in 0.3 mL of EtOAc and filtered through silica gel. The filtrate was concentrated to give 2 mg of the title compound as a white solid. MS (ESI): 452.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-picolylamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccc([N+](=O)[O-])cc3)c2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Yield: 90.7 %

Procedure:
3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 98, 70 mg) was dissolved in 25 mL of anhydrous EtOH and treated with 10% palladium on carbon (20 mg). The mixture was subjected to hydrogen for 4 h at 30 psi. The mixture was filtered through diatomaceous earth. The filtrate was concentrated and dried via vacuum line to afford 55 mg of 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate aniline was then dissolved in 1 mL of MeOH and treated with 5 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The resulting yellow semi-solid was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.007 g of the title compound as a light yellow solid. MS (ESI): exact mass calculated for C20H22N4, 318.18. found, m/z 319.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.34 (m, 1H), 6.94-6.90 (m, 2H), 6.68-6.65 (m, 2H), 5.23 (s, 2H), 3.11-3.06 (m, 4H), 2.99-2.96 (m, 2H), 2.91-2.88 (m, 2H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.Cl.[NH2:19][CH2:20][CH2:21][SH:22].[OH-].[Na+]>CN(C)C=O.O>[NH2:19][CH2:20][CH2:21][S:22][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3
Reactant: NCCS
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CSCCN)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a suspension of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (0.882 g) in dimethylformamide (40 ml), cysteamine hydrochloride (3.41 g) and caustic soda (2.40 g) in water (20 ml) were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated and the residue was crystallized from chloroform--n-hexane to obtain 0.714 g of the title compound as pale yellow prisms (mp.: 182°-184° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:13]1([NH:12][C:4]2[C:5]3[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=3[N:7]=[C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)[N:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1cc2c(NC3CCC3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Yield: 7.8 %

Procedure:
A mixture of 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (55 mg, 0.23 mmol), 6-aminoindazole (62 mg, 0.46 mmol) and trimethylsilyl chloride (0.040 mL, 0.31 mmol) in nBuOH (2 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (6 mg). MS 334.4 (M+H); UV 239.1, 316.2 nm
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:30]([Si:33](Cl)([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine (656, 0.877 g, 2.42 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (60% dispersion in mineral oil, 140 mg, 3.6 mmol) was added at room temperature. After 20 minutes, triisopropylsilyl chloride (513 μL, 2.42 mmol) was added dropwise. The reaction was stirred for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate and brine. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was adsorbed onto silica gel and purified by silica gel chromatography using 20-80% ethyl acetate/hexane. The resulting material was purified a second time with 5-30% gradient ethyl acetate/hexane to provide the desired compound (657, 831 mg, 66%). MS (ESI) [M+H+]+=519.4.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[C:12]2[CH2:13][CH2:14][CH:15](I)[C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>O>[N:20]([CH:15]1[CH2:14][CH2:13][C:12]2[C:7]([F:6])=[CH:8][CH:9]=[CH:10][C:11]=2[NH:17][C:16]1=[O:18])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2cccc(F)c2CCC1I
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2c(F)cccc2NC1=O
Reaction time: 8 h

Procedure:
DMF (300 ml) was added to a mixture of 6-fluoro-3-iodo-1,3,4,5-tetrahydro-1-benzazepin-2-one (42.5 g) and sodium azide (13.59 g, 209 mmol) at room temperature and the reaction was stirred overnight. The mixture was diluted with water (2000 mL) and a precipitate formed, which was filtered off and washed with water. The precipitate was taken up in dichloromethane and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude 3-Azido-6-fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one was isolated as a dark brown solid. Residual DMF remains in the sample, which was used without further manipulation in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:21]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C@@H:20]3[N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:21]3[CH2:22][NH:23][CH2:24][CH2:25][C@@H:20]3[N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23
Reactant: CN1CCN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CNCC[C@@H]12
Yield: 78.6 %

Procedure:
The hydrochloride salt of the title compound was prepared from tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (50 mg) using the deprotection procedures described in Example 275, Step B. The salt formed was free-based with 6 N NaOH to give the title compound (31 mg, 80%). 1H NMR (CD3OD, 300 MHz) δ 1.80-1.90 (m, 1H), 1.96-2.10 (m, 1H), 2.50 (m, 2H), 2.76-2.90 (m, 5H), 2.93-3.1 (m, 2H), 3.20-3.50 (m, 4H), 3.50-3.60 (m, 2H), 6.40 (d, 1H), 6.5 (d, 1H), 7.22-7.32 (m, 2H), 7.44 (d, 1H) ppm. MS-CI m/z=374 [C20H21Cl2N3+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Ethyl-3,4-dihydroxy benzoate, 4 (27.3 g, 150 mmol), benzyl bromide (40.4 mL, 340 mmol) and potassium carbonate (41.4 g, 300 mmol) in acetone (350 mL) were reacted in a similar manner as described for 8 to afford 9. Yield 41.4 g (76%); mp 68-69° C.; MS (FAB) 363 (M++1); IR (KBr) 1889, 1707; 1H NMR (200 MHz, CDCl3) δ 7.65 (s, 1H), 7.63 (dd, J=8.7 Hz, 1.7 Hz, 1H), 7.48-7.25 (m, 10H), 6.91 (d, J=8.3 Hz, 1H), 5.19 (s, 2H), 5.18 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:12]3(N3CCCC3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>O.S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:12]=3[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1CCCC2C(c3ccc(Cl)c(Cl)c3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)c(Cl)c3)noc2C1
Temperature: 120 °C
Yield: 17.9 %

Procedure:
5 g (0.012 mol) of methyl 3-(3,4-dichlorophenyl)-3a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate were dissolved in a mixture of 5 ml of water, 5 ml of concentrated sulfuric acid and 5 ml of glacial acetic acid and heated at 120° C. for 1.5 hours. The mixture was cooled, whereupon the crystals which formed were filtered off and washed firstly with glacial acetic acid and then with water. After drying in a vacuum and crystallization from methanol, there was obtained 0.7 g of 3-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 183°-185° C.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([OH:3])=[O:2].[C:16](=O)([O-])O.[Na+].CN(C)C=O.S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:2][C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)=[O:3]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 58.5 %

Procedure:
5-Carboxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (2 g.) and sodium hydrogen carbonate (1.25 g.) were suspended in acetone (50 ml.) and N,N-dimethylformamide (5 ml.) and, under stirring, dimethyl sulfate (2 ml.) was added dropwise to the mixture. The reaction mixture was refluxed under heating for 24 hours, and, after cooling, the solvent was evaporated off under reduced pressure. The residue was diluted with water and the solution was extracted with ethyl acetate. The extract was washed with aqueous solution of sodium hydrogen carbonate and dried. After removing the solvent by evaporation under reduced pressure, the residue was recrystallized from methanol to give colorless needles of 5-methoxycarbonylspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.25 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 5-bromo-1-indanone (2.0 g, 9.5 mmol) in THF (20 mL) was added NaBH4 (0.5 g, 12.8 mmol). After stirring at room temperature overnight, the solution was quenched by addition of water. The resulting solution was extracted with EtOAc twice. The combined EtOAc layers were dried over Na2SO4 and concentrated under vacuum to give 2.0 g of the title compound as a solid. MS calculated for C9H9BrO: (M+H)+212.9; found 194.9 (M+H—H2O)+, 197.0 (M+H—H2O)+.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(I)CC>>[C:1]([C:3]1[N:7]([CH2:20][CH2:21][CH3:22])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Agent: [K+]
Solvent: CCCI
Product: CCCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.2 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and propyl iodide (0.056 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.2%).
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].[C:20]1([O:28][CH3:29])[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][CH3:23]>>[CH3:23][O:22][C:21]1[C:20]([O:28][CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC

Procedure:
In Scheme G, step c, 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is reacted with lithiated veratrole to give 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@:10](C(OCC)=O)([C:11](=[O:23])[N:12]3[CH2:22][CH2:21][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]3=4)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:10]([C:11](=[O:23])[N:12]3[CH2:22][CH2:21][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]3=4)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@]12CN(Cc3ccccc3)C[C@@H]1c1cccc3c1N(CC3)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@@H]2c2cccc3c2N1CC3
Temperature: 100 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
To a solution of (±)-cis ethyl 9-benzyl-7-oxo-4,5,8,9,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-7a(7H)-carboxylate (3.9 g, 10.4 mmol) in 50 mL of 1,4-dioxane was added 50 mL of 3N HCl and the resulting mixture was stirred at 100° C. for 24 h. The dioxane and most of the water was removed in vacuo, and the residue was basified with sat'd aq Na2CO3 and extracted with ethyl acetate. The layers were separated and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 3.1 g (96%) of (±)-cis-9-benzyl-4,5,8,9,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-7(7aH)-one free base, which was sufficiently pure to be used without purification. LRMS (ES)+: 305.1 (M+H)+. A portion of this material (50 mg, 0.16 mmol) was dissolved in 5 mL of ether and 1 mL of absolute ethanol. Then there was added 2M HCl in ether (0.165 mL, 0.33 mmol). The resulting solid was filtered, washed twice with ether and dried in vacuo to afford the title compound of EXAMPLE 107 as a pale yellow powder. 1H NMR (dmso-D6) δ: 7.60-7.50 (m, 2H), 7.48-7.38 (m, 3H), 7.19-7.15 (m, 1H), 7.12-7.07 (m, 1H), 6.98-6.90 (m, 1H), 4.45-4.37 (m, 1H), 4.30-4.18 (m, 1H), 4.02-3.90 (m, 2H), 3.87-3.77 m, 2H), 3.68-3.40 (m, 3H), 3.21-3.05 (m, 3H). LRMS (ES)+: 305.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].B([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1)(O)O>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Product: Nc1ncc(-c2ccc(CCC(=O)O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-(4-boronophenyl)-propanoic acid gives the compound “A32”; HPLC/MS: 1.28 min, [M+H]=363;
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](Cl)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2CCCCC2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCCC1.CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:57][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:51]4)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Cc1c(Cl)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1c(CC2CCCCC2)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of EXAMPLE 107A (60 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 4.58 mg) and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) in tetrahydrofuran (0.5 mL) and 1-methyl-2-pyrrolidinone (0.5 mL) was stirred at room temperature for 5 minutes while bubbling N2 through the reaction mixture. To this solution was added 0.5 M (cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. The reaction mixture in a sealed tube was heated in a preheated oil bath at 100° C. overnight and cooled. The reaction mixture was quenched with water and diluted with dichloromethane. The dichloromethane layer was washed with water and concentrated. The residue was purified by flash chromatography, and eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C=O)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a 500-mL round bottom flask with stirbar was added 4-amino-benzaldehyde (2.0 g, 0.0165 mol) and diluted hydrochloric acid (4 N, 150 mL). The mixture was cooled in ice-water bath to keep the temperature around 0° C. Sodium nitrite (2.28 g, 0.033 mol) solution in water (20 mL) was added to the above mixture at 0° C. and stirred for 0.5 h, and then sodium azide (2.15 g, 0.033 mol) solution in water (20 mL) was added to the above mixture dropwise to keep the temperature at 0° C. (a lot of foam were formed in this process). The reaction was warmed gradually to room temperature over 1 h, and then permitted to react at room temperature overnight. TLC showed that there was only one main product in the reaction mixture so the reaction was stopped. The crude product was extracted with EtOAc (50 mL×5) and the combined organic layers were dried with anhydrous MgSO4. After removing the solvent, a light yellow liquid was obtained as the pure final product (2.30 g, 95% yield). IR (neat): 3062, 2114, 1693, 1597, 1578, 1503, 1282, 1166, 1126, 852 cm−1. 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 7.91 (dt, J=8.8, 2.0 Hz, 2H), 7.19 (dt, J=8.8, 2.0 Hz, 2H); 1H NMR (400 MHz, MeOD): δ 7.45 (dt, J=8.8, 2.0 Hz, 2H), 7.08 (dt, J=8.8, 2.0 Hz, 2H), 5.38 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.7, 146.4, 133.2, 131.6, 119.5.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.ClCCl.[Br:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32][O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1
Reactant: BrC/C=C/CBr
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A heterogenous mixture of 1.59 g (4.35 mmol) of trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 5.1), 5.0 ml of dichloromethane , 37.2 g (174 mmol) of (E)-1,4-dibromo-2-butene, 15.0 ml of 50% w/w sodium hydroxide solution and 0.44 g (1.3 mmol) of tetrabutylammonium hydrogensulfate was stirred vigorously at room temperature for 3 days. Afterwards, 30 ml of deionized water were added and the reaction mixture was extracted with 3 portions of n-hexane. The combined organic phases were then washed with water (3 times), 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine and were finally dried over magnesium sulfate and evaporated under reduced pressure. The excess of the (E)-1,4-dibromo-2-butene was distilled off under reduced pressure (0.5 torr) at 100° C. The residue thus obtained was chromatographed on silicagel with a 3:1 v/v mixture of dichloromethane and hexane as the eluent giving 1.51 g (69.6%) of trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as pale yellow solid, MS: 515 (MNH4+, 1Br).