Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=O.[CH3:25][NH2:26].[BH4-].[Na+]>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][CH:17]2[NH:26][CH3:25]
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCC(NC)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: 25 °C

Procedure:
8-(2-Benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1 g) and methylamine (40% methanol solution, 7.4 ml) were dissolved in methanol (15 ml) and the solution was refluxed for 14 hours. After allowing to cool, sodium borohydride (630 mg) was added by portions with stirring at room temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and the resulting residue was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-methylamino-1,2,3,4-tetrahydroquinoline (970 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=3[N:13]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CSc1ncc2ccc(-c3cnn(C)c3)nc2n1
Yield: 34.6 %

Procedure:
A suspension of 7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 57, 31 mg, 0.146 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43 mg, 0.21 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol) and CsF (67 mg, 0.44 mmol), in DME/MeOH (3/1 mL) was stirred at 150° C. under microwave irradiation for 30 minutes. The reaction mixture was filtered, concentrated in vacuo onto silica gel and purified by Biotage silica gel column chromatography eluting with 80% EtOAc in cyclohexane to afford title compound as an yellow oil (13 mg, 35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1N
Yield: 58 %

Procedure:
Prepared from (2-nitro-4-thiazol-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F7) (205 mg, 0.59 mmol) by reduction with SnCl2.2H2O (668 mg, 2.95 mmol) according to the general procedure G (method b). Obtained as a yellow solid (108 mg).
Reaction SMILES: Br.C([O:4][P:5]([C:10]1[CH:15]=[CH:14][C:13]([P:16]([O:21]CC)(=[O:20])[O:17]CC)=[CH:12][CH:11]=1)(=[O:9])[O:6]CC)C.C(OCC)C.C(=O)=O>C(O)(=O)C.C(O)C>[C:13]1([P:16]([OH:21])(=[O:17])[OH:20])[CH:12]=[CH:11][C:10]([P:5]([OH:6])(=[O:4])[OH:9])=[CH:15][CH:14]=1
Reactant: CCOP(=O)(OCC)c1ccc(P(=O)(OCC)OCC)cc1
Agent: Br
Agent: O=C=O
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=P(O)(O)c1ccc(P(=O)(O)O)cc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
93 ml of HBr at 33% by weight in acetic acid are added to 6.68 g of 1.4-benzene-diphosphonic acid tetra-ethyl ester and the mixture is heated to 80° C. for 4 hours. After cooling to ambient temperature 200 ml of diethyl-ether are added and the mixture, after brief agitation, is cooled to -78° C. in a bath of ethanol and dry ice. The oily precipitate obtained is recovered by decantation and subjected twice more to the dispersion process with ether and low-temperature precipitation. The oily residue obtained is vacuum dried (1 mm Hg) at 50° C. for 8 hours, obtaining 4.0 g of 1,4-benzene-diphosphonic acid in the form of a white solid. Yield in moles 89%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[F:8][C:6]1[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:22])[CH:18]=2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2cc(F)cc(F)c2)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(3,5-difluorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid. MS (ESI+): m/z=276.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([O:25][CH3:26])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(CNCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of benzylamine (13.1 mL, 0.12 mol) and 4-benzyloxy-3-methoxybenzaldehyde (24.2 g, 0.1 mol) in 1,2-dichloroethane (50 mL) and chloroform (250 mL) was added sodium triacetoxyborohydride (31.79 g, 0.15 mol). The mixture was stirred at room temperature for 18 hrs, saturated NaHCO3 was added. The organic phase was separated and aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil in 76% yield (25.2 g). Rf: 0.17 (petrol:ethyl acetate; 1:1). 1H NMR (270 MHz, CDCl3) δ 3.73 (2H, s), 3.79 (2H, s), 3.89 (3H, s), 5.13 (2H, s), 6.75-6.84 (2H, m), 6.91 (1H, d, J=1.4), 7.23-7.44 (10H, m); HRMS (ESI+) calcd. for C22H24NO2 (M++H) 334.1802, found 334.1787; LC/MS (ES+) tr=1.19 min, m/z 334.5 (M++H);
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1>C(Cl)Cl.O>[CH2:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:50][CH2:51][N:42]1[CH2:41][CH:40]([OH:52])[CH2:39][NH:38][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(C(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A solution of 4-sulfamoylbenzoic acid (88.4 mg, 0.44 mmol), HATU (182.4 mg, 0.48 mmol) and TEA (48.48 mg, 0.48 mmol) in DCM (10 mL) was stirred at 22° C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.48 mmol) was then added and the solution was stirred at 22° C. for another 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (49.5 mg, Yield 29%). 1H NMR (CD3OD, 400 MHz): δ 7.92 (s, 4H), 7.16-7.09 (m, 3H), 7.05-7.02 (m, 1H), 4.14-4.12 (m, 1H), 3.77 (s, 2H), 3.58-3.39 (m, 2H), 2.94-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.75-2.66 (m, 2H). LCMS (m/z): 390.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([O:8][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ncc(O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1ncc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 2-aminopyrimidin-5-ol (0.500 g, 4.50 mmol) in dry MeOH (10 mL), K2CO3 (0.622 g, 4.50 mmol) and benzyl bromide (0.535 mL, 4.50 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, then dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel using 50% ethyl acetate in petroleum ether. The desired fractions were concentrated to give 5-(benzyloxy)pyrimidin-2-amine as an off-white solid (0.222 g 25%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.06 (s, 2H), 6.21 (s, 2H), 7.28-7.30 (m, 5H), 7.45 (s, 2H). LCMS: RT 1.060 min; 202.2 (M+H).
Reaction SMILES: C(C1C=C([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12]C2CCNCC2)=[O:11])C=CC=1)#N.C(N(CC)CC)C.C1(CS(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH:19]1([NH:9][C:10]([NH2:12])=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Agent: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
N-(3-Cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea (2.07 g, 6.95 mmol) in tetrahydrofuran (100 ml) with triethylamine (7.64 mmol, 0.77 g, 1.1 ml) was cooled to 0° C. and a-toluenesulfonyl chloride (1.46 g, 7.64 mmol) in tetrahydrofuran (60 ml) was added dropwise. The reaction was allowed to cool to ambient temperature and was stirred for 18 h. The solvent was removed in vacuo and the residue patitioned between water and 5:1 ethyl acetate:acetone. The organic layer was washed with 1N HCl and 1N NaOH, then brine. It was dried (Na2SO4) and evaporated to give 2.63 g of crude product. Purification by medium pressure liquid chromatography on a silica gel column (350 g) gave N-(3-cyanophenyl)-N′-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea (1.81 g, 4.0 mmol, 58%, mp 203-204° C.); HRMS (M+H)+ calc. 453.196038, found 453.198085.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:39])[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[CH2:40](I)[CH3:41]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:40][CH3:41])[C:31](=[O:39])[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)c(Cl)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC1CCCCC1)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and cyclohexyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (65 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (87 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[OH-].[K+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+].[I-]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-].O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[CH:8]=[CH:7]3)[CH2:23][CH2:24]1
Reactant: O=S(=O)(O)c1ccc2cccc(O)c2c1
Reactant: ClCCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(O)c1ccc2cccc(OCCCN3CCOCC3)c2c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
To a solution of 8-hydroxynaphthalene-2-sulfonic acid (Intermediate 26A, 300 mg, 1.34 mmol) and pulverized KOH (300 mg, 5.35 mmol) in DMF (2.0 mL) was added 4-(3-chloropropyl)morpholine (438 mg, 2.68 mmol) and NaI (401 mg, 2.68 mmol). The resulting reaction mixture was stirred at 60° C. for 12 h. TBAI (494 mg, 1.34 mmol) was then added followed by 4-(3-chloropropyl)morpholine (438 mg, 2.68 mmol). The reaction mixture was stirred at 60° C. for an additional 12 h, then diluted with water and filtered. The filtrate was purified directly using preparative HPLC to give the title compound (150 mg, 29%). 1H NMR (DMSO-d6) δ 8.49-8.34 (m, 1H), 7.80-7.70 (m, 1H), 7.70-7.60 (m, 1H), 7.36-7.19 (m, 2H), 6.89-6.77 (1 H, m), 3.95 (br s, 2H), 3.65 (br s, 4H), 3.48-3.32 (m, 2H), 3.26-3.06 (m, 2H), 2.57-2.44 (m, 2H), 2.37-2.13 (m, 2H); MS(ESI−) m/z 350.4 (M−H)−.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.[C:28]([O:32][C@@H:33]([C:38]1[C:39](I)=[C:40]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:46]=3[S:45][C:41]2=[N:42][C:43]=1[CH3:44])[C:34]([O:36][CH3:37])=[O:35])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:28]([O:32][C@@H:33]([C:38]1[C:39]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:18])=[CH:8][CH:7]=2)=[C:40]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:46]=3[S:45][C:41]2=[N:42][C:43]=1[CH3:44])[C:34]([O:36][CH3:37])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: CC1(C)OB(c2ccc(C(F)F)cc2)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)F)cc1)CCCC3
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
2-(4-(Difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.04 g, 4.09 mmol), potassium phosphate (1.35 g, 6.36 mmol), water (750 μL) and dichloro [1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II)™ (101 mg, 155 μmol) were added to a stirred solution of (S)-methyl 2-(tert-butoxy)-2-(4-iodo-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (750 mg, 1.58 mmol) in dioxane (11 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, sealed and then stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (30 mL) and then passed through a pad of celite. The layers of the filtrate were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography eluting with ethyl acetate in heptane (10%) to give the title compound (639 mg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=0.96 (s, 9H), 1.85-1.35 (m, 6H), 2.72 (s, 3H), 2.85-2.75 (m, 2H), 3.67 (s, 3H), 4.95 (s, 1H), 6.76 (t, 1H), 6.45 (d, 1H), 7.61-7.51 (m, 3H). LCMS (run time=5 minutes, basic): Rt=3.37 minutes; m/z 474.23 [M+H+].
Reaction SMILES: CS(O)(=O)=O.[NH2:6][N:7]=[CH:8][NH:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[CH:23]([OH:24])[CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11].[CH3:25]S(O)(=O)=O>CO>[NH2:6][N:7]=[CH:8][NH:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[CH:23]([O:24][CH3:25])[CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11]
Reactant: NN=CNC(=O)c1[nH]c2cccc3c2c1CCC3O
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC1CCc2c(C(=O)NC=NN)[nH]c3cccc1c23
Yield: 109.2 %

Procedure:
A mixture of the N-(aminoiminomethyl)-1,3,4,5-tetrahydro-5-hydroxy-benz[cd]indole-2-carboxamide methanesulfonate (0.13 g, 0.37 mmol) obtained in Example 7, methanesulfonic acid (0.036 g, 0.37 mmol) and methanol (20 ml) was heated under reflux for 2 hours. Subsequently, the reaction mixture was concentrated to a volume of about 5 ml under reduced pressure and a 5% aqueous sodium chloride solution was added to the residue. The resulting mixture was made basic with 28% aqueous ammonia and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=96/4) to obtain N-(aminoiminomethyl)-1,3,4,5-tetrahydro-5-methoxy-benz[cd]indole -2-carboxamide (0.11 g). This compound (0.11 g) was treated with a solution of methanesulfonic acid (0.05 g) in tetrahydrofuran (2.5 ml) to obtain N-(aminoimino-methyl)-1,3,4,5-tetrahydro-5-methoxy-benz[cd]indole-2-carboxamide methanesulfonate (0.08 g).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:45])[C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:26]=[C:25]([Cl:24])[C:32]([O:33][C:34]3[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=3)=[C:31]([Cl:45])[CH:30]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3,5-dichloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[C:17]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:16]([O:28][CH3:29])=[CH:15][C:14]=2[N+:30]([O-])=O)[CH:3]=1.O[Li].O.C(N(CC)CC)C.O.O.Cl[Sn]Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:7])[NH:30][C:14]3[CH:15]=[C:16]([O:28][CH3:29])[C:17]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[CH:18][C:13]=3[NH:12][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1cc(OCOCC[Si](C)(C)C)c(OC)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl[Sn]Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)Nc1cc(Cl)ccc1C(=O)N2
Temperature: 65 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of Example 476F (11.4 g, 23.6 mmol), LiOH.H2O (2.97 g, 70.8 mmol), methanol (200 mL), THF (100 mL) and water (10 mL) was heated at 65° C. for 4.25 hours. When hydrolysis was complete, triethylamine (65.8 mL, 472 mmol) was added, followed by SnCl2.2H2O (26.6 g, 118 mmol). The mixture was heated at 65° C. overnight, then cooled to room temperature when hydrogenation was complete. DMF (200 mL), triethylamine (16.5 mL, 118 mmol) and HATU (17.95 g, 47.2 mmol) were added and the mixture was stirred overnight, filtered through diatomaceous earth (Celite®), concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. Hexane was added to a solution of the concentrate in diethyl ether to invoke formation of a solid which was filtered, rinsed with hexane, and dried under vacuum to give 8.8 g (89%) of the desired product. MS (ESI) m/e 421 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.69 (s, 1H), 7.81 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.91 (dd, J=2.0, 8.5 Hz, 1H), 6.76 (s, 1H), 6.65 (s, 1H), 5.11 (s, 2H), 3.67 (s, 3H), 3.65-3.72 (m, 2H), 0.86-0.94 (m, 2H), -0.03 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH2:34])[CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH:34][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=1)=[O:22])[CH3:33]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: C[C@@H](N)c1cnn(C)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnn(C)c3Cl)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), (R)-1-(5-chloro-1-methyl-1H-pyrazol-4-yl)ethanamine hydrochloride (24 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light yellow solid.