Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([Cl:37])[CH:31]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].CCOCC>C(Cl)Cl.CN(C=O)C>[C:17]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:32]([Cl:37])[CH:31]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:19])[CH3:18]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(N)c(Cl)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
Oxalyl chloride (0.047 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.077 g) in DCM (2.5 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 2 hours and was then added to a solution of 4-(4-acetamidophenylsulphonyl)-2-chloroaniline (Method 10) (0.160 g) in DCM (2.5 ml) and stirred a further 2 hours. Ether (50 ml) was added and the mixture was washed with water (2×50 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-70% ethyl acetate/toluene to give the title compound (0.025 g) as a solid. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.1-7.3 (brm, 1H), 7.8 (d, 2H), 7.9 (m, 3H), 7.97-8.05 (brs, 2H), 8.25 (d, 1H), 10.36 (brs, 1H); MS (ESP−): 463; EA: found: C, 47.8; H, 3.6; N, 5.4%; C18H16ClF3N2O5S.0.2 C7H8 requires: C, 48.2; H, 3.7; N, 5.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C1C=CC=CC=1.[Ag]=O>[CH3:23][O:22][C:20]([CH2:19][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:21]
Reactant: O=C(OCc1ccccc1)C1CCCCNC1
Reactant: COC(=O)CBr
Agent: O=[Ag]
Solvent: c1ccccc1
Product: COC(=O)CN1CCCCC(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 1.46 g 3-benzyloxycarbonylperhydroazepine and 1.06 g methyl bromoacetate in 30 ml benzene add 1.06 g silver oxide. Stir the reaction in the dark for 24 hr., filter and concentrate the filtrate in vacuo. Dissolve the residue in HCl (pH 1.5) and wash the solution with ether. Make the aqueous phase to pH 12 and extract with ethyl acetate. Dry and concentrate the extracts to obtain 1-methoxycarbonylmethyl-3-benzyloxycarbonylperhydroazepine.
Reaction SMILES: CS(C)=O.[N+]([C:8]1[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=1)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophene carbonitrile (5.00 g, 32.4 mmol) were added 4-fluorophenol (5.45 g, 48.6 mmol) and potassium carbonate (11.2 g, 81.0 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 60° C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:10→1:5) to obtain the title compound (6.10 g, 85.9%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32](=[O:35])[CH:33]=[CH2:34])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:27]([O:31][C:32](=[O:35])[CH2:33][CH2:34][O:20][CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[CH:12]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CCOCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
0.2 g of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propan-1-ol was suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran. 60 μl of acrylic acid-tert-butyl ester, 13 mg of tetrabutylammonium hydrogen sulfate, and 1.47 ml of 32% sodium hydroxide solution were added to it, and it was allowed to stir for 48 hours. Another 60 μl of acrylic acid-tert-butyl ester and 13 mg of tetrabutylammonium hydrogen sulfate were added, and the mixture was left for 48 hours in an ultrasound bath. Then, it was diluted with water and extracted three times with toluene. The combined organic phases were washed with water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [CH3:1][C:2]1[C@H:7]([OH:8])[CH2:6][C@:5]23[C@:28]4([CH3:35])[C:29]5([C@H:32]([O:34][C@@H:4]2[CH:3]=1)[CH2:33][C@H:27]4[O:26][C:24](=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]([CH:36]([OH:38])[CH3:37])[O:18][CH2:17][CH:16]([OH:39])[C:14]1([CH3:40])[O:15][CH:13]1[C:11](=[O:12])[O:10][CH2:9]3)[O:31][CH2:30]5>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C@H:7]([OH:8])[CH2:6][C:5]23[C@:28]4([CH3:35])[C@@:29]5([C@@H:32]([O:34][C@@H:4]2[CH:3]=1)[CH2:33][C@H:27]4[O:26][C:24](=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][C@H:19]([C@@H:36]([OH:38])[CH3:37])[O:18][CH2:17][C@H:16]([OH:39])[C@@:14]1([CH3:40])[O:15][C@@H:13]1[C:11](=[O:12])[O:10][CH2:9]3)[O:31][CH2:30]5
Reactant: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)C=CC=CC(C(C)O)OCC(O)C5(C)OC5C(=O)OC[C@@]2(C[C@H]1O)[C@]4(C)C31CO1
Agent: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)/C=C\C=C\C(C(C)O)OCC(O)C5(C)OC5C(=O)OC[C@@]2(C[C@H]1O)[C@]4(C)C31CO1
Agent: CC1=C[C@H]2O[C@H]3C[C@H]4OC(=O)/C=C\C=C\[C@H]([C@H](C)O)OC[C@H](O)[C@@]5(C)O[C@@H]5C(=O)OCC2(C[C@H]1O)[C@]4(C)[C@@]31CO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1=C[C@H]2O[C@H]3C[C@H]4OC(=O)C=CC=C[C@H]([C@H](C)O)OC[C@H](O)[C@@]5(C)O[C@@H]5C(=O)OCC2(C[C@H]1O)[C@]4(C)[C@@]31CO1

Procedure:
Preparative TLC of fraction CC on silica gel with 10% methanol in chloroform as eluent gave some baccharinol (B4) (Fraction DD) which was combined with Fraction BB as above, and a residue (Fraction EE) which was crystallized from methanol-chloroform-ether. Recrystallization from acetone-hexane gave isobaccharinol (B6, 0.20 g, 0.00037%): mp 249°-251° C.; [α]D24 +149° (c 0.66, MeOH); uv max (EtOH) λ (ε) 260 nm (20,400); ir (KBr) 3420, 1750, 1720, 1650, 1605 cm-1 ; NMR (CDCl3) ε 0.83 (3H, s, 14-H), 1.16 (3H, d, J=6 Hz, 14'-H), 1.65 (3H, s, 12'-H), 1.83 (3H, s, 16-H), 2.84, 3.13 (each 1H, d, J=4 Hz, 13-H), 3.38 (1H, s, 2'-H), 4.24, 4.46 (2H, ABq, J=12 Hz, 15-H), 5.52 (1H, d, J=5 Hz, 10-H), 5.8 (1H, m, 4-H), 5.81 (1H, d, J=11 Hz, 10'-H), 5.92 (1H, dd, J=15 and 3 Hz, 7'-H), 6.59 (1H, dd, J=11 and 11 Hz, 9'-H), 7.40 (1H, dd, J=15 and 11 Hz, 8'-H); mass spectrum (chemical ionization: methane reagent gas) m/e 563.2493 (M+ +H, calcd, for C29H39O11, 563.2492). Anal. Calcd for C29H38O11 :C, 61.91; H, 6.81. Found: C, 61.86; H, 6.85.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:31][NH:32][CH3:33]>CN1C(=O)CCC1.CO>[CH3:31][N:32]([CH3:33])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CNC
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
1-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-phenylurea A6 (50 mg, 0.12 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.60 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt the reaction is purified by preparative LCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34]Cl)=[N:26][C:27]=2[O:32][CH3:33].[CH3:36][NH:37][CH3:38].[I-].[Na+].[Cl-].[NH4+]>CC(O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34][N:37]([CH3:38])[CH3:36])=[N:26][C:27]=2[O:32][CH3:33]
Reactant: CNC
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CCl)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CC(C)O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN(C)C)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.34 g) and triphenyl-phosphine (0.43 g) in N,N-dimethylformamide (4 mL) was added carbon tetrachloride (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 10% aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/20) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.34 g). The mixture of the obtained 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (50 mg), dimethylamine (50% aqueous solution, 0.1 mL) and sodium iodide (14 mg) in 2-propanol (1 mL)-acetonitrile (1 mL) was stirred at 60° C. for 4 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=7/3). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (12 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-].[Na+].IC>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2-chloro-3-hydroxypyridine (25.4 g, 196 mmol) in dry DMF (250 mL), at 0° C., was added sodium methoxide (11.5 g, 213 mmol). After 5 min, the reaction mixture was allowed to warm to RT. After 1 hour, the mixture was cooled to 0° C. and iodomethane (24 mL, 386 mmol) was added. The reaction mixture was stirred at 0° C. for 5 minutes, before allowing to warm to RT. After 2 hours, the reaction mixture was concentrated under reduced pressure. The resultant residue was partitioned between diethyl ether and water. The aqueous phase was isolated and extracted twice with diethyl ether. The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (22.2 g, 79%) as an orange solid. LCMS (Method A): RT=2.76 min, [M+H]+=144/146.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.Cl>CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[S:34][CH:35]=[CH:36][N:37]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:41]3[CH2:42][CH2:43][C@@H:39]([F:38])[CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2
Reaction time: 2 h

Procedure:
A mixture of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (92 mg, 0.165 mmol) and (R)-3-fluoropyrrolidine.HCl (41.6 mg, 0.331 mmol) in N,N-dimethylformamide (2 mL) was stirred in a sealed vial at 40° C. for 1 hour, then at 55° C. for a further 2 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford ((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (17 mg). LCMS (Method F, ES-API): RT 2.39 min, m+H=609.2; 1H NMR (400 MHz, CDCl3): δ 8.46 (1H, d, J=2.6 Hz), 7.95 (1H, d, J=3.1 Hz), 7.64 (1H, dd, J=9.0, 2.4 Hz), 7.61 (1H, d, J=3.1 Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.3 Hz), 6.27 (1H, d, J=9.1 Hz), 5.48-5.35 (2H, m), 4.17 (1H, d, J=16.8 Hz), 3.92-3.59 (6H, m), 2.92-2.82 (2H, m), 2.77 (1H, d, J=12.3 Hz), 2.59-2.42 (3H, m).
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]2[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:7]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 3.4 %

Procedure:
To a solution of 9-(2-azido-2-(pyridin-4-yl)ethyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800 mg, 2.3 mmol) in ethanol-water (9 mL:1 mL) were added zinc dust (600 mg, 9.2 mmol) and ammonium chloride (490 mg, 9.2 mmol) and the reaction mixture stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyridin-4-yl)ethanamine (25 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (s, 2H), 7.62 (bs, 2H), 7.23 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.9 (m, 1H), 4.8-4.58 (m, 3H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.6-3.4 (m, 2H), 3.1 (bs, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:15]3[C:16]4[CH:22]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:20]=[N:19][C:17]=4[NH:18][C:14]=3[CH:13]=[N:12][C:11]=2[C:26]#[N:27])[CH2:5][CH2:4]1)[CH3:2]>[Pd].C(N(CC)CC)C>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[C:15]3[C:16]4[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[N:19][C:17]=4[NH:18][C:14]=3[CH:13]=[N:12][C:11]=2[C:26]#[N:27])[CH2:7][CH2:8]1)[CH3:2]
Reactant: C=C(C)c1cnc2[nH]c3cnc(C#N)c(OC4CCN(CC)CC4)c3c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncc(C(C)C)cc4c23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A suspension of 5-(1-ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (98 mg, 0.271 mmol), 10% palladium on carbon (50 mg) and triethylamine (0.5 mL) in IMS (5 mL) was stirred at ambient temperature under a hydrogen atmosphere for 18 h. The mixture was filtered through a PTFE filter and the filtrate concentrated in vacuo to give a brown solid. The resultant solid was purified by flash chromatography (silica, 12 g column, ISCO, 0-5% MeOH in DCM) to afford the title compound as a white solid (27 mg, 27%). 1H NMR (DMSO-Do, 300 MHz): 12.96 (s, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 5.11-4.77 (m, 1H), 3.65-3.48 (m, 2H), 3.28-3.18 (m, 2H), 3.14-2.90 (m, 3H), 2.42-2.18 (m, 4H), 1.37 (d, J=6.9 Hz, 6H), 1.29-1.17 (m, 3H). LCMS (Method H): RT=7.10 min, M+H+=364.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]([CH3:46])([C:44]#[CH:45])[CH3:43])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:45]#[C:44][C:42]([CH3:46])([N:39]3[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]3)[CH3:43])[S:17][C:10]=12
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CC(C)(C)N1CCN(C)CC1
Product: CN1CCN(C(C)(C)C#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 18.8 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (11.2 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.16) eluting with 10% MeOH/DCM. The compound was re-purified by preparative TLC (0.5 mm thickness, Rf=0.84) eluting with 15% MeOH (containing 7N NH3) in CHCl3, to obtain product of adequate purity. The product was obtained as a beige powder (4 mg, 18%). HPLC: 95% purity (220 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 629 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.40 (br s, 1H), 7.73 (m, 1H), 7.54 (s, 1H), 7.44 (m, 2H), 7.21 (m, 2H), 7.06 (t, J=9 Hz, 2H), 6.54 (d, J=5 Hz, 1H), 2.84 (m, 4H), 2.65 (m, 4H), 2.39 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H), 1.51 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: O=c1cnc2ncc(Br)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ncc(Br)cc21
Yield: 64.2 %

Procedure:
7-Bromopyrido[2,3-b]pyrazin-2(1H)-one (368 mg, 1.628 mmol) was suspended in dry DMF (10 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (741 mg, 5.372 mmol) and allyl iodide (331 μL, 3.581 mmol). It was then stirred for 2 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid which was purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a light brown solid (278 mg, 64%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)COB([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:30][CH:31]=2)OC1.C(OC(=O)NCC1C=CC(C2SC3C=C(C(=O)N)C=CC=3N=2)=CN=1)(C)(C)C>>[C:14]([O:13][C:12]([NH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[N:30][CH:31]=3)[S:3][C:4]=2[CH:10]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(Br)sc2c1
Reactant: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Agent: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(C(N)=O)cc3s2)cn1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(NC(=O)OC(C)(C)C)cc3s2)cn1
Yield: 80.3 %

Procedure:
tert-Butyl (2-bromo-1,3-benzothiazol-6-yl)carbamate (100 mg, 0.30 mmol) and tert-butyl [5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl]methylcarbamate (0.146 g, 0.46 mmol) were subjected to the procedure used for the preparation of tert-butyl[5-(6-carbamoyl-1,3-benzothiazol-2-yl)pyridin-2-yl]methylcarbamate. This gave the product (110 mg) as a white solid. MS m/z (M−H) 455.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)nc[nH]1

Procedure:
6-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-phenylbenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.36-2.39 (m, 4H), 3.43-3.48 (m, 6H), 5.32 (s, 1H), 7.25-7.40 (m, 8H), 7.80 (s, 1H), 12.20 (br s, 1H). Mass spectrum (ES) MH+=347.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: Cc1ncoc1CSCCN
Product: Cc1ncoc1CSCCNC(=S)NCCN(C)C

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 to give the title compound.