Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:15]>>[NH2:15][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Clc1cc(-c2ccncc2)ccn1
Agent: [OH-]
Product: Nc1cc(-c2ccncc2)ccn1
Temperature: 180 °C

Procedure:
The mixture of 2-chloro-4,4′-bipyridine (2.40 g, 12.59 mmol) and concentrated ammonium hydroxide (100 mL) in a steel bomb was heated to 180° C. for 36 h. The volatiles were then removed in vacuo to give 2-amino-4,4′-bipyridine as a solid. 1H NMR (CDCl3) δ 8.71 (m, 2H), 8.18 (d, 1H, J=5.3), 7.48 (m, 2H), 6.8 (m, 1H), 6.72 (s, 1H). LRMS m/z (M+H) Calcd: 172.2, found: 172.2.
Reaction SMILES: N[C@@H](C(N)=O)CC(C)C.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])(O)=O.[Na+].CO.C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)C[C@@H](N)C(N)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2cc(CO)ccc21
Reaction time: 2 h
Yield: 13.1 %

Procedure:
D-Leucinamide (1.0 g, 6.0 mmol), 1-(t-butyloxycarbonyl)-5-formylindole (Example 1, 1.23 g, 5.0 mmol) and DCE (15 mL) were mixed at room temperature. Sodium triacetoxyborohydride (1.48 g, 7.0 mmol) was added in one portion with vigorous stirring. After 2 h, another portion (0.15 g, 0.7 mmol) was added and stirring was continued for an additional 6 h. The reaction mixture was diluted with a saturated NaHCO3 solution (10 mL). Three extractions with EtOAc, washing the combined organic layers with brine, drying over Na2SO4 and filtration provided a solution. Removal of solvent in vacuo afforded an oil. Column chromatography (DCM:MeOH:95:5) provided three fractions, after removal of solvent in vacuo: (1) 1-(t-Butyloxycarbonyl)-5-hydroxymethylindole (162 mg, 11% yield, Rf=0.5): 1H NMR (CDCl3, 300 MHz): 8.11 (d, 1H, J=8), 7.61 (d, 1H, J=2), 7.54 (s, 1H), 7.31 (dd, 1H, J=8,2), 6.55 (d, 1H, J=3), 4.75 (s, 2H), 1.69 (s, 9H); (2) 2R-bis-(1-t-butyloxycarbonylindol-5-ylmethyl)amino-4-methylpentanamide BMS594447 (382 mg, 12% yield, Rf=0.4): 1H NMR (CDCl3, 300 MHz): 8.1 (d, 2H, J=8), 7.61 (d, 2H, J=2), 7.52 (s, 2H), 7.31 (dd, 2H, J=8,2), 6.62 (m, 1H), 6.56 (d, 2H, J=4), 6.05 (br s, 1H), 3.85 (d, 2H, J=16), 3.66 (d, 2H, J=16), 3.35 (m, 1H), 1.69 (s, 18H), 0.96 (d, 3H, J=7), 0.87 (d, 3H, J=7); MS (ES+): 589.4 (C35H45N3O5) and (3) the title product (986 mg, 55% yield, Rf=0.3): 1H NMR (CDCl3, 300 MHz): 8.10 (d, 1H, J=8), 7.61 (d, 1H, J=2), 7.49 (d, 1H, J=1), 7.28–7.20 (m, 3H), 6.55 (d, 1H, J=4), 3.93 (d, 1H, J=16), 3.77 (d, 1H, J=16), 3.28–3.20 (m, 1H), 1.69 (s, 9H), 0.94 (d, 3H, J=7), 0.85 (d, 3H, J=7); MS (ES+): 360 (C20H30N3O3, M++H).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:40])=[C:24]([NH:28][CH2:29][C:30]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:31]=4[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[F:39][C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][N:28]([C:24]3[C:23]([CH3:40])=[C:22]([C:7]4[C:8]5[C:16]6[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=6)[NH:10][C:9]=5[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=4)[CH:27]=[CH:26][CH:25]=3)[C:32]2=[O:34])=[CH:38][CH:37]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(F)cc4C(=O)O)c3C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N4Cc5ccc(F)cc5C4=O)c3C)c12
Temperature: 45 °C
Yield: 51 %

Procedure:
A mixture of 2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-fluorobenzoic acid, TFA (31.6 mg, 0.048 mmol), N,N-diisopropylamine (0.013 mL, 0.072 mmol), BOP (27.7 mg, 0.063 mmol), and N-methylmorpholine (0.021 mL, 0.188 mmol) in DMF (4 mL) was heated at 45° C. for 1 hr. The mixture was diluted with ethyl acetate (60 mL), washed sequentially with water (3×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (13.3 mg, 0.025 mmol, 51.0% yield) as a yellow solid. LCMS (M+H)+=525.09. 1H NMR (500 MHz, DMSO-d6) δ: 11.72 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.82-7.79 (m, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.63-7.58 (m, 2H), 7.50 (d, J=6.9 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 6.76 (dd, J1=8.9 Hz, J2=2.2 Hz, 1H), 5.08 (d, J=17.2 Hz, 1H), 4.98 (d, J=17.2 Hz, 1H), 4.21 (m, 2H), 3.77 (m, 2H), 3.40 (s, 3H), 1.92 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 583.4 [(M+H+]; mp 184° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])=[CH2:2].Cl.[NH2:32][OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1)=[NH:29]
Reactant: C=C(C)n1c(=O)n(Cc2nc3cc(C#N)ccc3n2CCC(C)C)c2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(C)n1c(=O)n(Cc2nc3cc(C(=N)NO)ccc3n2CCC(C)C)c2ccccc21
Yield: 26.1 %

Procedure:
2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (110 mg, 0.275 mmol) was treated with hydroxylaminehydrochloride (57 mg, 0.275 mmol), K2CO3 (55.3 mg, 0.4 mmol) and heated to reflux in EtOH(10 ml) for 6 h. The solvent was removed and the residue dissolved in CH2Cl2 and washed with H2O. The solvent was removed to give 31 mg (26%) of N-hydroxy-2-(3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine as a white solid.
Reaction SMILES: [BH4-].[Na+].O.C([O:6][C:7]([C:9]1([NH:13][C:14]([C:16]2[C:17]3[CH2:18][C@H:19]4[CH2:30][C@H:20]4[C:21]=3[N:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:23]=2)=[O:15])[CH2:12][CH2:11][CH2:10]1)=O)C>O1CCOCC1>[OH:6][CH2:7][C:9]1([NH:13][C:14]([C:16]2[C:17]3[CH2:18][C@H:19]4[CH2:30][C@H:20]4[C:21]=3[N:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:23]=2)=[O:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(NC(=O)c2nn(-c3cnccn3)c3c2C[C@H]2C[C@@H]32)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(CO)CCC1)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a solution of sodium borohydride (0.206 g, 5.44 mmol) in dioxane (2.0 mL) with water (1.0 mL) was added 1-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-cyclobutanecarboxylic acid ethyl ester (1.0 g, 2.72 mmol) at 0° C. The mixture was stirred at room temperature until the starting materials were consumed. The mixture was concentrated and added 2 M HCl was added to adjust pH to 3. The isolated precipitate was dissolved in DCM and purified by silica gel column chromatography to give the title compound (0.5 g) as a solid. LCMS m/z=326.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (dd, J=8.0 and 4.7 Hz, 1H), 1.26 (td, J=7.8 and 4.9 Hz, 1H), 1.85-2.26 (m, 2H), 2.21-2.40 (m, 5H), 2.73-2.78 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6 and 6.3 Hz, 1H), 3.90 (s, 2H), 7.21 (bs, NH, 1H), 8.42 (dd, J=2.3 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: ClCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCN2CCNCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 1-(3-chloropropyl)piperazine (179 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (20% methanol/chloroform) to give the subject compound (10 mg, yield 5%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][C:25](=[O:27])[C:24]4([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[N:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O>CN(C)C=O>[N:9]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:23][C:24]3([C:25]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])=[CH:20][CH:21]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C1OC(c2ccc(CN3CCOCC3)cc2)=NC12CCCCC2
Reactant: CSCC[C@H](N)CO
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
43 mg (0.32 mmol) of L-methioninol was added to a solution of 100 mg (0.29 mmol) of 2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added thereto and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to give 65 mg (49%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[O:14][CH3:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:15][O:14][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:2]=1[O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)/C=C/c1ccc(OCCCCCCO)c(OC)c1

Procedure:
A mixture of 0.5 g of methyl (E)-4-hydroxy-3-methoxycinnamate, 10 ml of 2-butanone, 0.35 ml of 6-bromohexanol and 1 g of ground potassium carbonate was heated under reflux for 5 hrs. Then, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate, filtered and evaporated. Chromatography on 100 g of silica gel with toluene/ethyl acetate (1:1) gave 750 ml of methyl (E)-3-[3-methoxy-4-(6-hydroxyhexyloxy)phenyl]acrylate as a colorless solid, λmax. (CH2Cl2): 323 nm (ε=20513).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:11]=[C:10]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2,4-difluoro-5-nitrobenzoate (35 g, 161.20 mmol) in N,N-dimethylformamide (1000 ml) was added DIEA (41.3 g, 319.56 mmol). Then (4-methoxybenzylamine (28.72 g, 209.64 mmol) was added dropwise with stirring for 1 hour at 25° C. The reaction mixture was diluted with water (2 L). The solids were collected by filtration to afford methyl 2-fluoro-4-(4-methoxybenzylamino)-5-nitrobenzoate as a yellow solid (44 g, 82%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][C:16]4([CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCOC(C)=O>C(Cl)Cl.CCCCCCC>[O:24]=[C:15]1[C:16]2([CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:17][CH2:18][N:14]1[C:11]1[CH:10]=[CH:9][C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([O:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N(c2ccc([C@H]3CC[C@@H](O)CC3)cc2)CCC12CCOCC2
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of cis-2-[4-(4-hydroxy-cyclohexyl)-phenyl]-8-oxa-2-aza-spiro[4.5]decan-1-one (Intermediate 20) (280 mg. 0.85 mmol) in DCM (5 mL) was added Et3N (20.2 mL, 1.7 mmol, 2 equiv.). The solution was cooled to an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (146 mg, 1.2 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred with the ice-water bath on all the time for 1 h. TLC (50% EtOAc in heptane) indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed successively with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM to afford 300 mg (87%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]C)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17].C(OCC)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[NH:17][N:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Oc1cc(-c2ccc(F)cc2)n[nH]1

Procedure:
A mixture of methyl 3-(4-fluorophenyl)-3-oxopropanoate (10.0 g, 0.051 mol) and hydrazine hydrate (1.1 eq, 2.8 g, 0.056 mol) in 20 mL glacial acetic acid is heated 3 h under reflux. The resulting suspension is cooled down and 10 mL diethyl ether is added. The precipitate is filtered off, dried in vacuo and 9 g (100%) of 3-(4-fluorophenyl)-1H-pyrazol-5-ol are obtained as white solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:16]=[CH:15][C:12](C#N)=[C:11]([F:17])[CH:10]=1)(C(C)(C)C)(C)C.C1([Mg]Br)CC1.[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1.O.Cl>C1COCC1>[CH:23]1([C:27]([C:12]2[CH:15]=[CH:16][C:9]([OH:8])=[CH:10][C:11]=2[F:17])=[O:26])[CH2:24][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)c(F)c1
Reactant: C1CCOC1
Agent: Br[Mg]C1CC1
Agent: Cl
Solvent: O
Product: O=C(c1ccc(O)cc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon atmosphere, 4-(tert-butyldimethylsilyloxy)-2-fluorobenzonitrile (10.00 g), which can be prepared according to the method described in Reference example 1, etc., was dissolved in dehydrated THF (30 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0° C., 1 mol/L-cyclopropylmagnesium bromide-THF solution (80 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added dropwise thereto. Upon the completion of the dropwise addition, the reaction solution was stirred for 10 minutes at 0° C., and stirred for 1.5 hours at reflux. The reaction solution was cooled to 0° C., added with water (50 mL) and 5 mol/L hydrochloric acid (50 mL), and stirred at reflux overnight. After cooling to the room temperature, the reaction solution was extracted three times with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was dissolved in dehydrated THF (100 mL; manufactured by Kanto Chemical Co., Inc.), added with 1 mol/L-TBAF-THF solution (31.5 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred for 20 minutes at room temperature. To the reaction solution, water and brine were added and extraction was carried out three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. N-hexane was added to the residue and the insoluble matters were suspended by ultrasonication. The insoluble matters were filtered to obtain the target compound as a crude product (6.5156 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Product: CCCCOC(=O)c1nc(-c2cnccn2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 4-bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and 2-(tributylstannyl)pyrazine: MS (m/z) 345.2 (M+1)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4].CNC(C1C2C=C3C(C)=CCCN(S(C)(=O)=O)C3=NC=2OC=1C1C=CC(F)=CC=1)=O.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[CH:14]([CH3:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: C=C1CCCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: [Pd+2]
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)=CCCN3S(C)(=O)=O
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)CCCN3S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The mixture of 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methylene-6,7,8,9-tetrahydro-5H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide and 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methyl-8,9-dihydro-7H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide (15 mg), Pd(OH)2 (20% on carbon, 4.9 mg), MeOH (0.56 ml) and EtOAc (0.14 ml) was stirred under hydrogen for 1.5 h at rt. The mixture was filtered through a 0.2 μM PTFE syringe filter and concentrated to give the title compound as an off-white solid. MS (ESI) m/z 432.3 (M+1). Retention time=1.23 min (Method A). 1H-NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.94-7.86 (m, 2H), 7.31-7.23 (m, 2H), 5.88 (br, 1H), 3.51 (s, 3H), 3.39-3.31 (m, 1H), 2.10-1.62 (m, 6H), 1.49 (d, 3H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Yield: 52 %

Procedure:
5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and 3-methanesulfonyl phenyl boronic acid (3.08 g, 15.0 mmol), in a manner analogous to Step 73c. The residue was purified on a 80 g Isco silica gel column using a gradient of 0-20% methanol in dichloromethane as an eluent. 5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.10 g, 52%) was isolated as a beige powder. MP=181-182° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.45 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.82 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.55 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.09 (s, 2H), 3.30 (s, 3H). MS=289 (MH)+. 78b) [5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (137 mg, 0.475 mmol) and 4-(4-bromo-phenyl)-morpholine (138 mg, 0.57 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine (53.8 mg, 24%) as a yellow powder following purification on a 40 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=163° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.38 (s, 1H), 8.76 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.88 (t, J=15.5 Hz, 8.5 Hz, 1H), 7.67 (m, 1H), 7.57 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 6.88 (d, J=8.50 Hz, 2H), 3.73 (m, 4H), 3.33 (s, 3H), 2.99 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH3:32])[C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(C)C(C)=O
Yield: 17.3 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}acetamide (72.0 mg, 0.159 mmol) in N,N-dimethylformamide (1.6 mL) was added sodium hydride (60%, 7.6 mg, 0.19 mmol). After the resultant mixture was stirred at room temperature for 30 min, methyl iodide (0.0119 mL, 0.191 mmol) was added, and the resultant mixture wad stirred at 60° C. for 2 hr. After sodium hydride (60%, 7.6 mg, 0.19 mmol) and methyl iodide (0.0119 mL, 0.191 mmol) were added again, the resultant mixture was stirred at 60° C. for 2 hr, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (12.8 mg, 0.0275 mmol, 17%).