Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: -5 °C
Yield: 99 %

Procedure:
5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1-Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100% ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80° C. with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82° C. (+/−3° C.). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25° C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1×1 L), 50% ethanol (1×1 L), and 95% ethanol (1×1 L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99% yield) under vacuum at about 50° C. in a vacuum oven.
Reaction SMILES: [NH:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH3:18][N:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1
Reactant: O=c1c2[nH]cnc2nc2n1CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2nc3n(c(=O)c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60% sodium hydride was added to the suspension at 0° C. After 30 minutes, 0.433 ml (6.95 mmol) of iodomethane was added and the mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by filtration and recrystallized from isopropanoldiisopropyl ether to afford 0.700 g (54.3%) of Compound 25 as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25]O)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:27]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+].[N-:56]=[N+:57]=[N-:58].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[N:56]([CH2:25][C:7]1([C:21]([F:24])([F:23])[F:22])[C:6]2[CH:27]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](=[O:20])[O:8]1)=[N+:57]=[N-:58]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN2C(=O)OC(CO)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)OC(CN=[N+]=[N-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Reaction time: 1 h

Procedure:
6-Bromo-4-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (61.3 g, 0.137 mol) was dissolved in chloroform (400 mL) and 2,6-dimethylpyridine (48.0 mL, 0.412 mol), and while stirring the solution at 0° C., trifluoromethanesulfonic anhydride (46.4 mL, 0.275 mol) was added dropwise thereto. After the reaction solution was stirred for 1 hour under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added thereto. Then, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in DMF (270 mL), and sodium azide (26.7 g, 0.411 mol) was added thereto. After the reaction solution was stirred at 80° C. for 3 hours, the temperature of the solution was brought to room temperature and water was added thereto. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with an aqueous citric acid solution, water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/3) and further the resulting yellow solid was washed with hexane, whereby the objective compound (46 g, 71%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[C:20](=[NH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20](=[N:33][C:2]1[N:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(N=C(c3ccccc3)c3ccccc3)nc12
Temperature: 100 °C
Yield: 35.3 %

Procedure:
2-Bromo-7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (0.346 g, 1.01 mmol), benzhydrylideneamine (0.19 mL, 1.11 mmol), Cs2CO3 (658 mg, 2.02 mmol), Pd(OAc)2 (23 mg, 0.101 mmol) and BINAP (63 mg, 0.101 mmol) were dissolved in THF (10 mL) and heated at 100° C. for 63 hr, cooled to RT, partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 158 mg of benzhydrylidene-[7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine as a yellow liquid (20% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH2:16][CH2:17][N+:18]([O-:20])=O)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[O-].[Li+].[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[O:20][N:18]=1
Reactant: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1F
Reactant: C#Cc1cccnc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccn3)cc2F)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To a methanol (20.0 mL) solution of 2-(3-fluoro-4-(2-nitro-ethyl)-phenoxymethyl)pyridine (400 mg, 1.45 mmol) described in Manufacturing Example 95-1-3 was added lithium methoxide (110 mg, 2.90 mmol) under nitrogen atmosphere at room temperature, which was stirred for 30 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and anhydrous dichloromethane (20.0 mL) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (510 μL, 4.64 mmol) was added dropwise into the reaction mixture on a dry ice-ethanol bath (−78° C.), which was stirred for 60 minutes at room temperature. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (360 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (180 mg) and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 1 hour at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (25.2 mg, 19.7%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C#N)c2)CC1

Procedure:
tert-Butyl 4-(3-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.52 mmol) was combined with 20% Pd(OH)2/C (1 g) in 25 mL of methanol. This mixture was stirred under a hydrogen atmosphere using a hydrogen filled balloon for 5 h. The reaction mixture was filtered through a celite plug and the filtrate was concentrated. Purification by MPLC (silica, 38% ethyl acetate/hexanes) gave tert-butyl 4-(3-cyanophenyl)piperidine-1-carboxylate. ESI-MS calc. for C17H22N2O2: 286; Found: 309 (M+Na+).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:22](=[O:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
The mixture of 2-phenoxyaniline (100 g, 540 mmol), triethylamine (0.090 L, 648 mmol) and 1 L dichloromethane was cooled to 0° C. by ice bath. Acetyl chloride (0.04 L, 567 mmol) was added dropwise. After the addition completed, the reaction was stirred under room temperature for 2 h. The mixture was concentrated and diluted by dichloromethane. The organic phase was washed by water and dried over sodium sulfate. The crude product was purified by silica gel column (20% EtOAc in hexane) to give red brown oily solid N-(2-phenoxyphenyl)acetamide (120 g, 98% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@H:3]2[CH2:7][O:6][C:5](=[O:8])[NH:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1N[C@@H](CO)CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COC(=O)N2)cc1

Procedure:
To a stirred solution of Intermediate 98 (11.0 g, 94.0 mmol) in dichloromethane (250 mL), 4-dimethylamino pyridine (22.94 g, 188.0 mmol) and p-toluene sulfonylchloride (26.88 g, 141.0 mmol) were added at 0° C. and it was stirred for an hour before bringing to the room temperature, and the reaction was stirred for an hour. The reaction mixture was washed with 1.5N hydrochloric acid (50 mL), water (50 mL), saturated sodium bicarbonate (50 mL) and finally with brine. The organic layer was dried over sodium sulfate and the solvent was removed under vacuum. The crude product was then purified by flash column chromatography in silica gel using a gradient of ethyl acetate in pet. ether. 1H NMR (300 MHz, DMSO-d6) δ: 2.49 (s, 3H), 3.91-3.95 (m, 2H), 3.99-4.02 (m, 2H), 4.30 (t, 1H), 7.49 (d, 2H), 7.80 (d, 2H), 7.88 (s, 1H). Yield: 12.0 g (47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cc(F)ccc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.027 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.129 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 163-165° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].C1CCN2C(=NCCC2)CC1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCOCC1>[CH:17]1([NH:23][C:24]([NH:4][CH2:3][C:2]([CH3:1])=[CH2:5])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=C(C)CN
Reactant: O=C=NC1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)CNC(=O)NC1CCCCC1
Temperature: 60 °C
Yield: 86.7 %

Procedure:
A solution of 2-methylallylamine (0.156 g, 2.197 mmol) in dioxane (5 mL) was treated with DBU (0.030 mL, 0.200 mmol) and cyclohexyl isocyanate (0.25 g, 1.997 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-cyclohexyl-3-(2-methylallyl)urea (340 mg, 87%). 1H NMR (400 MHz, DMSO-d6): δ 5.80 (m, 1 H), 5.72 (d, J=8.0 Hz, 1 H), 4.72 (m, 1 H), 4.68 (m, 1 H), 3.50 (d, J=5.3 Hz, 2 H), 3.30 (m, 1 H), 1.70 (m, 2 H), 1.61 (s, 3 H), 1.60 (m, 1 H), 1.48 (m, 1 H), 1.27 (m, 2 H), 1.13 (m, 4 H); MS (ESI) m/z: 197.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:22]3[CH2:23][CH2:24][C:19]([OH:18])([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-hydroxy-4-phenylpiperidine. Yellow solid. MS (m/e): 395.1 ([M+H]+, 100%).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[S-:11][C:12]#[N:13].[K+].[I-].[Na+].O>CN(C)C=O>[CH:1]([CH:3]([N:13]=[C:12]=[S:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(N=C=S)c1ccccc1
Temperature: 150 °C

Procedure:
Vinylbenzyl isothiocyanate was prepared in the following manner. 76 g (0.5 moles) of vinylbenzyl chloride were dissolved in 300 ml of dimethylformamide (DMF). To this solution were added 56 g (0.575 moles) of potassium thiocyanate and 28 g (0.187 moles) of sodium iodide. The mixture was heated for 30 minutes at 150°C and then the major portion of DMF was flashed off with a water aspirator vacuum. The solid flask residue was extracted with 750 ml of diethyl ether. The filtered diethyl ether phase yielded 80 g of yellowish liquid. Vacuum distillation gave 30 g (35% yield) of pale yellow vinylbenzyl isothiocyanate liquid, ##SPC9##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=O.[BH3-]C#[N:26].[Na+]>CO>[NH2:26][CH:7]1[C:6]2[C:22](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cccc(Br)c12
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1cccc(Br)c12
Yield: 133.1 %

Procedure:
To a stirred solution of tert-butyl 7-bromo-3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (196 mg, 0.52 mmol) in MeOH (20 mL) were added NH4OAc (795 mg, 10.3 mmol) and NaCNBH3 (324 mg, 5.2 mmol). The mixture was heated at reflux for 1 d. The mixture was concentrated under reduced pressure, diluted with EtOAc (90 mL), washed with 1M aq NaOH (25 mL) and dried over Na2SO4. Removal of the solvent gave crude (±)-tert-butyl 3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (264 mg) which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CON(C)[C:28](=[O:31])[CH2:29][CH3:30].O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:28](=[O:31])[CH2:29][CH3:30])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)N(C)OC
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
6-Bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (1.33 g, 4.07 mmol) in THF (20.3 mL) was cooled to −78° C. under nitrogen and butyllithium (2.5 M in hexanes, 3.75 mL, 9.4 mmol) added. The reaction was stirred at this temperature for 30 minutes. To this was added N-methoxy-N-methyl-propionamide (0.71 g, 6.1 mmol) and the reaction was stirred for 1 h. Water and EtOAc were added and the organic layer separated, washed with brine (3×) and dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (0.823 g), MS: [M+H]+=305, as a 2:1 mixture with 3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Yield: 43.8 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (80.0 mg) obtained in Step C of Example 12, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (93.0 mg), tetrakis(triphenylphosphine)palladium(0) (25.3 mg) and 2M aqueous sodium carbonate solution (0.550 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (35.7 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH3:4].N1C(C)=CC=CC=1C.C(Cl)(=O)C(Cl)=O.[I:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=O.C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[I:20][C:21]1[CH:22]=[C:23]([C:24]2[N:2]([CH3:1])[C:3]([CH3:4])=[N:27][N:26]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: CNC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nnc(-c2cccc(I)c2)n1C
Reaction time: 0.67 h

Procedure:
N-Methylacetamide (0.087 mL, 1.14 mmol) and 2,6-lutidine (0.266 mL, 2.28 mL) were dissolved in dichloromethane (5.7 mL), and the mixture was stirred for 40 minutes after adding oxalyl chloride (0.100 mL, 1.14 mL) at 0° C. The mixture was stirred for 5 hours after adding 3-iodobenzohydrazide (300 mg, 1.14 mmol) obtained in Step 1 of Example 52, and then at 100° C. for 3 hours after adding a saturated aqueous sodium bicarbonate solution (5.7 mL). After cooling, water and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 3-(3-iodophenyl)-4,5-dimethyl-1,2,4-triazole as a crude purified product (250 mg). The resulting crude purified product (250 mg) of 3-(3-iodophenyl)-4,5-dimethyl-1,2,4-triazole, (S)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (376 mg, 1.50 mmol)) obtained in Reference Example 3, copper iodide(I) (142 mg, 0.750 mmol), and tripotassium phosphate (532 mg, 2.51 mmol) were dissolved in 1,4-dioxane (4.6 mL), and the mixture was stirred at 100° C. for 10 hours after adding ethylenediamine (0.10 mL, 1.50 mmol). Insolubles were filtered through sellite, and the residue was washed with chloroform. The filtrate was collected, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (74.2 mg, 15%).