Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:29]1[CH:43]=[CH:42][C:32]2[C:33]3[CH2:34][N:35]([CH3:41])[C:36](=[O:40])[C:37]=3[CH:38]=[CH:39][C:31]=2[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[CH2:3][CH3:4].C1COCC1>C(O)=O>[OH:1][C:2]([C:29]1[CH:43]=[CH:42][C:32]2[C:33]3[CH2:34][N:35]([CH3:41])[C:36](=[O:40])[C:37]=3[CH:38]=[CH:39][C:31]=2[CH:30]=1)([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
7-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (100 mg) was dissolved in 90% formic acid (1 mL) and THF (1 mL) and the mixture was stirred with heating at 60° C. for 30 min. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with a mixed solution of ethyl acetate-THF (1:1), dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound (48 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].O>O1CCCC1>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]2([O:26][CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 36 mg, 0.8 mmol) was added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (1.45 g, 4.50 mmol) and methyl vinyl sulfone (0.95 g, 8.9 mmol) in tetrahydrofuran (18 mL). The reaction mixture was stirred at room temperature for 1 hour and additional methyl vinyl sulfone (0.47 g) was added. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 1.2 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclopentyl}methyl)-1H-imidazo[4,5-c]quinoline as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:24][C:25]4[CH:31]=[C:30]([C:32]([O-:34])=O)[CH:29]=[CH:28][C:26]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:7]2[NH:6][C:5]3[CH:9]=[CH:10][C:2]([NH:1][C:32]([C:30]4[CH:29]=[CH:28][C:26]5[N:27]=[C:23]([C:20]6[CH:19]=[CH:18][C:17]([N:14]7[CH2:15][CH2:16][O:11][CH2:12][CH2:13]7)=[CH:22][CH:21]=6)[NH:24][C:25]=5[CH:31]=4)=[O:34])=[CH:3][C:4]=3[N:8]=2)=[CH:18][CH:19]=1)#[N:24]
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: Nc1ccc2nc[nH]c2c1
Product: N#Cc1ccc(-c2nc3cc(NC(=O)c4ccc5nc(-c6ccc(N7CCOCC7)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 298 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyano)phenyl)-5-aminobenzimidazole and 2-(4-morpholinophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O2: 540.21; found: 539.97.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N+:13]2[O-])=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccc(NC)nc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a −70° C. solution of 7-(ethoxycarbonyl)quinoline 1-oxide (1.67 g, 7.70 mmol) in dichloromethane (80 mL) was added trifluoromethanesulfonic anhydride (1.43 mL, 8.47 mmol) dropwise, under a nitrogen atmosphere. The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (21 mL, 42 mmol, 2.0 M) was added dropwise at −70° C. The mixture was stirred for 5 minutes and then the reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (720 mg, 41%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.42 (s, 1 H), 7.84-7.82 (m, 2 H), 7.63-7.61 (m, 1 H), 6.72-6.70 (m, 1 H), 4.92 (br. s., 1 H), 4.44-4.38 (m, 2 H), 3.12-3.11 (m, 3 H), 1.44-1.40 (m, 3 H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:3]1.[Cl-].[OH:31][NH3+:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:31][NH:32][C:26](=[NH:27])[C:25]1[CH:28]=[CH:29][C:22]([N:4]2[CH2:5][CH2:6][N:7]([C:8]3[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)[N:13]=3)[C@H:2]([CH3:1])[CH2:3]2)=[CH:23][CH:24]=1
Reactant: [NH3+]O
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.50 mg, 3.87 mmol) in ethanol (8.0 ml) and water (4.0 ml) was added hydroxylammonium chloride (807 mg, 11.6 mmol) and sodium carbonate (2.05 g, 19.4 mmol), and the reaction mixture was stirred for 2 hours under reflux. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was used for next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:18][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([F:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-fluorobenzonitrile (15.6 g, 100 mmol) was dissolved in triflic acid (75 mL) at 0° C., then NBS (17.8 g, 100 mmol) was added. The reaction was warmed up to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with DCM (2×). DCM layers were washed with NaHCO3 and brine. The DCM was dried over Na2SO4 then filtered and concentrated. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10-20% ethyl acetate/hexane solvent system to yield 3-bromo-2-chloro-6-fluorobenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=[O:14]>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cnc2ccccc2c1
Agent: O=[Pt]
Product: COc1cnc2c(c1)CCCC2O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 3-methoxyquinoline (1.06 g, 6.7 mmol) in TFA (22 mL) under nitrogen was added platinum oxide (225 mg, 1.3 mmol) and the suspension bubbled with hydrogen gas 16 h at 60° C. The mixture was then cooled to room temperature, neutralized to pH 12 with 10 N NaOH and extracted with CH2Cl2 (3×50 mL). The organic extracts were dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:2) to give the desired 3-methoxy-5,6,7,8-tetrahydroquinoline (0.95 g, 87%). 1H NMR (CDCl3) δ1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J=6.0 Hz), 2.85 (t, 2H, J=6.0 Hz), 3.81 (s, 3H), 6.88 (d, 1H, J=1.5 Hz), 8.07 (d, 1H, J=1.5 Hz).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[N:11](CC3C=CC(OC)=CC=3)[C:10](=[O:21])[O:9][C:8]([CH2:26][NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)([C:22]([F:25])([F:24])[F:23])[C:7]=2[CH:37]=1)#N.Br.[C:39]([OH:42])(=[O:41])C>O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:27][CH2:26][C:8]2([C:22]([F:25])([F:24])[F:23])[C:7]3[CH:37]=[C:3]([C:39]([OH:42])=[O:41])[CH:4]=[CH:5][C:6]=3[NH:11][C:10](=[O:21])[O:9]2)=[O:36])=[CH:34][CH:33]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(C#N)ccc32)cc1
Agent: Br
Solvent: O
Product: O=C1Nc2ccc(C(=O)O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{[6-cyano-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide was dissolved in 25% hydrogen bromide-acetic acid (5 mL) and water (1 mL), and the solution was stirred overnight at 100° C. The temperature of the solution was brought to room temperature, and water was added thereto under stirring. After the solution was stirred at room temperature for 30 minutes, the resulting brown solid was dried under reduced pressure, whereby the objective compound (317 mg, 55%) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5 g, 14.9 mmol) in THF (20 ml), 2 M solution of i-PrMgCl in THF (22.4 ml, 44.9 mmol) was added at −40° C. under nitrogen atmosphere. The resulting mixture was allowed to stir for 10 min at −40° C. and cooled to −78° C. The reaction mixture was treated with DMF (7.29 ml, 89.8 mmol) and slowly warmed to RT. The mixture was stirred for 1 h at RT and quenched with saturated aqueous solution of NaHCO3. The crude was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Yield 3 g. LC-MS: [M+1]=285.15.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([N:40]6[CH:44]=[CH:43][N:42]=[CH:41]6)[CH:38]=5)[C:33]([CH3:45])=[CH:32][C:31]4=[O:46])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:47].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:47].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([N:40]6[CH:44]=[CH:43][N:42]=[CH:41]6)[CH:38]=5)[C:33]([CH3:45])=[CH:32][C:31]4=[O:46])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(-n3ccnc3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(-n3ccnc3)ccc12
Reaction time: 2 h

Procedure:
To 0.5 mL of methanol solution containing 45 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 2 hours. Ethyl acetate was added, and the resulting solid was filtered to give 32 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCC(O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OCC(O)CNc1cccc(Br)n1
Yield: 30.2 %

Procedure:
A stirred solution of 2,6-dibromopyridine (0.76 g, 3.20 mmol), 1-amino-2,3-dihydroxypropane (0.29 g, 3.20 mmol) and DIPEA (0.56 mL, 3.24 mmol) in toluene (3.2 mL) was heated to 160° C. under microwave irradiation in a sealed tube for 2 h, and then concentrated in vacuo. Water (5 mL) was added, the mixture sonicated for 10 minutes, and then filtered through Celite®. The filtrate was concentrated in vacuo to yield the title compound (0.239 g, 30%) as a white solid that was used without further purification. δH (DMSO-d6) 7.29-7.18 (1H, m), 6.92-6.79 (1H, m), 6.61 (1H, d, J 7.3 Hz), 6.51 (1H, d, J 8.3 Hz), 4.79 (1H, d, J 4.9 Hz), 4.58 (1H, t, J 5.8 Hz), 3.65-3.54 (1H, m), 3.15-3.04 (1H, m). Exchangeable protons were not observed. LCMS (ES+) 247.0 and 249.0 (1:1 ratio) (M+H)+, RT 2.07 minutes (Method 1).
Reaction SMILES: Br[CH2:2][CH:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Ba+2]>C(O)C>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:9]2[CH:3]([CH2:2][O:21][CH2:20][CH2:19][Cl:18])[O:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: COc1cc2c(cc1OC)C(CBr)OCCC2
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(COCCCl)OCCC2
Reaction time: 46 h

Procedure:
A mixture of 10.33 g (0.343 moles) of 1-bromomethyl-1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin, 10 ml of 2-chloroethanol, and 6.77 g of barium carbonate is stirred at 90° for 46 hours. The reaction mixture is then cooled, ethanol is added, and the solids are removed by filtration. The filtrate is taken to dryness in vacuo and the resulting oil is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is then taken to dryness and chromatographed on silica gel using 10 ethylacetate:Skellysolve B as eluent to give 4.18 g (41d) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl chloride, m.p. 90°-91°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][CH:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH3:43])[CH2:30][CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.3 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.12 g, 94%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1>CC(C)=O.O=[Mn]=O>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: Cn1cnc2cc(CO)ccc21
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: Cn1cnc2cc(C=O)ccc21
Reaction time: 72 h
Yield: 98.3 %

Procedure:
A solution of 5-hydroxymethyl-1-methylbenzimidazole (0.8 g, 4 mmol) in acetone (40 mL) was treated with MnO2 (4 g) and the mixture was stirred for 3 days. The solid was filtered off and the solvent removed under reduced pressure to give 0.63 g of product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([Cl:12])=[N:10][C:9]([CH3:13])=[N:8][C:7]=1[NH:19][C:18]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(Cl)nc(C)nc1Nc1c(C)cc(C)cc1C
Yield: 52.1 %

Procedure:
A mixture of (2-methyl-4,6-dichloro-pyrimidine-5-yl)-acetic acid ethyl ester (1.470 g, 5.9 mmol) and 2,4,6-trimethylaniline (2.56 ml, 17.7 mmol), in 15 ml of dimethylsulfoxide was heated at 120° C. overnight and 138° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a brown oil. The oil was purified through silica gel column chromatography to give 1.070 g (52%) of the title compound as a tan solid. 1H NMR (CDCl3) δ 1.30 (t, 3H), 2.14 (s, 6H), 2.32 (s, 3H), 2.37 (s, 3H), 3.79 (s, 2H), 4.23 (q, 2H), 7.00 (s, 2H), 7.02 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10](I)[C:3]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:3]=12
Reactant: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: C=CC(=O)N(C)c1cccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) phenyl)-N-methylacrylamide (50) (147 mg, 0.35 mmol) and 4-chlorophenylboronic acid (66 mg, 0.42 mmol) in DME/H2O (4 mL/1 mL) were added Pd(dppf)Cl2(14 mg, 0.018 mmol) and K3PO4.3H2O (280 mg, 1.05 mmol). The resulting mixture was purged with N2 (3×) and stirred at 80° C. overnight. Solvents were removed in vacuo. The residue was pre-purified by flash chromatography (silica gel, 0 to 10% MeOH in DCM with 0.3% TEA) and followed by prep HPLC to provide N-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (51) (39 mg, 28%) as a white solid. LC-MS (ESI): m/z (M+1) 405.1. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.62 (m, 3H), 7.28 (m, 1H), 6.17 (m, 2H), 5.59 (m, 1H), 3.30 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([Br:22])[C:19]([Cl:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:22][C:20]1[C:19]([Cl:23])=[CH:18][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]3[N:6]([C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=3)[C:7]=2[CH:21]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc2c(cc1Br)-n1c(Br)nnc1CN=C2c1ccccn1
Product: CN1CCN(c2nnc3n2-c2cc(Br)c(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,9-dibromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 9-bromo-8-chloro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[CH:22]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(C)cccc23)cc1
Yield: 40.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.057 g) as a white solid.