Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A solution of 2.00 g (7.24 mmol) 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 40 mL of CH3CN was treated with solid 1.25 g (7.02 mmol) NBS and stirred at RT for 15 min. The solvents were evaporated in vacuo, the residue was taken up in EtOAc (70 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 10-25% EtOAc-hexanes afforded 3.12 g (97%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C12H16N2O2Br, 299.0 (M−C4H9+2H), found 299.1/301.1.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].[C:10]([O:20][CH3:21])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1(C)C=CC=CC=1.CO>[C:1]([CH:3]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][C:10]([O:20][CH3:21])=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: COC(=O)C=Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1ccccc1)C(C#N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 5 g of methyl cyanoacetate, 20 mL of methanol, and 20 mL of toluene was added 1.61 g of sodium hydride (55% oil-dispersion) under ice-cooling. After stirring at room temperature for 30 minutes, to the reaction mixture was added 3.24 mL of methyl cinnamate, followed by stirring at 66° C. for 15 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was then added thereto to adjust the pH of the solution to about 7. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5.19 g of dimethyl 2-cyano-3-phenylpentanedioate.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16].Cl.C([O-])([O-])=O.[Na+].[Na+].O>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16]
Reactant: CC1(C)OCC(CCOc2ncncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OCCC(O)CO
Reaction time: 4 h
Yield: 60.1 %

Procedure:
At room temperature (25° C.), to a solution of 5-amino-2-(2,6-difluorophenyl)-N-(4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)pyrimidin-5-yl)thiazole-4-carboxamide (38) (20 mg, 0.0419 mmol) in methanol (2 mL) was added concentrated HCl (0.5 mL) and the solution was stirred for 4 hours. 10% Na2CO3 solution was added to neutralize the solution to pH=7, the water (20 mL) was added and a precipitate was formed. An off white solid product 49 (11 mg, 0.0252 mmol) was obtained after filtration and air drying at 25° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCCC4)c3)nn12
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 7-fluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 251, 50 mg, 0.145 mmol), 1-(2-chlorethyl)pyrrolidine hydrochloride (25 mg, 0.145 mmol) and Cs2CO3 (99 mg, 0.305 mmol) in DMF (1 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.06 min (conditions 3), MH+=442.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.34 (d, 1H); 8.08 (m, 2H); 8.03 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.26 (t, 2H); 2.83 (m, 2H); 2.44 (m, 4H); 1.62 (m, 4H)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]2.[CH3:44][N:45]1[CH:49]2[CH2:50][CH:51](O)[CH2:52][CH:46]1[CH2:47][CH2:48]2>C(N(CC)CC)C.ClCCl>[CH3:44][N:45]1[CH:49]2[CH2:48][CH2:47][CH:46]1[CH2:52][CH:51]([O:32][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]3)[CH2:50]2
Reactant: O=c1[nH]ccc2cc(O)ccc12
Reactant: CN1C2CCC1CC(O)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(Oc1ccc3c(=O)[nH]ccc3c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
8 mL of dry dichloromethane were added to 814 mg (1.73 mmol) of polystyrene bound triphenyl phosphine. At 0° C. 234 μL (1.48 mmol) of diethyl azodicarboxylate were added. 200 mg (1.24 mmol) of 6-hydroxy-2H-isoquinolinone (66), 210 mg (1.49 mmol) of tropine and 261 μL of triethylamine were added and the reaction mixture was allowed to warm to room temperature and stirred overnight. Another 279 mg of PS-triphenyl phosphine, 43 mg of tropine, 26 μL of diethyl azodicarboxylate and 2 mL of dry dichloeomethane were added and stirring was continued overnight. The solids were filtered off and washed with THF. The mixture was evaporated and purified by flash chromatography to give 158 mg of 6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one (53). Rt=0.79 min (Method B). Detected mass: 279.2 (M+H+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[N+:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[NH:25][CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)([O-:11])=[O:10]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: NCC1CCN(c2ccncc2)CC1
Product: O=[N+]([O-])c1cnccc1NCC1CCN(c2ccncc2)CC1
Yield: 72.9 %

Procedure:
Using a similar procedure to that described in Example 4, Part A, 4-methoxy-3-nitropyridine (250 mg, 1.62 mmol), and 1-(4-pyridyl)piperidin-4-ylmethylamine (310 mg, 1.62 mmol) yielded 370 mg (73%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CCN(CC)CC>C1COCC1>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:21])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: NCc1ccccn1
Reactant: O=C(Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccn1)Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 45 %

Procedure:
2-{[(4-nitrophenoxy)carbonyl]amino}phenyl 4-(trifluoromethyl)-benzenesulfonate (0.25 mmol, 120 mg) is dissolved in THF, and 2-(aminomethyl)pyridine (0.25 mmol, 26 μl) and Et3N (0.3 mmol, 42 μl) are added to the solution. The reaction mixture is heated at 60° C. for overnight. After purification by preparative HPLC, 2-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl 4-(trifluoromethyl)benzenesulfonate is obtained in 45% yield. 1H NMR (400 MHz, MeOD-d6) 8.54 (d, 1H), 8.01(d, 2H), 7.82(m, 4H), 7.42(d, 1H), 7.34(t, 1H), 7.26(m, 4H), 7.05(t, 1H), 4.41(s, 2H). ESI+ for C20H16F3N3O4S m/z=452, (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[NH2:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[N:5]=[C:3]([C:2]([F:14])([F:15])[F:1])[N:4]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(NN=C(N)C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(4-methylphenyl)ethanehydrazonamide (0.62 g, 2.85 mmol), 4-methoxybenzoyl chloride (584 mg, 3.43 mmol), and pyridine (0.277 mL, 3.43 mmol) in dioxane (6 mL) was refluxed with stirring for 1 hour. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-ethyl acetate 8:1-1:1). The desired product was recrystallized from hexane and dried in vacuo to give 5-(4-methoxyphenyl)-1-(4-methylphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (370 mg, 38.9% yield).
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C(C1C=CC(S(C)(=O)=O)=C(Cl)C=1)CC1CCCC1)C.[CH3:46][NH:47][C:48]([NH2:50])=[O:49].CO>C[O-].[Mg+2].C[O-]>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:50][C:48]([NH:47][CH3:46])=[O:49])=[O:22])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CNC(N)=O
Agent: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Yield: 19 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (268 mg) and methyl urea (110 mg, 1.5 mmol) in magnesium methoxide in methanol (7.4 wt %, 1.6 mL, 1.1 mmol) was heated to 100° C. for 8 h. At this time, the reaction was concentrated in vacuo. The residue was then dissolved in ethyl acetate (50 mL), filtered through a plug of silica gel, and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (55 mg, 19% yield) as a white foam: FAB-HRMS m/e calcd for C17H23ClN2O4S (M+H)+387.1145, found 387.1156.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1.[Cl-].[CH3:19][O:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:19]([C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1)=[O:20]
Reactant: O=C1CCC(COc2cccc(F)c2F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Yield: 78.7 %

Procedure:
13.8 g of 1-((4-oxocyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 23.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 7.7 g of potassium-t-butoxide was added dropwise at an internal temperature of 10 to 25° C., and the solution was stirred for 30 nm. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 mL of THF, and 100 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 3 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline, saturated sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. To the residue, 30 mL of methanol and 20% sodium hydroxide aqueous solution were added, and the solution was stirred with ice-cooling for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN1C(=O)COc2c(C(=O)Cc3ccc(Br)cc3Cl)cccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cccc2c1OCC(=O)N2C)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 8-[2-(4-bromo-2-chloro-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an orange oil. MS (m/e)=408.3 [M+H+].
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=3[C:22]3[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:19][S:33]([CH3:32])(=[O:35])=[O:34])=[O:18])=[CH:15][C:14]=3[C:22]3[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide (0.39 g, 1.00 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (0.09 g, 2.25 mmol). The reaction mixture was stirred at ambient temperature for 2 h, methanesulfonyl chloride (0.12 mL, 1.54 mmol) was added; stirring was continued for 46 h at ambient temperature and quenched by addition of 5% hydrochloric acid (1.0 mL). Diluted with ethyl acetate (100 mL) and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography using 10% to 50% gradient ethyl acetate in hexanes to afford the title compound as a colorless solid (0.13 g, 27%): 1H NMR (300 MHz, CDCl3) δ 8.73 (br s, 1H), 8.21-8.17 (m, 1H), 7.88-7.83 (m, 1H), 7.78-7.65 (m, 1H), 7.55-7.50 (m, 1H), 7.00-6.93 (m, 2H), 3.88 (s, 3H), 3.53 (s, 2H), 3.40 (s, 3H), 1.90 (br s, 3H), 1.69-1.31 (m, 12H); MS (ES−) m/z: 469.1 (M−1).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[CH:16]([O:21][CH3:22])([O:19][CH3:20])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:22][O:21][CH:16]([O:19][CH3:20])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(OC)c(C(OC)OC)c1
Yield: 97 %

Procedure:
Ethyl 3-formyl-4-methoxybenzoate (500 mg) obtained in step C of Example 1-2-1 was dissolved in 10 mL of methanol. Trimethyl orthoformate (263 μL) and 41 mg of p-toluenesulfonic acid monohydrate were added to the solution, and then the mixture was heated for 2 hours under reflux. After the reaction solution was cooled, 5 mL of a saturated aqueous solution of sodium bicarbonate was added, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with purified water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, whereafter the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 596 mg (97%) of ethyl 3-dimethoxymethyl-4-methoxybenzoate.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]3[N:8]([N:11]=[CH:12][N:13]=3)[CH:9]=[N:10][C:5]=2[S:4][CH:3]=1.[Cu][C:15]#[N:16]>CN(C=O)C>[N:13]1[CH:12]=[N:11][N:8]2[C:7]=1[C:6]1[C:2]([C:15]#[N:16])=[CH:3][S:4][C:5]=1[N:10]=[CH:9]2
Reactant: N#C[Cu]
Reactant: Brc1csc2ncn3ncnc3c12
Solvent: CN(C)C=O
Product: N#Cc1csc2ncn3ncnc3c12
Temperature: 150 °C

Procedure:
9-Bromothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.16 g, 4.55 mmol) was dissolved in DMF (23 mL), and copper(I) cyanide (817 mg, 9.1 mmol) was added. This mixture was heated to 150° C. for 23 h, whereupon the reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography. LCMS method [4], retention time=0.890 min; MS (ESI) 202.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.36 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: ClC1C=CC2N3C(C4CC4)=NN=C3[CH2:9][N:8]=[C:7](C3C=CC=CC=3Cl)C=2C=1.O.NN.[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH:44]1CC1>C(O)COCCO>[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH2:44][N:8]([CH3:9])[CH3:7]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C3CC3)n1-2
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: Cc1nnc(CN(C)C)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A solution of 7.38 g. of 8-chloro-6-(o-chlorophenyl)-1-(dimethylamino)methyl-4H-s-triazolo[4,3 -a][1,4] benzodiazepine (III) (20.0 mmol.) and 5.0 ml. of hydrazine hydrate in 50 ml. of diethylene glycol is heated to about 140° C. for about 18 hours. The reaction is quenched in a cold aqueous 5% sodium hydroxide solution, and the product extracted with chloroform. The extracts are dried and concentrated in vacuo to yield 8.5 g. of oil, which is crystallized from ethyl acetate/hexane mixtures to give 4.0 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4 -triazole (I), isomer A, m.p. 142°-144° C., an analytical sample of which melts at 148°-150° C. and has infrared (mull) spectral absorptions at 3380, 3270, 3200, 3070, 2770, 1610, 1590, 1570, 1530 and 1520 cm-1.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:24][C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc(OC)c1OC

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-ylamine (68, 9.72 mg, 0.04 mmol) and 3,4,5-trimethoxy-benzaldehyde (69, 15.7 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=424.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH:8]=2)[NH:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[CH:22]=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:29]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])=[CH:6][CH:5]=4)[CH:27]=2)[CH:22]=[N:21]1
Reactant: O=C1Cc2cc(C(=O)Nc3ccccc3)ccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)Nc3ccccc3)cc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 24.2 %

Procedure:
A scintillation vial was charged with 2-oxo-N-phenylindoline-5-carboxamide (22 mg, 0.087 mmol), 1H-indazole-6-carbaldehyde (14 mg, 0.096 mmol), piperidine (1 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more MeOH (2 mL). The yellow solid was then filtered and washed with MeOH (10 mL) to give 8.0 mg, 24% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 13.42 (s, 1H), 11.02 (s, 1H), 10.16 (s, 1H), 9.01 (s, 1H), 8.39 (s, 1H), 8.14 (s, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.79 (d, J=6.5 Hz, 2H), 7.36 (t, J=6.6 Hz, 2H), 7.11-7.09 (m, 1H), 6.96 (d, J=6.9 Hz, 1H); MS ESI 381.1 [M+H]+, calcd for [C23H16N4O2+H]+ 381.14.