Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][N:3]([CH3:24])[N:4]=[N:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][N:3]([CH3:24])[N:4]=[N:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CO)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Solvent: c1ccncc1
Product: CC(=O)OCN(C)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(3′-chlorophenyl-amino)-6-aminoquinazoline (100 mg, 0.318 mmol) in acetonitrile (20 mL) kept at 0° C. in an ice bath, nitrosonium tetrafluoroborate (74.3 mg, 0.637 mmol) was added dropwise. The solution was stirred for 20 min and 0.9 mL of a mixture of methylamine 40% (0.075 mL, 0.954 mmol), formaldehyde 37% (0.75 mL, 9.54 mmol), and concentrated HCl (0.1 mL) was added all at once. The diazonium solution was subsequently alkalinized with potassium carbonate (400 mg, 2.86 mmol) and the precipitate was filtered to give a white solid contaminated with excess potassium carbonate. The precipitate was therefore re-suspended in THF and the resulting solution filtered. The organic solvent was further evaporated to give 6-(3-hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown solid (90 mg, 73%). 6-(3-Hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.258 mmol) was dissolved in pyridine (2 mL) after which acetic anhydride (0.055 mL, 0.516 mmol) was slowly added. The solution was further kept on ice for 1.5 h and the pyridine evaporated as an azeotrope with toluene to give 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown residue (105 mg, 95%). 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.260 mmol) was dissolved in anhydrous methanol (2.5 mL) and stirred at room temperature for 24 h. The methanol was then evaporated to provide the title compound 6-(3-methoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline) as a pure brown residue (91 mg, 98%): EI m/z 357.0 (MH+), 253.2 (M-3-methoxymethyl-3-methyl-triazene); 1H NMR (400 MHz, DMSO-d6) d 9.94 (s, 1H, NH), 8.60 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H, J=9.2 Hz), 7.88 (d, 1H, J=6.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.39 (t, 1H, J=6.6 Hz), 7.14 (d, 1H, J=9.2 Hz), 5.17 (s, 2H, CH2), 3.25 (s, 3H, CH3,), 3.24 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC=C1CCc2c(Cl)cc3nn(C)cc3c21
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
2-(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (105 mg, 0.424 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine (88.6 μL, 0.636 mmol) and acetic anhydride (48.1 μL, 0.509 mmol) were added under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (96.7 mg, yield 79%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][N:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][N:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccncc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccncc3=O)cc2F)C1)c1ccc(Cl)s1

Procedure:
71.2 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide. White solid. MS 476.0 ([M+H]+)
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Nc1ccccc1C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-butyryl-4-chloro-7-benzoyloxymethylquinoline (3.68 g, 10 mmol) and o-toluidine (1.61 g, 15 mmol) in dioxan (100 ml) were refluxed for 2.5 hours, then allowed to cool and stand for 16 hours. The solvent was evaporated and the product converted to the free base and recrystallized from ethanol to give the title compound (1.8 g) m.p. 110°-12°.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25]C(=O)C)[CH:20]=1)[CH3:4]>CO.C(OCC)(=O)C.O>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1)[CH3:4]
Reactant: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 75 °C
Yield: 87 %

Procedure:
A 2 M sodium hydroxide solution (20 mL) was added to a solution of N-(4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 24-6 (2.5 g, 7.04 mmol) in methanol (20 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred under reflux at 75° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature and then diluted with ethyl acetate and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:9-0:1-ethyl acetate:methanol=49:1-24:1) to obtain the title compound (1.92 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:27](=O)[NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CSC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:32])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Temperature: 65 °C
Yield: 24.6 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Ethylcarbamoyl -pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (0.21 g, 0.459 mmol) in dry tetrahydrofuran (5.25 mL) is added 2 M toluene solution of BH3.dimethylsulfide (0.104 g, 1.378 mmol) at 0° C. Reaction heated to 65° C. for 16 hours. Quenched with Methanol (2 mL). Volatiles were removed under reduced pressure to obtain crude material purified by column chromatography eluting in 6% methanol in CH2Cl2 to afford title compound (0.05 g): 1H-NMR (400 MHz, DMSO-d6): δ: 1.09 (t, 3H, J=7.15 Hz), 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.15 (m, 2H), 3.82-3.89 (m, 2H), 3.95 (s, 2H), 4.10 (m, 1H), 4.45-4.55 (m, 2H), 5.12 (d, 1H, J=7.24 Hz), 7.52 (d, 1H, J=8.20 Hz), 7.57 (d, 2H, J=8.20 Hz), 7.75 (d, 2H, J=8.24 Hz), 8.09 (dd, 1H, J=7.88 Hz, J=2.08 Hz), 8.84 (d, 1H, J=1.92 Hz). LC-MS (m/z): [M+H]=444.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C)C(=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([F:39])([F:38])[F:27])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2C(F)(F)F)CC1
Temperature: 115 °C
Yield: 29.8 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.00 g, 3.35 mmol) in N,N-dimethylacetamide (purged with nitrogen) (12 mL). Add potassium carbonate (1.11 g, 8.04 mmol) and 2-trifluoromethylbenzeneboronic acid (764 mg, 4.02 mmol) then purge with nitrogen for 15 min. Add deoxygenated water (6 mL) and tetrakis(triphenylphosphine)palladium(0) (0.039 g, 0.034 mmol) and purge with nitrogen for 15 min. Heat at 115° C. for 21 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (4×20 mL). Concentrate the DCM extracts and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:isohexane), to give 3′-(2-trifluoromethylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (408 mg, 29%). MS (ES): m/z=409 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][CH2:29][NH:30][S:31]([NH:34]C(=O)OC(C)(C)C)(=[O:33])=[O:32])=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]>O>[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][CH2:29][NH:30][S:31]([NH2:34])(=[O:32])=[O:33])=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-butyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40-50° C., the solvents removed in vacuo, and chased with dichloromethane (3×2 L). The resulting white solid was dried in a vacuum drying oven at 50° C. overnight. A total of 5409 g was processed in this manner (4990 g, quant. yield). LCMS for C12H12BrFN7O5S (M+H)+: m/z=463.9, 465.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J=8.7 Hz, 1 H), 6.67 (t, J=5.9 Hz, 1 H), 6.52 (t, J=6.0 Hz, 1 H), 3.38 (dd, J=12.7, 6.3 Hz, 2 H), 3.11 (dd, J=12.3, 6.3 Hz).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O.[N-:23]=[C:24]=[O:25]>CO.CCCCC>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([NH:1][NH:2][C:3]([NH:5][NH:6][C:24]([NH:23][C:13]2([N:12]=[N:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:25])=[O:4])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: NNC(=O)NN
Reactant: [N-]=C=O
Solvent: CCCCC
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=O)NNC(=O)NNC(=O)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a slurry of 2.25 grams (.025 moles) of carbohydrazide in 30 ml of methanol stirred by a magnetic stirrer in a 50 ml erlenmeyer flask was added 10.5 grams (.05 moles) of 1-t-butylazo-1-isocyanatocyclohexane (from Example XVIII). The carbohydrazide slowly went into solution over 1 hour. The reaction solution was allowed to stand overnight at room temperature. The next morning the solution was poured into 200 ml water and the product extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure to leave a sticky solid. The sticky solid was redissolved in pentane and the pentane evaporated under reduced pressure to give a light yellow crystalline solid that weighed 12.0 grams (94% crude yield). The product did not melt sharply but began to decompose around 100° C. The infrared spectrum of the product contained a strong broad carbonyl band at 1660-1700 cm-1 and NH bands at 3280 -3370 cm-1 and the isocyanate band of the starting material was absent.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>CO>[Cl:18][C:17]1[C:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([CH2:5][O:2][CH3:1])[CH:7]=2)=[N:14][N:15]([CH3:23])[C:16]=1[O:19][CH:20]([F:22])[F:21]
Reactant: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
1.6 g (9.0 mmol) of a 30% strength by weight solution of sodium methylate in methanol was added dropwise to a solution of 2.3 g (6.0 mmol) of 3-(3-bromomethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 60 ml of methanol. The reaction mixture was stirred at 40° C. for 3 hours and then concentrated. The residue was taken up in water and dichloromethane, after which concentrated hydrochloric acid was added until the acid reaction took place. Product remaining in the aqueous phase was extracted with dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and concentrated. Yield: 1.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:11]([NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: COc1ccc(N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(NC(C)C)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-amino-2-methoxypyridine (747 mg, 6.02 mmol) in CH2Cl2 (50 mL) was added acetone (500 μL) and sodium triacetoxyborohydride (1.95 g, 9.20 mmol). The reaction was stirred at room temperature for 20 hours and was diluted with aqueous NaHCO3. The aqueous solution was washed with CH2Cl2 (3×) and the combined organic solutions were washed with brine (1×), dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (5% EtOAc in hexanes to 50% EtOAc in hexanes) to provide 810 mg of isopropyl-(6-methoxy-pyridin-3-yl)-amine. 1H NMR (CDCl3) δ 7.55 (s, 1H), 6.96 (dd, 1H), 6.61 (d, 1H), 3.86 (s, 3H), 3.52 (m, 1H), 1.19 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ncc(Br)cn2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxetan-3-one (0.452 mL, 7.72 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water and brine, then dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure. The resulting crude brown oily solid was absorbed onto a 25 g KP-Sil Biotage column with minimal DCM, and eluted using a Biotage Isolera 4 with 10-100% ethyl acetate in heptanes, to afford the title compound (687 mg, 42%) as a crystalline yellow solid. δH (500 MHz, DMSO-d6) 9.07 (s, 2H), 6.43 (s, 1H), 4.94 (d, J 6.5 Hz, 2H), 4.67 (d, J 6.5 Hz, 2H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[Si]([C:28]#[N:29])(C)C.N>C(O)(=O)C>[C@@H:1]1([N:10]2[CH2:15][CH2:14][C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:28]#[N:29])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCN([C@H]2CCc3ccccc32)CC1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccccc1
Agent: N
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN([C@H]2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(S)-1-Indan-1-yl-piperidine-4-one (31 mmol) was dissolved in acetic acid (28 ml). Aniline (33 mmol) and trimethylsilylcyanide (31 mmol) were added and the mixture was stirred for 45 min. at room temperature. The reaction mixture was poured into cold ammonia solution (water/28% ammonia, 50 ml/30 ml). The solution was adjusted to pH 10 and extracted with methylene chloride. Organic phases were pooled, dried with sodium sulfate and concentrated. Crystallization from diethylether yielded the desired product as a solid. 8.1 g (80%) of (S)-1-indan-1-yl-4-phenylamino-piperidine-4-carbonitrile, m.p. 157-160° C. and MS: m/e=318.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]2)[C:5]2[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=2[N:3]=1.Cl>C(O)C>[CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=2[N:3]=1
Reactant: CC(=O)N1CCC(n2c(C)nc3cc(C)ncc32)CC1
Agent: Cl
Solvent: CCO
Product: Cc1cc2nc(C)n(C3CCNCC3)c2cn1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
A solution of 1-[4-(2,6-dimethyl-imidazo[4,5-c]-pyridin-3-yl)-piperidin-1-yl]-ethanone (20 mg, 0.074 mmol) in ethanol (0.5 mL) was treated with concentrated HCl (0.5 mL). The reaction mixture was heated at 100° C. for 18 h. The solvent was evaporated and the mixture was diluted with water (2 mL). The mixture was washed twice with diethyl ether and the aqueous phase was adjusted to pH=10 by addition of a solution of 25% aqueous NaOH. The aqueous mixture was extracted with CH2Cl2 (5×10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2,6-dimethyl-3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine (13 mg, 77%) as a light yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2O[CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CO[CH2:30][CH2:31]OC>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[CH:31]=[CH:30][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCN1CCOCC1
Reactant: COCCOC
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Product: N#Cc1c(NCCN2CCOCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 4-(2-aminoethyl)morpholine in DME. ES-MS m/e (%): 325 (M+H+, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[CH:23]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1
Solvent: NCc1ccccc1
Product: Brc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Yield: 74.9 %

Procedure:
The title compound (0.38 g) was prepared from 0.66 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL of benzylamine, and 0.63 g of 1-bromo-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H19BrN2, 366.07; found, m/z 367.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.48 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.25 (m, 3H), 7.19-7.16 (m, 2H), 5.14 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(O[C@@H]4C[C@H](C)CC[C@H]4C(C)(C4C=CC=CC=4)C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:39][CH2:40][C:41](=[O:42])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].Br.[OH-].[NH4+]>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:39][CH2:40][C:41](=[O:42])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2CC(=O)C3=C(C2)NC2=C(C(=O)CC2)C3c2ccc(F)c(Cl)c2)C1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cl
Product: O=C1CCC2=C1C(c1ccc(F)c(Cl)c1)C1=C(CNCC1=O)N2
Reaction time: 72 h
Yield: 49.2 %

Procedure:
The product from Example 38B (0.2 g, 0.33 mmol) was treated with 48% hydrogen bromide in acetic acid (4 mL), stirred for 72 hours, neutralized with concentrated ammonium hydroxide, and extracted with methylene chloride (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Purification of the residue on silica gel (10% ethanol/ammonia saturated methylene chloride) to provide the title compound (0.03 g) which was converted to the HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cc(Cl)ccn1
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(Cl)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-(bromoacetyl)4-chloropyridine hydrobromide*.