Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[OH:10])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[O:10][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])[CH3:20])=[O:4]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(Br)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 98.3 %

Procedure:
5-Bromo-3-hydroxy-thiophene-2-carboxylic acid methyl ester (1.67 g, 7.04 mmol, 1.0 Eq.), 1-(2-Chloro-phenyl)-ethanol (1.43 g, 9.16 mmol, 1.3 Eq.) and triphenylphosphine (2.40 g, 9.16 mmol, 1.3 Eq.) were dissolved in anhydrous THF (30 mL) under nitrogen. The resultant solution was cooled to 0° C. and DEAD (1.4 mL, 9.16 mmol, 1.3 Eq.) was added dropwise. The reaction was warmed to ambient temperature and stirred for 4.5 hours. The crude reaction was purified by column chromatography (10% EtOAc/petroleum ether) to give the sub-title compound as a yellow solid (2.60 g, 6.92 mmol, 98%); 1H NMR (400 MHz, CDCl3) δ 1.68 (3H, d), 3.88 (3H, s), 5.71 (1H, q), 6.65 (1H, s), 7.23-7.33 (2H, m), 7.37 (1H, dd), 7.66 (1H, dd).
Reaction SMILES: [C:1]([C:3](=[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)SC)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:27][NH2:28]>CCO>[NH2:2][C:1]1[NH:28][N:27]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: CSC(Nc1ccc(N2CCN(C(C)C)CC2)cc1)=C(C#N)C(N)=O
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(Nc3n[nH]c(N)c3C(N)=O)cc2)CC1
Temperature: 75 °C

Procedure:
2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamide was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a purple powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4].[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([N:10]([CH3:33])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1COCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1COCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.2 %

Procedure:
To a slurry of 0.3 g (0.658 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid methyl ester (Example 26, Step 1) and potassium carbonate (0.182 g, 1.32 mmol) in DMF (10 mL) was added iodomethane (0.103 g, 0.723 mmol). The reaction was stirred at 25° C. for 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide a crude oil (0.42 g) that was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate:hexanes, to afford 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid methyl ester as an amorphous white solid (0.270 g, 87%). MS: 471 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[N:41][CH:40]=[N:39][CH:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate (1.1 g) in ethyl acetate (10 mL), methanol (20 mL), and dioxane (20 mL), 10% palladium-carbon (0.57 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 20 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 70-0% hexane/ethyl acetate] to obtain 0.73 g of tert-butyl 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethyloxyethyl)-N-phenethyl-3-phenethyloxy-propanamide (Example 3a), 0.23 g) was dissolved in dioxane (5 mL) and treated with concentrated hydrochloric acid (1.5 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was then poured into dichloromethane (20 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.13 g) as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:15][N:16]([CH:18]=O)[CH3:17].COC(OC)N(C)C>CCOC(C)=O>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:1]/[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc(C(=O)OC(C)(C)C)cn1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)/C=C/c1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 5-methylpyrazine-2-carboxylate (1.35 g), DMF (25 mL) and N,N-dimethylformamide dimethylacetal (25 mL) was stirred at 130° C. for 5 h. The reaction solution was cooled to RT and diluted with EtOAc. The mixture was washed with a saturated NaCl solution three times. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (648 mg). 1H-NMR (CDCl3) δ (ppm): 1.63 (s, 9H), 3.00 (s, 6H), 5.16 (d, J=12.8 Hz, 1H), 7.72 (d, J=12.8 Hz, 1H), 8.16 (d, J=1.2 Hz, 1H), 8.81 (d, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH:6]([CH3:10])[CH2:7][CH2:8][OH:9])#[N:2].[CH2:11](O)[CH2:12][CH:13]([OH:15])C.C(#N)C=C>>[C:13]([O:9][CH2:8][CH2:7][CH:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:10])(=[O:15])[CH:12]=[CH2:11]
Reactant: CC(O)CCO
Reactant: CC(CCO)OCCC#N
Solvent: C=CC#N
Product: C=CC(=O)OCCC(C)OCCC#N

Procedure:
Following the procedures described in Example 1, 3-(2-cyanoethoxy)-1-butanol (bp 145°-150° C./2.5 mm Hg) is prepared from 1,3-butanediol and acrylonitrile, acrylation of which gives the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[CH:22]=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31][N+:32]([CH3:34])=[CH2:33].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH2:31][N:32]([CH3:34])[CH3:33])=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]
Reactant: CC(C)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)n1c(CN(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 25 mL scintillation vial was charged with 4-Chloro-N-[5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide (60 mg, 0.14 mmol), Eschenmoser salt (25 mg, 0.2 mmol) and anhydrous DMF (2 mL). The resultant mixture was heated to 130° C. and stirred for 3 h. After cooling to room temperature, the residue was purified through preparative HPLC (10% to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford the title compound. 1H NMR (400 MHz, CDCl3) 8.35 (d, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.50 (d. 1H), 5.40 (m, 1H), 3.65 (s, 2H), 2.23 (s, 6H), 1.42 (d, 6H). MS (ES) [M+H]+ expected 537.0, found 537.0.
Reaction SMILES: C(OC(=O)[NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[N:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:8]1)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:25][O:24][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][C@@H:7]([CH2:6][NH2:5])[CH2:8]1
Reactant: CCOC(=O)NC[C@@H]1CCN(CCc2ccnc3ccc(OC)nc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a stirred solution of ethyl[((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.80 g, 2.09 mmole) in MeOH (30 mL) and H2O (15 mL) at RT was added potassium carbonate (1.44 g, 10.5 mmole). After 18 h, the reaction contents were concentrated under reduced pressure and filtered through celite (EtOH) to give the title compound (0.59 g, 99%) as a light brown oil: LC-MS (ES) m/e 289 (M+H)+.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4]([OH:8])(=[O:7])[CH:5]=[CH2:6]>O>[C:4]([O-:8])(=[O:7])[CH:5]=[CH2:6].[Mg+2:2].[C:4]([O-:8])(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
A 50 percent solution of magnesium acrylate is prepared by reacting 466 g of magnesium hydroxide in 1050 ml of water with 1152 g of acrylic acid in a stirred, cooled reaction vessel. Acrylic acid is added slowly to the magnesium hydroxide. The temperature of the reaction mixture does not exceed 30° C. during the addition. The reaction mixture is filtered to yield a clear, slightly yellow solution.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH2:10][C@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]([F:21])([F:20])[C:14]1=[O:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:27]([O:26][C:24]([NH:23][C@H:11]([CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]([F:20])([F:21])[C:14]1=[O:22])[CH2:10][C:9]([OH:31])=[O:8])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)CN1C(=O)CCC(F)(F)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)CN1C(=O)CCC(F)(F)C1=O
Yield: 106 %

Procedure:
(S)-3-t-butoxycarbonylamino-4-(3,3-difluoro-2,6-dioxo-piperidin-1-yl)-butyric acid benzyl ester (310 mg, 0.70 mmol) synthesized in Section (2) was dissolved in methanol and 10% Pd/C (31 mg, 0.1 eq) was added thereto. The mixture was stirred for 1 hour under 1 atm hydrogen gas. After the reaction was complete, a solid material was removed by celite filtration to afford 260 mg of the crude title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1cnc2ccccc2c1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 365.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=Cc2cc(Cl)cc(Cl)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC1CCC(Cc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 60 h
Yield: 90.9 %

Procedure:
A mixture of 7.5 grams (0.031 mole) of 4-(3,5-dichlorophenylmethylene)cyclohexanone and 1.0 gram (catalyst) of 10% palladium on charcoal (Degussa type) in 100 mL of ethanol was placed in a hydrogenation bottle and hydrogenated using a Parr hydrogenation apparatus. Upon completion of 2 hours at 50 psi, the reaction had used 25% of the theoretical amount of hydrogen. After this time the reaction mixture was filtered, and an aliquot was concentrated under reduced pressure to a residue. An NMR spectrum indicated that complete hydrogenation had not taken place. The hydrogenation was again conducted using the cyclohexanone above, and 1.0 gram of fresh 10% palladium on charcoal in 100 mL of ethanol. Upon the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered. The filtrate was allowed to stand about 60 hours and then was concentrated under reduced pressure, yielding 7.3 grams of 4-(3,5-dichlorophenylmethyl)cyclohexanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][N:19]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>CN(C)C=O.C(OCC)C>[NH2:13][C:14]1[C:15]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[O:22])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1nccnc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of 19.09 g (0.0776 mol) of 1,1'-carbonyldiimidazole in approximately 200 ml of dimethylformamide was added slowly to a cold (0° C.) solution of 15.78 g (0.1135 mol) of 3-aminopyrazine-2-carboxylic acid in 150 ml of dimethylformamide. The resulting solution was gradually warmed to 25° C. and stirred for about two hours. A solution of 14.75 g (0.118 mol) of N-(3-aminopropyl)imidazole in approximately 40 ml of dimethylformamide was added and the resulting solution was allowed to react for four hours. After four hours, the reaction solution was reduced to dryness under reduced pressure. The resultant semi-solid was suspended in diethyl ether and the portion which did not dissolve was recovered by filtration. The recovered solid was then suspended in diethyl ether containing a small amount of ethyl acetate and the resulting mixture was stirred for about 48 hours. After stirring for 48 hours, the undissolved solid was isolated by filtration. This solid was purified by filtration through silica gel using 4% methanol in dichloromethane. The resultant purified material was recrystallized from a 1:4 dichloromethane/diethyl ether solution to provide 24.4 g of the desired subtitled intermediate (m.p. 118°-120° C.).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]([NH:37][CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:35][CH:34]([N:37]([CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=1)[CH:38]([CH3:40])[CH3:39])[CH3:36]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)C(C)C
Temperature: 140 °C
Yield: 64.4 %

Procedure:
A 5-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.200 g, 0.378 mmol, Intermediate B) diisopropylamine (0.077 g, 0.757 mmol), potassium carbonate (0.105 g, 0.757 mmol), in 3 mL of MeCN. The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (40 g of silica gel, 10 to 40% EtOAc in hexanes) to afford 2-(4-((2S)-2-((bis(1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.130 g) as
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C:20]([Cl:36])=[CH:19][N:18]=1>>[Cl:36][C:20]1[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl
Yield: 12 %

Procedure:
The compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide to yield a yellow solid (12%). LCMS: m/z=497.15 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.05 (s, 1H), 7.77 (m, 2H), 7.31 (m, 5H), 6.88 (d, 1H, J=8.6 Hz), 6.51 (m, 1H), 3.41 (m, 2H), 2.37 (m, 2H), 2.06 (m, 2H), 1.35 (s, 6H), 1.14 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([O:46]C)[CH:45]=1)[CH2:5][C:6]1[C:14]2[C:13]([NH:15][C@H:16]([C:18]3[N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22](=[O:30])[C:21]4=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]4[N:19]=3)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=2[N:8](COCC[Si](C)(C)C)[CH:7]=1.B(Br)(Br)Br.N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([OH:46])[CH:45]=1)[CH2:5][C:6]1[C:14]2[C:13]([NH:15][C@H:16]([C:18]3[N:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:22](=[O:30])[C:21]4=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]4[N:19]=3)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1
Reactant: COc1cc(F)cc(Cc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Cc5cc(O)cc(F)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 58.9 %

Procedure:
(S)-2-(1-((5-(3-Fluoro-5-methoxybenzyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (3 mg, 0.01 mmol) was treated with boron tribromide (1M in dichloromethane, 148 μL, 0.15 mmol) in dichloromethane (280 μL) and then with a solution of ammonia (7N in methanol, 280 μl, 1.96 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 100% dichloromethane-ethyl acetate) to obtain 3 mg (38% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:26][OH:27].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[N:26][OH:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 4-(2-Fluoro-3-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (11.6 g, 34.4 mmol), hydroxylamine hydrochloride (2.87 g, 41.3 mmol) and pyridine (50 mL) was stirred at room temperature under nitrogen overnight. The yellow reaction solution was poured into cold water (500 mL) and the mixture aged at 0° C. for 15 min. The product was collected by filtration, washed with water, and dried under vacuum at 50° C. to afford 11.6 g (96%) of the desired product as a white powder. Proton NMR showed product to be a 2:1 mixture of Z- to E-isomers.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1c(F)cccc1F)N1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(F)cccc3F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.