Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].CC([Si](C)(C)[O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][NH:39][CH2:40]2)=[CH:35][C:34]=1[O:43][CH3:44])(C)C.C(N)C>C(#N)C>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:33]([OH:32])=[C:34]([O:43][CH3:44])[CH:35]=3)[CH2:40]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Agent: CCN
Solvent: CC#N
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 150.7 %

Procedure:
A mixture, under argon, of 2.17 g of product from Example 113, 1.8 g of product from Example 28, 13.0 ml of N,N-diidopropyl ethylamine and 80 ml of acetonitrile is heated under reflux temperature for 8 hours. The reaction is cooled and concentrated in vacuo and dried under high vacuum for 1 hour. The crude residue is dissolved in 70 ml of tetrahydrofuran and 10.0 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added and the mixture is stirred at room temperature, under argon, for 2.5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried, filtered, and concentrated in vacuo to give 4.0 g of a brown oil. The oil is purified by chromatography (silica gel: 1%, 1.5% and 2% methyl alcohol/methylene chloride)to give 2.1 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.[OH:24]OS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])(=[O:24])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)(=O)=O)[nH]2)ncc1Br

Procedure:
35 mg (0.086 mmol) of (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is dissolved in 4 ml of MeOH/water (4:1) and stirred with 25 mg of oxone (0.25 mmol) at room temperature. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is digested with ethyl acetate. 19 mg (0.045 mmol, 52% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfonyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])(C)(C)C.[C:17]([C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:28][O:29][CH3:30])[C:25](=[O:27])[S:26][C:22]=2[CH:21]=1)(=[O:19])[CH3:18].CCOC(C)=O>C1COCC1>[OH:19][C:17]([C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:28][O:29][CH3:30])[C:25](=[O:27])[S:26][C:22]=2[CH:21]=1)([C:11]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9][CH:10]=1)[CH3:18]
Reactant: c1cnn(C2CCCCO2)c1
Reactant: COCn1c(=O)sc2cc(C(C)=O)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1c(=O)sc2cc(C(C)(O)c3ccnn3C3CCCCO3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Add 1-tetrahydropyran-2-yl-pyrazole (1.5 Eq, 202 mmoles, 30.8 g)(Aldrich) and THF (900 mL) to a flame dried 2 L 3 neck round bottom flask and cool to −78° C. (dry ice/acetone bath). Add t-butyl lithium (2.5 M in THF)(1.5 Eq, 202 mmoles; 81.0 mL) dropwise, maintaining at least −68° C., and stir for 60 min at −78° C. Add a solution of 6-acetyl-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one (32.0 g, 134 mmoles) in THF (450 mL) dropwise over 45 min, and stir at −78 for 30 min. Remove the dry ice bath and allow to warm to −50° C. and stir for 1 hr. (do not let temp. rise above −45° C.). Quench the reaction with MeOH (80 mL). Transfer to a separatory funnel, add EtOAc (2000 mL), and wash with water (500 mL) and then brine (500 mL). The organic layer is dried over Na2SO4, filter and concentrate to give a crude yellow oil. Purify the material by HPLC, eluting with hexanes/EtOAc (6:4) to yield 6-[1-hydroxy-1-(1-tetrahydropyran-2-yl-1H-pyrazol-5-yl)ethyl]-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one as a white foam (44 g, 113 mmoles, 84% yield) (Racemic mixture of diasteromers). LCMS (Low) rt=1.76 min., M+1=288, and rt=1.86 min., M+1=288
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:14]([S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:14]([S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])(=[O:17])=[O:18])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 2-[(4-{[(tert-butoxycarbonyl) (methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (524 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (3 mL) was added at 0° C. The mixture was stirred at 0° C. for 1 hr, and at room temperature for 16 hr, cooled again to 0° C., acidified with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→0:1) to give the title compound as a colorless amorphous (yield 256 mg, 50%).
Reaction SMILES: [CH:1]1([C:4]2[C:24]([C:25]([O:27]C)=[O:26])=[C:7]3[CH:8]=[C:9]([CH3:23])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[F:22])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.CS(C)=O>[CH:1]1([C:4]2[C:24]([C:25]([OH:27])=[O:26])=[C:7]3[CH:8]=[C:9]([CH3:23])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[F:22])[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(OCc2c(F)ccc(F)c2F)n2nc(C3CC3)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 78.9 %

Procedure:
A solution of 462 mg (1.01 mmol; purity 85%) of methyl 2-cyclopropyl-5-methyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylate from Example 156A in 10.5 ml of dioxane and 3 ml of DMSO was admixed with 5.55 ml (11.10 mmol) of 2 N sodium hydroxide solution, and the mixture was stirred at 100° C. for 6.5 h. Another 1 ml (2 mmol) of 2 N sodium hydroxide solution was added and the mixture was stirred at 100° C. for a further 2.5 h. The reaction solution was cooled down to 0° C. and adjusted to pH 2 with 1 N hydrochloric acid. The solids that precipitated out were stirred for 30 min, filtered off and dried under high vacuum. 300 mg of the title compound were obtained (74% of theory, 93% purity) and were converted without further purification.
Reaction SMILES: I[C:2]1[C:7]2[C:8](=O)[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC4C=CC=CC=4)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>>[N:30]1[NH:31][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[CH2:12][CH2:11][C:10]4=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=[C:9]4[C:8]=1[C:7]=23
Reactant: O=C(Nc1cccc2c1CCc1cccc(I)c1C2=O)OCc1ccccc1
Reactant: NN
Solvent: O
Product: Nc1cccc2c1CCc1cccc3[nH]nc-2c13

Procedure:
50 mg of benzyl N-(6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)carbamate prepared in Example 8-a was treated with hydrazine monohydrate by the procedure of Example 1-h and purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 15 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.I[CH3:27].[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:25]([CH3:27])[CH:24]=[N:23][N:5]2[C:6](=[N:17][CH2:18][C:19]([F:21])([F:20])[F:22])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1cnn2c(=NCC(F)(F)F)c(-c3c(F)cc(F)cc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.78 mmol) in 4 mL of dimethylsulfoxide at room temperature is added iodomethane (146 μL, 2.34 mmol) followed by sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol). The mixture is then stirred at room temperature for 18 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides N-[5-chloro-3-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-ylidene]-2,2,2-trifluoroethanamine as a white solid (76 mg). MS: m/z 396.0 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Reaction time: 2 h

Procedure:
Sodium hydride (60% suspension in oil, 1.8 g, 45.19 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (130 mL). Neat 3-methyl pyrazole (3.71 g, 45.19 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The (2-chloro-4-fluorophenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step D (8.11 g, 22.59 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 2 hrs. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 3:2) provided the desired product along with some mixed fractions containing the tide compound and its more polar 5-methylpyrazole regioisomer of Example 2. The title compound crystallized by sonication from hexane-ethanol as a white solid (6.4 g, 68%), m.p. 207° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:15]([F:35])=[CH:16][C:17]([O:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:18]([CH:26]=1)[C:19](N(CC)CC)=[O:20]>C1COCC1>[Br:13][C:14]1[CH:26]=[C:18]2[C:17](=[CH:16][C:15]=1[F:35])[O:27][C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][C:33]=1[C:19]2=[O:20]
Reactant: CCN(CC)C(=O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1c2cc(Cl)ncc2oc2cc(F)c(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (3.14 mL, 7.84 mmol) was added to a solution of diisopropylamine (1.341 mL, 9.41 mmol) in THF (40 mL) at −78° C. The resulting solution was stirred at 0° C. for 15 minutes before being added dropwise via cannula to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamide (2.1 g, 5.23 mmol) in THF (40.0 mL) cooled to −78° C. under positive pressure. The resulting solution was stirred 3 hours at −78° C. before being quenched with saturated ammonium chloride (100 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with saturated aqueous NH4Cl, water, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by dissolving in a minimal amount of CH2Cl2 and filtering through a pad of silica gel by eluting with 1:10 EtOAc in hexane, to provide 7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-c]pyridin-5-one as a off-white solid. MS m/z=330.0 [M+H].
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Yield: 20 %

Procedure:
The title compound (0.03 g, 20%) was prepared from the product of Example 7 Step 6 and N,N-dimethylethylenediamine using the method of Example 7 Step 7; 1H NMR (CDCl3) 8.68 (2H, s), 8.52 (2H, d, J 8 Hz), 7.82 (1H, d, J 10 Hz), 7.57 (H, s), 7.46 (1H, d, J 10 Hz), 7.39 (2H, J 8 Hz), 6.67 (1H, s), 5.90 (1H, m), 3.53 (2H, m), 3.18 (2H, t, J 5 Hz), 2.77 (2H, t, J 8 Hz,), 2.56 (2H, t, J 5 Hz) 2.29 (6H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH:25]=O)[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C.[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:18]([NH:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH2:1][NH:35][CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29][CH2:28][NH2:27])[CH:24]=[C:23]([CH2:25][NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:22]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Reactant: CC(C)CN(CCCOc1cc(C=O)cc(C=O)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CNCCCOc1cc(CNCCCNCCCN)cc(CNCCCNCCCN)c1
Reaction time: 24 h

Procedure:
tert-Butyl (3-(3,5-diformylphenoxy)propyl)-(isobutyl)carbamate (0.15 g, 0.42 mmol) and MeOH (10 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (0.20 g, 0.84 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.06 g, 1.69 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added, the layers separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as clear oil which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][CH:18]=2)[N:13]=1.[H-].[Na+].[CH3:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29](=[O:31])[CH3:30]>>[CH3:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:4]([CH2:30][C:29](=[O:31])[CH2:28][CH2:27][CH:26]([CH3:32])[CH3:25])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[N:13]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)CCC(C)C
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 3-hydroxy-2-(7-methyl-1,8-naphthyridin-2-yl)-1-isoindolinone (7.9 g), an oily suspension (50% by weight; 2 g) of sodium hydride and 5-methyl-2-hexanone (6.2 g), and stirring the reaction mixture for 3 hours at a temperature in the region of -5° C., and then for 2 hours at 0° C., 2-(7-methyl-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (1 g), m.p. 155° C., is obtained after recrystallization in ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Br:16])[N:6]=1)=O.O.[NH2:18][NH2:19].O>CO>[NH2:11][C:10]1[C:5]([C:3]([NH:18][NH2:19])=[O:2])=[N:6][C:7]([Br:16])=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Temperature: 85 °C

Procedure:
A suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (1.00 g, 3.34 mmol) in dry MeOH (20 ml) was stirred at reflux (85° C.) for 30 min and then treated with hydrazine monohydrate (324 ul, 6.69 mmol). The mixture was returned to heat at reflux for 5 h 30 min and allowed to cool to RT. Water was added and the resulting precipitate was collected by filtration and dried in a vacuum oven to afford the title compound as a biege solid;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 19.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.6 g) described in Preparation Example 65 and (R)-4-ethyloxazolidin-2-one (553 mg) described in Preparation Example 26, the title compound (336 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Cl.[CH2:13]([OH:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14]
Reactant: CCO
Reactant: COc1ccccc1CC#N
Agent: Cl
Product: CCOC(=N)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 500 mL round-bottomed flask was added 2-(2-methoxyphenyl)acetonitrile (50.45 g, 343 mmol) in ethanol (101 mL). HCl (10.42 mL, 343 mmol) gas was bubbled through the suspension for 15 minutes. The HCl bubbler was removed and the reaction was stirred at ambient temperature for 48 hours. The reaction was diluted with 200 mL ether, and the suspension was filtered. The collected solid was washed with ether and dried under vacuum to provide the title compound as the hydrochloride salt. MS (DCI+) m/e 194.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=2[F:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)cc(F)c1F)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1F)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-3-o-tolyl-1-(2,3,5-trifluoro-phenyl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI−): m/z=446.0 ([M−H]−, 1Br).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.[C:6]([N:10]1[CH:18]=[C:17]2[C:12]([C:13](=[O:37])[NH:14][C:15]3([CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:35]=[C:34]5[C:29]([CH:30]=[CH:31][N:32]=[C:33]5Cl)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:16]2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([N:10]1[CH:18]=[C:17]2[C:12]([C:13](=[O:37])[NH:14][C:15]3([CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:35]=[C:34]5[C:29]([CH:30]=[CH:31][N:32]=[C:33]5[N:2]([CH3:3])[CH3:1])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:16]2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(Cl)c4c3)CC1)C2
Reactant: CNC
Solvent: CO
Product: CN(C)c1nccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc12
Temperature: 60 °C
Reaction time: 65 h
Yield: 61 %

Procedure:
A solution of dimethylamine in methanol (1.75 mL, 3.50 mmol, 2 M) was added to 2′-tert-butyl-1-(1-chloroisoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (158 mg, 0.350 mmol). The reaction vessel was sealed and the mixture was heated to 60° C. and stirred for 65 hours. The reaction was cooled to room temperature and concentrated. Purification by flash column chromatography (1-15% methanol/dichloromethane) gave the title compound (99 mg, 61%) as a white solid. +APCI (M+H) 461.4; 1H NMR (400 MHz, CDCl3, δ): 8.16-8.20 (m, 1H), 8.12 (d, J=5.9 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.58-7.64 (m, 1H), 7.37 (s, 1H), 7.14 (d, J=5.9 Hz, 1H), 6.00 (br. s., 1H), 3.40-3.71 (m, 4H), 3.10-3.28 (m, 6H), 2.85 (s, 2H), 1.64-1.99 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CN
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 259d, 10 g) in dioxane (25 mL) was treated with methylamine (15 mL of a 40 wt % aqueous solution). The resulting mixture was stirred at 100° C. for 16 h in a sealed tube. The reaction mixture was cooled, filtered and the solvents removed in vacuo to give crude product (˜10 g). The crude product (˜8.0 g) was purified by RPHPLC (Waters X-Bridge column, 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as mobile phase). The product containing fractions were combined, evaporated and triturated with diethyl ether overnight. The white solid was collected by filtration and dried in vacuo to afford the title compound (4.14 g). NMR consistent with that described above in example 259.