Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[OH:14].[C:16]([C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25][OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25][O:26][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[C:5]([OH:14])[CH:6]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Product: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(O)c2)cc1

Procedure:
The title compound was prepared as a white solid (3.056 g, 76%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to that of step 1 of example 6. mp=161.4-162.7° C.; mass spectrum (+APCI, M+H) m/z 358. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 8.24 (s, 1H), 7.68 (d, 1H), 7.54 (d, 2H), 7.42 (d, 2H), 6.52 (m, 2H), 4.40 (t, 2H), 4.29 (t, 2H), 1.38 (s, 9H). Elemental analysis: Calcd. for C20H23NO5: C, 67.21; H, 6.49; N, 3.92, Found: C, 66.86; H, 6.42; N, 3.88.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:19][C:20]1[N:21]([CH2:28][C@:29]2([CH3:32])[CH2:31][O:30]2)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1>>[Cl:19][C:20]1[N:21]([CH2:28][C@@:29]([CH3:32])([OH:30])[CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:1])[F:18])=[CH:16][CH:15]=3)[CH2:10][CH2:11]2)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Product: C[C@](O)(CN1CCC(Cc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl

Procedure:
Using 4-(4-trifluoromethoxybenzyl)piperidine and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]propan-2-ol (crude) as a yellow oil in the same manner as in Example 270.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:12])([CH3:11])[CH2:5]2.C([Li])CCC.[N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[CH3:11][C:6]1([CH3:12])[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:3]2)=[CH:7]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1(C)Cc2ccc(Br)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=c2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2=C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
5-Bromo-2,2-dimethyl-indan 45b (2.4 g, 10.7 mmol) was dissolved in 20 mL of dry tetrahydrofuran. Upon cooling by a dry ice-ethanol bath to −78° C., n-butyllithium (12.1 mL, 30.2 mmol) was added dropwise. Upon completion of the addition, the mixture was stirred for 2 hours. A solution of di-tert-butyl azodicarboxylate (3.27 g, 14.2 mmol) in 20 mL of dry tetrahydrofuran was added to the above mixture. The reaction mixture was reacted at the same temperature for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(2,2-dimethyl-inden-5-yl)hydrazine-1,2-dicarboxylate 45c (2.68 g, yield 66.8%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([N:17]1[CH2:21][C:20](=O)[N:19]=[CH:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:9]([N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(=O)c2ccccc2)C=N1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(NC2=NCCN2C(=O)c2ccccc2)n(C)n1

Procedure:
5-amino-1,3-dimethylpyrazole (20.0 g.) and 1-benzoyl-2-imidazolinone (British patent 1,392,849) (28.4 g.) were reacted as described in Example I to give 22.02 g. product. mp 147°-149°
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].[C:33]([O:37][C:38](=[O:61])[NH:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][N:47]=2)[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:33]([O:37][C:38](=[O:61])[NH:39][CH:40]1[CH2:41][CH2:42][N:43]([C:46]2[CH:51]=[CH:50][C:49]([C:2]3[CH:22]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][C:11]4[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=4[CH:17]([CH3:19])[CH3:18])[C:5]([CH3:23])=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:3]=3)=[CH:48][N:47]=2)[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: [Na+]
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.35 g, 0.69 mmol), tert-butyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-yl)carbamate (0.33 g, 0.83 mmol), and tetrakis (0.079 g, 0.069 mmol) in dioxane (5 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.263 g, 2.48 mmol, 2 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.31 g, 63%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2C(C)(C)C)cc1

Procedure:
91 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-phenylpiperazine (0.033 mL, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:25][CH2:26][C:27]1[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33]>ClCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:25][CH2:26][C:27]2[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Cc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 4-benzoylbenzoic acid (106 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (152 mg, 1.5 mmol) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL). The organic phase was separated, dried over sodium, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (50 mg, 29%). LRMS (M+H+) m/z: 346.17. found 346. HPLC purity (214 nm): 97%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.29 (t, J=4.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.28-7.13 (m, 7H), 5.85 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.96 (s, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[N:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>ClCCl>[N:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([F:31])[C:33]=4[CH3:41])=[CH:23][CH:22]=3)=[O:7])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reactant: Cc1c(F)cccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
To a solution of 0.25 g of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 0.0914 g of triethylamine in 6 ml of dichloromethane under argon is added a solution of 0.156 g of 3-fluoro-2-methylbenzoyl chloride in 1.5 ml of dichloromethane. The mixture is stirred overnight at room temperature and is washed with H2O and saturated NaHCO3. The organic layer is treated with activated carbon and filtered through magnesium sulfate. The filtrate is evaporated, ethyl acetate added and the solvent removed to give 0.38 g of white crystals, m.p. 245°-250° C.: Exact mass by mass spectrometry--441.1720(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:30](O)=[O:31])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:28])([F:27])[F:29])=[CH:23][N:22]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a light yellow oil. MS (ISP): m/z=467.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[O:10])=[CH:3][CH:4]=1
Reactant: Nc1cccc2cnccc12
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cccc3cnccc23)cc1

Procedure:
Anisoyl chloride was reacted with 5-aminoisoquinoline according to the procedure of Example 8 to produce 5-(4-methoxybenzamido) isoquinoline. This product was then reduced according to the procedure of Example 8 to yield 5-(4-methoxybenzamido)-1,2,3,4-tetrahydroisoquinoline HCl. After purification from water it had a melting point of 289°-290° C.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[CH3:20]COCC>>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH3:20]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOCC
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
A 3-neck, 250 mL round bottom flask was charged with a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (9.9 g) in Et2O (120 mL). The flask was purged with nitrogen and then cooled in a CO2/acetone bath. Methylmagnesium bromide (26.8 mL of a 3.0 M solution in Et2O, 80 mmol) was added dropwise over 10 min to the amide. The resulting thick mixture was warmed to 0° C. and then stirred for 40 min before being poured into 2 M HCl solution (50 mL). The mixture was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give tert-butyl 4-acetylpiperidine-1-carboxylate (7.3 g, 32.1 mmol, 80% yield) as a colorless oil. The product partly crystallized on standing at RT. 1H-NMR (400 MHz, CDCl3) δ ppm 4.06 (2 H, s), 2.74 (2 H, s), 2.42 (1 H, s), 2.12 (2 H, s), 1.78 (2 H, s), 1.49 (2 H, s), 1.41 (9 H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([Cl:28])[N:25]=[C:24]2[N:29]([CH3:32])[N:30]=[CH:31][C:23]=12>C1COCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([C:22]1[N:27]=[C:26]([Cl:28])[N:25]=[C:24]2[N:29]([CH3:32])[N:30]=[CH:31][C:23]=12)[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N(C(=O)OC(C)(C)C)c3ccc(S(C)(=O)=O)cc3)nc(Cl)nc21
Temperature: 25 °C

Procedure:
To (4-methanesulfonyl-phenyl)carbamic acid tert-butyl ester (280 mg) in dry THF (3 ml) was added sodium hydride (60% wt suspension in mineral oil, 1.4 equiv., 33.3 mg) at 0° C. After the effervescence ceased, added 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 (113 mg) and the reaction mixture was allowed to warm up to room temperature overnight. DCM/brine extraction gave crude (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)carbamic acid tert-butyl ester, which was reacted with indazole boronic acid pinacol ester in General Procedure A to give 142 as a beige solid (118 mg). NMR (d6-DMSO): 3.24 (3H, s), 4.15 (3H, s), 7.56 (1H, t), 7.74 (1H, d), 8.01 (2H, d), 8.28 (2H, d), 8.32 (1H, d), 8.41 (1H, s), 8.99 (1H, s), 10.54 (1H, br), 13.25 (1H, br). MS: MH+ 420.13
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[F:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: C#CCCn1cc2c(F)cccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3c(F)cccc3n2)n1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (0.12 g, 0.61 mmol) and 2-but-3-ynyl-4-fluoro-2H-indazole (104 mg, 0.5 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 60 mg (0.20 mmol, 36%) of 4-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:33])=[O:32]
Reactant: CC(O)CN1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CN1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a mixture of benzyl 4-(2-hydroxypropyl)piperazine-1-carboxylate (from step 1, 1.7 g, 6.1 mmol) in DCM (20 mL) was added DIPEA (2.1 mL, 12 mmol) followed by methanesulfonyl chloride (0.70 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide crude product (2.22 g) which was used in next step without further purification. LCMS calculated for C16H25N2O5S(M+H)+: m/z=357.1; Found: 357.3.
Reaction SMILES: [CH3:1][N:2]([CH2:22][CH:23](O)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[C:6]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:15]([O:14][C:6]1[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][N:9]2[CH:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][N:2]([CH3:1])[C:3](=[O:4])[C:5]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2cccnc2)c1OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1cccnc1
Reaction time: 2 h

Procedure:
To a solution of N-methyl-N-[2-hydroxy-2-(pyridin-3-yl)ethyl]-4-benzyloxy-3-methoxycarbonyl-1H-pyrazole-5-carboxamide (1.0 g, 2.44 mmol) and triphenylphosphine (2.24 g, 8.53 mmol) in THF (30 mL) was added diethyl azodicarboxylate (1.55 mL, 8.53 mmol) dropwise over a period of 5 minutes. The mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Waters prep LC 4000 System using a Waters Nova Pak column (3 100×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) at 60 mL/minute). Appropriate fractions were combined and the solvents were removed under reduced pressure to give a gum. 1H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 8.50 (s, 1H), 7.5-7.6 (m, 4H), 7.3-7.4 (m, 3H), 5.96 (t, J=4.4 Hz, 1H), 5.28 (AB quartet, J=10.9 Hz, 2H), 4.20 (dd, J=13, 4.2 Hz, 1H), 4.00 (dd, J=13, 4.4 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 3H); ES MS (M+1)=393.
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH3:17])[C:11]=2[Cl:15])[CH:6]=1)=[O:4].[ClH:19].Cl.[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:15].[ClH:19].[CH2:21]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]([C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH3:17])[C:11]=3[Cl:15])[CH:6]=2)=[O:4])[CH3:18])[CH2:32][CH2:31]1)[C:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(CC(=O)c4ccccc4)CC3)ccc2c1Cl
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (3.8 mmol), N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) and K2CO3 (1.56 g, 11.2 mmol) in 30 ml of DMF are stirred at 50° C. for 10 h, then was treated according to the general preparation 2 to give compound(IV-19), 1.09 g (61%), M+ 451.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH3:41][NH:42][CH3:43].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[CH2:26][CH:27]([N:42]([CH3:43])[CH3:41])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3n(n2)CCC(N(C)C)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) was added to a mixture of dimethylamine (2M in THF, 1.07 mL, 2.14 mmol), and sodium cyanoborohydride (1.0 M in THF, 857 μL, 0.857 mmol) in ethanol (1.1 mL). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (59.5 mg, 43% yield) as a TFA salt. LC-MS (M+H)+ 496.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.90-7.99 (1 H, m), 7.32-7.39 (1 H, m), 7.19-7.25 (1 H, m), 7.09-7.17 (4 H, m), 6.91-7.04 (2 H, m), 4.99 (1 H, br. s.), 4.70 (1 H, ddd, J=15.2, 5.3, 2.4 Hz), 4.03 (1 H, dd, J=14.2, 12.1 Hz), 3.86-3.97 (3 H, m), 3.39-3.55 (1 H, m), 3.03 (1 H, dd, J=13.9, 5.6 Hz), 2.74-2.88 (6 H, m), 2.52 (1 H, br, s.), 2.17-2.33 (1 H, m), 1.97-2.13 (1 H, m), 1.37-1.51 (1 H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1.C(N(C(C)C)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20])(C)C>C(Cl)Cl>[C:19]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: OCCNc1ccc(F)c(Cl)c1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OCCNc1ccc(F)c(Cl)c1
Yield: 59.9 %

Procedure:
N-2-hydroxyethyl-3-chloro-4-fluoroaniline (1.48 g, 7.81 mmol) in CH2Cl2 (20 ml) was reacted with N,N-diisopropyl O-tert-butyl-isourea (6.25 g, 31.2 mmol) at room temperature over night. The product was purified by silicagel chromatography, Eluant, ether/petroleum ether 5/95, 10/90 to give title compound (1.15 g, 60%).