Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(NC2CCCC2)n1
Reactant: OB(O)c1ccncc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccncc2Cl)c(NC2CCCC2)n1
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To a solution of 2 (2.57 g, 10.0 mmol) in dioxane (75 mL) were added 3-chloropyridine-4-boronic acid (4.72 g, 10.0 mmol), trans-dichlorobis(triphenylphosphine)-palladium(II) (702 mg, 1.0 mmol), and sodium carbonate (3.82 g, 36 mmol, in 36 mL of water). The mixture thus obtained was purged with N2 for 10 min and heated at 120° C. in a sealed tube for 22 h. The reaction mixture was diluted with water and the product was extracted with chloroform. The organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 2.5% methanol in dichloromethane to give the title compound (3) as a white solid (2.31 g, 80%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, s), 8.50 (1H, d, J=4.9 Hz), 7.51 (1H, s), 7.34 (1H, d, 1H, J=4.9 Hz), 6.21 (2H, d, 1H, br s), 5.97 (1H, d, J=7.6 Hz), 4.43 (1H, p, J=7.4 Hz), 1.84 (2H, m), 1.62 (2H, m), 1.40-1.49 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 290.0, Calculated 290.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.CO.N>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCC(=O)c1cccc(F)c1
Agent: N
Solvent: CO
Product: Fc1cccc(C2=NCCC2)c1
Yield: 78.7 %

Procedure:
4-(3-Fluoro-phenyl)-4-oxo-butyronitrile (1.60 g, 9.03 mmol) dissolved in MeOH (45 ml) and 3.5 N MeOH-NH3 (45 ml) was hydrogenated on Ra-Ni at RT for 16 h. The catalyst was filtered off, the filtrate evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/toluene 1:2) to give the product (1.16 g, 79%) as a colorless oil, MS: m/e=163 (M+).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][O:16][CH3:17])[CH2:9]1)C1C=CC=CC=1.[ClH:18]>[C].[Pd].CO>[ClH:18].[CH3:17][O:16][CH2:15][C@H:10]1[O:11][CH2:12][C@H:13]([CH3:14])[NH:8][CH2:9]1
Reactant: COC[C@@H]1CN(Cc2ccccc2)[C@@H](C)CO1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC[C@@H]1CN[C@@H](C)CO1

Procedure:
A solution of (2S,5S)-4-benzyl-2-methoxymethyl-5-methylmorpholine (0.86 g) in a mixture of concentrated hydrochloric acid (0.31 ml) and methanol (8.6 ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.2 g) at room temperature under atmospheric pressure for 3 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure to give (2S,5S)-2-methoxymethyl-5-methylmorpholine hydrochloride (0.71 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.[CH3:21][C:22]([CH3:28])=[C:23](B(O)O)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:24][C:23]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])=[C:22]([CH3:28])[CH3:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC(C)=C(C)B(O)O
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: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)=C(C)C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 66.15D (0.231 g, 0.60 mmol) in DMF (4.00 mL) at 23° C. was added 3-methylbut-2-en-2-ylboronic acid (0.14 g, 1.2 mmol, commercially available from Aldrich), and potassium carbonate (0.25 g, 1.8 mmol). Tetrakis(triphenylphosphine)palladium (0.069 g, 0.060 mmol) was then added to the reaction. The mixture was heated to 90° C. and stirring was continued for 18 hours. The reaction was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 69.12A as a colorless oil (0.100 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH3:38][C:39]1([C:43](O)=[O:44])[CH2:42][O:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:43]([C:39]3([CH3:38])[CH2:42][O:41][CH2:40]3)=[O:44])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CC1(C(=O)O)COC1
Product: CC1(C(=O)NS(=O)(=O)c2cnn3c(Nc4cc(Cl)ccc4Cl)c(C(=O)N4CCC(c5ccc(F)cc5)CC4)cnc23)COC1
Yield: 79.4 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.07 g, 0.12 mmol) obtained in Example 22 step 5 and 3-methyloxetane-3-carboxylic acid (0.072 g, 0.62 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.063 g, 76%) was obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=O)[C:6]=2[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH2:19][NH2:20]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[O:18])[NH:20][N:19]=[C:7]3[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][C:11]=1[C:6]=23
Reactant: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(F)c2[nH]1
Reactant: NN
Solvent: CCO
Product: O=C(O)C1=Cc2n[nH]c(=O)c3ccc(F)c(c23)N1
Temperature: 90 °C

Procedure:
To a solution of 35 (0.600 g, 2.39 mmol) in EtOH (5 mL) was added hydrazine (0.0840 g, 2.63 mmol). The resulting mixture was heated at 90° C. for 24 hand then cooled to room temperature. The resulting precipitate was filtered, washed with Et2O (25 mL), and dried in vacuum at 60° C. for 6 h to give a white solid (36, 0.484 g, 74.5%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.25-8.30 (m, 1H), 7.51-7.57 (m, 1H), 7.06 (s, 1H); Anal. Calcd for C11H6N3O3F (2H2O): C, 46.65; H, 3.56; N, 14.84. Found: C, 46.80; H, 3.59; N, 14.86.
Reaction SMILES: [OH:1][C@H:2]([C@@H:14]([NH:19][C:20](=[O:40])[O:21][C@H:22]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@@H]([C@@H](NC(=O)O[C@H](COC1C=CC(N2C=CN=C2)=CC=1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:2]([C@@H:14]([NH:19][C:20](=[O:40])[O:21][C@H:22]([CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:33][CH:34]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])(=[O:6])=[O:7]
Reactant: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To a solution of 96.6 mg (0.17 mmol) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate in 1.7 mL of chloroform was added 85 mg (0.2 mmol) of Dess-Martin periodinane, and the mixture was stirred at room temperature for 1 h. A second portion of 15 mg (0.035 mmol) of Dess-Martin periodinane was added, and the reaction mixture was stirred for 0.5 h. It was then diluted with ethyl acetate and a saturated aqueous sodium thiosulfate solution. The layers were mixed vigorously, before a saturated aqueous sodium bicarbonate solution was added. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with a methanol:chloroform solution (1:9) to yield 21.6 mg (23%) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z 572 (M+H) retention time=2.83 min. HRMS C28H37N5O6S m/z 572.2543 (M+H)Cal; 572.2526 (M+H)Obs.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:12])[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH2:40]([O:42][C:43](Cl)=[O:44])[CH3:41]>ClCCl>[F:30][C:26]1[CH:25]=[C:24]([NH:23][C:9](=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:20])([F:21])[F:22])=[O:12])[NH:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:43](=[O:44])[O:42][CH2:40][CH3:41])[CH2:3]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C(=O)N=C(Nc2cccc(F)c2)NC2CCCC(N)C2)c(C(F)(F)F)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NC1CCCC(NC(=NC(=O)c2cc(C)oc2C(F)(F)F)Nc2cccc(F)c2)C1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
N-(((3-Aminocyclohexyl)amino)((3-fluorophenyl)amino)methylene)-5-methyl-2-(trifluoromethyl)furan-3-carboxamide (0.150 g, 0.240 mmol) and diisopropylethyl amine (DIEA) (0.037 g, 0.288 mmol) were dissolved in dichloromethane (DCM) (5 mL). Ethylchloroformate (0.032 g, 0.288 mmol) was added and the reaction mixture was stirred for one hour. Then, the solvents were evaporated under a stream of nitrogen and the resulting residue purified by column chromatography (0-40%, hexanes:EtOAc) to yield 123 mg of the title compound (70% yield). LCMS (ESI): calc.=498; obs. M+H=499.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])=[N:6][CH:7]=1.BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cn1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Product: CC(CCc1ccc(Br)cn1)(C(=O)O)S(C)(=O)=O
Yield: 92.4 %

Procedure:
The title compound (1740 mg, 93%) was prepared from ethyl 4-(5-bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoate (2025 mg, 5.6 mmol) by a procedure analogous to that described for the preparation of compound (II) 4-(6-bromophenyl-3-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, Preparation 2, step 3. MS (LCMS) m/z 336.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.63 (s, 3H) 2.25 (ddd, J=13.27, 11.71, 5.07 Hz, 1H) 2.58 (ddd, J=13.27, 11.32, 5.07 Hz, 1H) 2.70-2.81 (m, 1H) 2.88-2.99 (m, 1H) 3.10 (s, 3H) 7.27 (d, J=8.20 Hz, 1H) 7.86-7.92 (m, 1H) 8.53 (d, J=1.95 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][C:27]([O:29]C)=[O:28])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:31](=[O:33])[NH2:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][C:27]([OH:29])=[O:28])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:31](=[O:33])[NH2:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc2ccccc12
Yield: 83.6 %

Procedure:
A solution of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (21 mg, 0.048 mM) and 0.05 mL (0.05 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 20 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 17 mg (80%) of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ8.4 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.8 (d, 1H, J=8 Hz), 7.75-7.2 (m, 8H), 7.1 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 6.15 (s, 2H), and 4.4 (s, 2H). IR (KBr, cm−1) 1664, 1615, 1595, 1455, 1408, 1324, 1275, and 775. MS (ES) m/e 423, 425.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(F)cc3)nc21

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 570 mg (3.31 mmol) of 4-fluorophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 143 mg (27%) of the diastereomer which elutes more rapidly, M.p. 103° C., and 111 mg (21%) of the diastereomer which elutes more slowly, M.p.: 107° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[BrH:16]>>[C:1]1([CH2:7][CH2:8][CH2:9][Br:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: Br
Agent: O=S(=O)(O)O
Product: BrCCCc1ccccc1
Temperature: 0 °C

Procedure:
To 3.2 g of 3-phenyl-1-propanol, were added 1.2 g of concentrated sulfuric acid and 6.08 g of 47% aqueous solution of hydrobromic acid, and the resultant solution was heated for 5 hours at 140-150° C. Then, the solution was poured into ice-water and extracted with ethyl acetate. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 4.3 g of 3-phenyl-1-bromopropane.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:27]1[CH:28]=[C:29]([NH:32][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:30][N:31]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1ccc(-c2cc(N)[nH]n2)c(C)c1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c(C)c1

Procedure:
The named compound is prepared by substituting 5-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.250 gms. 5-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[C:6]([CH2:8][C:9]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][N:21]4[C:24]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:26]=[C:20]4[CH:19]=3)[CH:15]=[N:14]2)[CH2:12][NH:11][CH2:10]1)#[N:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:6]([CH2:8][C:9]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][N:21]4[C:24]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:40])([F:41])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:26]=[C:20]4[CH:19]=3)[CH:15]=[N:14]2)[CH2:10][N:11]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:12]1)#[N:7]
Reactant: O=CC1CC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Cyclopropanecarboxaldehyde (4.2 mg, 0.060 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15 mg, 0.030 mmol) in methanol (1.0 mL). After stirring at r.t. for 20 min, sodium triacetoxyborohydride (13 mg, 0.060 mmol) was added. The reaction mixture was stirred at r.t. for 4 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=550.2.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:17][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CCOC(O)C(F)(F)F
Product: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
Trifluoroacetaldehyde ethyl hemiacetal and 4-chlorobenzamide were processed as described in Example 1 A to provide the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:1]
Reactant: CCOC(=O)CCCCCOc1c(CO)occc1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1c(C=O)occc1=O
Reaction time: 3 h

Procedure:
To a solution of 6.35 g (0.022 mole) of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone in 250 ml of acetone was added 12 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil. The oil was triturated with hexane/ether to give the crystalline aldehyde, 2-formyl-3-(5-carboethoxypentyloxy)-4- pyrone, weighing 4.1 g (65%), m.p. 32-34.5°.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:19])[CH3:20])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOc1ccc(C(C)(C)CC=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-pentene, 0.2 g of 5% Pd-C and 40 ml of ethyl acetate was put in a 200 ml autoclave and pressed up to 10 kg/cm2G with hydrogen gas, and stirred at 80° C. for three hours. After cooling, the reaction mixture was filtered and the solvent was evaporated, and the residue was purified by column chromatography on silica gel to 1.7 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:34]([C:36]1[C:44]2[C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=[CH:40][C:39]=2[N:38]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[N:37]=1)=O>O1CCCC1>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][N:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[C:44]=3[C:36]([CH:34]=[CH:2][O:3][CH3:4])=[N:37]2)=[CH:51][CH:52]=1
Reactant: COC(=O)c1cccc2c1c(C=O)nn2Cc1ccc(OC)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1nn(Cc2ccc(OC)cc2)c2cccc(C(=O)OC)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a −78° C. cooled suspension of (methoxymethyl)triphenylphosphonium chloride (119 g, 347 mmol) in tetrahydrofuran (1000 mL) was carefully added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 347 mL, 347 mmol). The resulting dark red mixture was stirred at −40° C. for 30 min. To this was added a solution of methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (45 g, 139 mmol) in tetrahydrofuran slowly and the mixture was stirred for 30 min. The reaction was quenched with sat. aqueous sodium chloride (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (4×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes) to afford methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 82%) as a yellow oil. A mixture of tetrahydrofuran (950 mL) and 6N hydrochloric acid (30 mL) was added to methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 114.5 mmol) and the resulting biphasic mixture was heated to reflux for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (1500 mL). The organic layer was separated and washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indazole-4-carboxylate (30 g, 77%) as a yellow solid: 1H NMR δ (300 MHz, DMSO-d3) 9.78 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.2, 0.6 Hz, 1H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.88-6.85 (m, 2H), 5.61 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H); MS (ESI+) m/z 339 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:19])=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(C(=O)OC(C)(C)C)oc2ccc(I)c(O)c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To 4.4 g (17.7 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 40 mL of carbon tetrachloride, the mixture was cooled with an water/ice bath while 1 equivalent of N-iodosuccinimide was added in small portions. After stirring at 0° C. for 3 h, the reaction mixture was loaded onto a column and purified by column chromatography to give 2.55 g mg (38% yield) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a white solid.