Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:29]=[C:30]4[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: N#Cc1ccnc(N)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#N)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (2.65 g, 5.69 mmol), 2-amino-4-cyanopyridine (1.42 g, 11.9 mmol, 2 equiv) and powdered activated 3 Å molecular sieves (10 g) in ethanol (22 mL) was heated for 4 h at the reflux temperature. The reaction mixture was cooled to room temperature, additional 2-amino-4-cyanopyridine (0.71 g, 6.0 mmol, 1 equiv) was added, and the resulting mixture was heated at the reflux temperature for 5 h. The resulting solution was separated between EtOAc (75 mL) and an saturated aqueous NaHCO3 solution (75 mL). The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 80% hexane/20% EtOAc for 3.0 min., gradient to 70% hexane/30% EtOAc over 13.7 min.) to give {1-[4-(7-cyano-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.57 g, 21%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11]N)=[CH:4][C:3]=2[O:2]1.C1C[O:29]CC1.CC(C[AlH]CC(C)C)C.Cl>C(O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: C1CCOC1
Reactant: NCC(c1ccc2c(c1)OCO2)C(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCO
Product: O=CC(c1ccc2c(c1)OCO2)C(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Compound 98 was prepared as follows: A mixture of 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine (18.0 g, 0.055 mol) and anhydrous THF (120 mL) at −70° C. was treated dropwise with a 1.0M solution of DiBAL (100 mL, 0.110 mol). The reaction was stirred for 1 hour at −70° C. and then at 25° C. for 1.5 hours. The reaction was cooled to 0° C. and treated with ethanol (20 mL) followed by 10% aqueous HCl (150 mL). Extraction with ethyl acetate, drying over anhydrous MgSO4, evaporation and purification by flash chromatography (silica gel) afforded 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropionaldehyde a solid. A mixture of this material (8.0 g, 0.024 mol), Rink amine resin (8.73 g, 0.0044 mol), and trimethylorthoformate (60 mL) was shaken for 4 days, filtered and washed twice with trimethylorthoformate, methylene chloride, and dichoroethane. The resulting resin was shaken with NaBH(Oac)3 (4.63 g, 0.022 mol), acetic acid (1.83 mL) and dichloromethane (60 mL) for two days. The resulting resin was washed with methanol, methylene chloride, 10% acetic acid/methylene chloride, 10% triethylamine/methylene chloride, methylene chloride, and methanol. This resin (0.235 g, 0.0001 mol) was shaken for 2 days with HATU (0.090 g, 0.00024 mol), diisopropylethylamine, (175 μL), 4-chlorophenylacetic acid (0.085 g, 0.0005 mol), and DMF (2 mL). The resin was filtered and washed three times each with DMF, methylene chloride, and methanol and dried. The dried resin was treated with 10% TFA/methylene chloride and filtered. The filtrate was blown dry with nitrogen to afford 0.042 g (87%) of compound 98, electrospray mass spectrometry m/e=484.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17](Cl)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:29]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:29]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:17](=[O:18])[C:16]1[CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:35]
Reactant: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)Cl)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 82 %

Procedure:
The reaction of 5-(decyloxy)-2-(phenylmethoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-(decyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester (82% yield, mp 37°-38°).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][CH:9]=1.Cl>O.C(O)C>[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=[CH:3][C:4](=[O:5])[CH3:6])=[CH:10][CH:9]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=CC=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
Sodium hydroxide (2 g) in water (35 ml) was added to a stirred mixture of acetone (9.7 g) and ethanol (20 ml) cooled in a water bath. 4-Fluorocinnamaldehyde (5 g) was added dropwise to the stirred solution such that the temperature did not exceed 25°. The mixture was stirred at room temperature for 5 min, diluted with water (250 ml), adjusted to pH 1 with 5 M hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (1×100 ml), dried (MgSO4) and evaporated to give an orange oil (6.1 g) which was used crude in the next stage.
Reaction SMILES: [C:1]([O:14][CH:15]1[CH:20]([CH3:21])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:18][CH:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:16]1[CH3:34])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC1(C)O[O:37]1>>[C:1]([O:14][CH:15]1[CH:16]([CH3:34])[CH:17]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:18]([OH:37])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]1[CH3:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC1(C)OO1
Reactant: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Product: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)N(O)C(c2ccccc2)C1C
Yield: 99.5 %

Procedure:
The general procedure of Example 2 is repeated using 29.9 g (64.5 mmol) of 2,6-diphenyl-3,5-dimethylpiperidin-4-yl laurate and 1.24 L (64.5 mmol) of dimethyldioxirane (0.050M in acetone). 30.8 g (98% yield) of the title compound is isolated: mp 108°-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.9169 g, 9.5 mmol) in CH2Cl2 (50 mL) was added Dess-Martin Periodinane (4.8470 g, 11.4 mmol), and the mixture was stirred at room temperature for 5 hours. CH2Cl2 (75 mL), saturated NaHCO3 (100 mL), and 20% aqueous sodium thiosulfate (100 mL) were added, and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (1×75 mL). The organic extracts were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-EtOAc) provided 1.80 g (95%) of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.93-2.02 (m, 2H), 2.46 (t, 2H, J=6 Hz), 3.58 (t, 2H, J=6 Hz), 4.00 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C:27]#[N:28])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](Br)=[CH:12][C:11]=1[CH2:25][CH3:26])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]([C:27]#[N:28])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)=[CH:12][C:11]=1[CH2:25][CH3:26])[CH3:3]
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: OB(O)c1ccc(F)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: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Yield: 92.8 %

Procedure:
A solution of 1.5 g of 2-methyl-2-cyano-7-(2-ethyl-4-bromo-5-benzyloxyphenoxy)heptane and 0.5 g of tetrakis(triphenylphosphine)palladium(0) in 70 mL of benzene was stirred with 15 mL of 2.0M sodium carbonate. A solution of 1.1 g of 4-fluorophenyl boronic acid in 15 mL of ethanol was added. The mixture was heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to provide 1.44 g (93%) of the desired title intermediate. NMR.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
n-Butyllithium (1.2 mL 1.92 mmol, 1.6 M/hexanes) was added to a −78° C. solution of 1,4-dibromobenzene (489 mg, 2.07 mmol) in THF (4.2 mL). After 30 min., a solution of cyclobutanone (141 mg, 2.01 mmol) in 1 mL THF was added by cannula, rinsing with 0.5 mL THF. The reaction was allowed to warm to room temperature and after 2 h, saturated NH4Cl solution was added. The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined ethyl acetate solution was washed with brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (5%→10% ethyl acetate/hexanes) gave 3-1 (235 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nc2ccccc2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and diethyl 3-oxopentanedioate as a pale yellow solid (25%). 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=8.0 Hz, 3H), 1.30 (t, J=8.0 Hz, 3H), 4.08 (m, 4H), 4.28 (q, J=8.0 Hz, 2H), 7.50 (m, 1H), 7.73 (m, 2H), 8.10 (bs, 2H), 8.53 (d, J=8.0 Hz, 1H). MS 303 (MH+).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22](=[C:27]1[C:32](=[O:33])[O:31][C:30]([CH3:35])([CH3:34])[O:29][C:28]1=[O:36])[CH2:23][CH:24]([CH3:26])[CH3:25]>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:23]([C@H:22]([CH:27]1[C:32](=[O:33])[O:31][C:30]([CH3:34])([CH3:35])[O:29][C:28]1=[O:36])[C:21]#[C:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: C#Cc1ccccc1
Reactant: CC(C)CC=C1C(=O)OC(C)(C)OC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C#Cc1ccccc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 85.2 %

Procedure:
A solution of copper (II) acetate monohydrate (10.0 mg, 0.050 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (20 mg, 0.10 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylaminol]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 33.1 mg, 0.050 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(1-isopentylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (53 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 24 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 5:1) to give 67 mg of the pure title compound as a white solid. (Yield: 85%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[CH3:12][O:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:14][O:13][CH3:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: COCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)OC)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a precooled solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (CAS registry 30766-12-2) (150 mg, 0.980 mmol) and 2-methoxyethanol (82 mg, 0.085 ml, 1.077 mmol) in THF (10 ml) was added at 0° C. triphenylphosphine (397 mg, 1.469 mmol) and the reaction mixture was stirred for 10 min at 0° C. A solution of DIAD (316 mg, 1.469 mmol) in THF (5 ml) was added and the mixture was stirred at room temperature for 19.5 h. After dilution with EtOAc, the crude mixture was extracted with water and brine, the aqueous layers were reextracted with EtOAc, the combined organic extracts dried over Na2SO4, filtered and the filtrate concentrated to yield the title compound after flash chromatography on silica gel (DCM/EtOAc gradient 0-3 min 60:40; 3-35 min 60:40 to 25:75).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH:34]([CH2:36][CH3:37])[CH3:35]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH:34]([CH2:36][CH3:37])[CH3:35])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(C(C)CC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromobutane (1.64 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.61 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1Br
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4Br)nc23)CC1
Yield: 96.8 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0099 mL (0.072 mMol) 2-bromobenzoyl chloride, 0.026 gm (96%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>C1COCC1>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:22])=[CH:23][CH:24]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (32.0 mg) obtained in Example 142 in THF (10 ml) were added pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. Pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) were added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give a mixture containing the title compound and the raw material (4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide. To a solution of the obtained 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide in THF were added triethylamine (0.055 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with the mixture containing the title compound, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.10 mg).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12](O)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-n3ncnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
3-(5-Isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (1.90 g, 6 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.73 g, 6 mmol), EDCI (1.69 g, 9 mmol), HOBt (1.20 g, 9 mmol) and NMM (3.2 mL) were added to 20 mL of acetonitrile. The reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere, then was partitioned between water and EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (IPA/DCM 1:4)) to give 1.63 g of 3-(5-isopropyl-[1,2,4]triazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=428.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:12][NH2:13]>CO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:13][CH3:12])=[O:10]
Reactant: CN
Reactant: COC(=O)c1ccccc1O
Solvent: CO
Product: CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of methyl salicylate (5.16 mL, 40 mmol) in methanol (10 mL) was added dropwise to aqueous 40% methylamine (18.1 mL, 210 mmol) at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature overnight. The volatiles were removed in vacuo to give the subtitled compound (5.48 g).
Reaction SMILES: BrCCC=C(C)C.[Br-].[CH3:9][C:10](=[CH:12][CH2:13][CH2:14][N+:15]([O-:17])=[O:16])[CH3:11].N([O-])=O.[Na+].[C:22]([O:27][CH3:28])(=[O:26])/[CH:23]=[CH:24]/[CH3:25]>CS(C)=O>[CH3:25][CH:24]([CH:14]([N+:15]([O-:17])=[O:16])[CH2:13][CH:12]=[C:10]([CH3:11])[CH3:9])[CH2:23][C:22]([O:27][CH3:28])=[O:26]
Reactant: CC(C)=CCC[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: CC(C)=CCCBr
Agent: O=N[O-]
Agent: [Br-]
Solvent: CS(C)=O
Product: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]

Procedure:
The bromo compound, 8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene, used to prepare the Grignard reagent in the first step in the synthesis is prepared by a series of reactions using 5-bromo-2-methyl-2-pentene as the starting material. The bromide is first converted to 2-methyl-5-nitro-2-pentene by reaction with sodium nitrite in dimethylsulfoxide. The nitro compound is then reacted with methyl crotonate to form methyl 3,7-dimethyl-4-nitro-6-octenoate. Reaction of the octenoate derivative with titanous chloride results in the formulation of the oxo compound, methyl 3,7-dimethyl-4-oxo-6-octenate. The oxo compound is then reacted with lithium aluminum hydride to form 3,7-dimethyl-4-hydroxy-6-octen-1-ol. The diol is converted to the mono-acetate by reaction with acetic anhydride and the mono-acetate is then converted to the tetrahydropyranyl derivative by reaction with dihydropyran. The tetrahydropyranyl derivative is converted to the corresponding alcohol by reaction with potassium carbonate in a mixture of methanol and water. The bromo compound is then obtained by reacting the alcohol 3,7-dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-ol with phosphorous tribromide or triphenylphosphine and carbon tetrabromide.