Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH2:8][O:9][CH:13]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)CO
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1COC(C(C(=O)OCC)C(=O)OCC)OC1
Yield: 89.4 %

Procedure:
A mixture of 17.45 g of 2-butyl-1,3-propanediol, 26.4 g of diethyl (ethoxymethylidene)-malonate, 250 ml of toluene and 0.285 g of p-toluenesulfonic acid monohydrate was heated to boiling for 1 hour, with moist toluene being distilled off and replaced by the addition of fresh toluene. The reaction mixture was neutralized with triethylamine and, after cooling, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (42.35 g) was chromatographed on 520 g of silica gel with hexane/ethyl acetate (4:1). 33.0 g of oily diethyl (5-butyl-1,3-dioxan-2-yl)-malonate were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[O-:28][C:29]#[N:30].[K+]>CC#N.O>[F:15][C:14]1[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]([NH2:30])=[O:28])[CH2:4][CH2:5]2)=[N:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[N:12][CH:13]=1
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a suspension of 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (26 mg, 0.070 mmol) in CH3CN (1 mL), an aqueous solution of potassium cyanate (34 mg, 0.42 mmol) in H2O (1 mL) was added. The mixture was stirred at 70° C. for 1 h. Solvents were removed in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 414.3 (M+H);); UV 205.8, 276.8 nm
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](Cl)(=[O:11])[CH3:10].O>N1C=CC=CC=1>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)cn1
Yield: 85 %

Procedure:
In 29 ml of pyridine was dissolved 1 g of 2-amino-5-bromopyridine which was then acetylated through reaction with 0.61 ml of acetyl chloride at room temperature for 15 hours with stirring. Following the addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer thus obtained was washed with brine. Dehydration, filtration and concentration under vacuum of the organic layer provided a solid which was then recrystallized in ethanol and hexane to obtain the title compound. 1.06 g. Yield 85%.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:8]=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[C:11]([CH3:13])[N:12]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)nc1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
tert-Butyllithium (1.040 mL, 1.77 mmol) was added dropwise to THF (5 mL) at −100° C. under an argon atmosphere. A solution of 6-bromo-3-methoxy-2,4-dimethylpyridine (191 mg, 0.88 mmol) in THF (3 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.74 mmol) in THF (7 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (3.54 mL, 4.42 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified on a silica gel column eluted with 0-10% 0.1 M NH3 in MeOH in DCM to give the title compound (272 mg, 84%). MS (ES+) m/z 440, 442 [M+1]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:16])[CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[O:16][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(O)ccc1C(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cc(OCC(=O)OCC)ccc1C(C)(C)C
Yield: 95.7 %

Procedure:
3-Butoxy-4-tert-butylphenol (640 mg, 2.9 mmol), potassium carbonate (1.2 g, 8.6 mmol) and ethyl bromoacetate (480 ul, 4.3 mmol) were treated in the same procedure described in Example 33(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 4/1) to furnish 856 mg (96% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:7]2[OH:23].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].O>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:8]2[C:7](=[O:23])[C:6]3[C:11]4=[C:2]([NH:1][C:31](=[O:32])[N:10]4[CH:9]=2)[CH:3]=[C:4]([CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:5]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(=O)[nH]c3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 3, 331 mg) and 1,1′-carbonyl diimidazole (215 mg) in DMF (2.5 mL) is heated at 80° C. for 1 h. A second portion of 1,1′-carbonyl diimidazole (167 mg) is added and heating is continued for an additional 1 h. After cooling, water (8 mL) is added and the resulting precipitate is filtered off, washed with water and dried to afford 261 mg of the title compound. Physical characteristics: M.p. 286° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ2.39, 3.57, 3.62, 4.57, 7.39, 7.61, 8.88, 10.0, 12.0. Anal. Found: C, 60.37; H, 4.78; N, 12.49.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>>[NH2:8][C:5]1[N:4]=[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:23]#[C:22][C:20]([CH3:21])([OH:24])[CH3:19])[CH:16]=3)[CH:11]=[N:10]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ncc(Br)c(-n2ncc3ccc(Br)cc32)n1
Product: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1

Procedure:
5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with 2-methyl-3-butyn-2-ol (1 eq) via Sonagashira Coupling to afford 0.7 g of 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol following flash column chromatography. 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol ester via Suzuki Coupling to afford 12.2 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 374. 1H NMR (400 MHz, DMSO) delta 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H), 7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H), 3.73 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH3:71])[CH2:64][C:63]2[CH:65]=[CH:66][CH:67]=[C:68]([CH2:69]O)[C:62]=2[O:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:69][C:68]2[C:62]3[O:61][C:60]([CH3:71])([CH3:59])[CH2:64][C:63]=3[CH:65]=[CH:66][CH:67]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc3c2OC(C)(C)C3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid 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 (0.67 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[NH:12]2)=[CH:7][C:6]=1[O:27][CH3:28])=[O:4].N1C=CC=CC=1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC(OC)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[N:12]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:7][C:6]=1[O:27][CH3:28])=[O:4]
Reactant: COC(=O)c1cc2c(cc1OC)[C@H](NC(=O)OCc1ccccc1)C[C@H](C)N2
Reactant: CCOC(=O)Cl
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of cis-4-benzyloxycarbonylamino-6-methoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (0.99 g, 2.6 mmol) in anhydrous dichloromethane (30 mL) was added pyridine (0.27 mL, 3.35 mmol). The mixture was cooled to 0° C., and ethyl chloroformate (0.29 mL, 3.1 mmol) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 2.5 h. Additional aliquots of pyridine and methyl chloroformate were added to drive the reaction to completion. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (75 ml) and water (25 ml). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by silica gel chromatography using 25% ethyl acetate/hexanes as eluent afforded the title product (1.06 g). MS m/z 457 (M+ +1); 1H NMR (DMSO-d6) δ 1.45 (d, 3H), 6.68 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Yield: 80.5 %

Procedure:
To a solution of (2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (1.0 g), 4-hydroxybenzaldehyde (0.58 g), and triphenylphosphine (1.48 g) in tetrahydrofuran (10 mL), a solution of 40% diisopropylazodicarboxylic acid diisopropyl in toluene (1.09 mL) was added under ice-cooling and the resultant reaction mixture was stirred under ice-cooling for 3 hours. A solution of diisopropyl azodicarboxylate in toluene (0.6 mL) was further added and the resultant reaction mixture was stirred at room temperature for 12 hours. From the reaction mixture, the solvent was distilled off under reduced pressure to give a residue and water was added to the resultant residue. The mixture was extracted with an organic solvent and the resultant organic phase was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-heptane:ethyl acetate=100:0 to 100:20) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[CH3:32])[C:10]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]1=2)=[O:6].[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:18][C:17]=3[CH3:32])[C:10]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]2=3)=[O:6])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCCl)c3cc(Cl)ccc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(CCCC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Yield: 51.5 %

Procedure:
7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate (0.5 g) was dissolved in acetonitrile (10 ml). 1-Acetylpiperazine (0.35 g), sodium iodide (0.41 g), and sodium carbonate (0.19 g) were added to the solution, and the mixture was heated under reflux for 19 hours. The reactant was poured into water, and the mixture was extracted with ethyl acetate, washed with water, dried over sodium carbonate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→100:10) to obtain 0.3 g of 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-(4-acetylpiperazin-1-yl)butyrate as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11]=[O:12]>>[CH:11]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[OH:1])=[O:12]
Reactant: N#CCc1ccc(O)cc1
Reactant: C=O
Product: N#CCc1ccc(O)c(C=O)c1
Yield: 74.5 %

Procedure:
Proceeding as in Reference 8, but substituting 4-hydroxyphenylacetonitrile (2.09 g, 15 mmol) and formaldehyde (3.6 g, 120 mmol) gave 3-formyl-4-hydroxyphenylacetonitrile (1.8 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:8])[CH3:9])=[O:6])=[CH:17][CH:16]=1
Reactant: CON=C(C(=O)N(C)C)C(C)=NO
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)N(C)C)C(C)=NOCc1ccc(C)cc1
Yield: 96.5 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 3-hydroxyimino-2-methoxyimino-N,N-dimethylbutyramide in 20 ml of acetone, 500 mg (3.5 mmol) of 4-methylbenzylchloride and 660 mg (4.8 mmol) of potassium carbonate were added and the mixture was heated under reflux for 16 hours. The reaction mixture was combined with 30 ml of water and extracted three times with 30 ml of diethylether. After washing with water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate and then the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 900 mg (yield: 96%) of 3-(4-methylbenzyloxyimino)-2-methoxyimino-N,N-dimethylbutyramide as a colorless crystal.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH3:18][NH2:19]>CO.CCO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[N:19][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CN
Reactant: O=Cc1ccc2c(c1)ncn2C1CCCCO1
Solvent: CCO
Solvent: CO
Product: CN=Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 64 (1.0 g, 4.34 mmol) in MeOH (10 mL) at 0° C. was added a solution of MeNH2 in EtOH (33%, 2 mL). After stirring at RT for 2 h, the mixture was concentrated under reduced pressure to afford 1.0 g (94%) of N-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methylene)-methanamine (66) as yellow oil: MS (ESI) m/z=244.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25](OCC)=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].ClC(OCC)=O.[NH3:40]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([NH2:40])=[O:26])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC(N)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
A solution of ethyl 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentanoate (173 mg, 0.360 mmol) and aqueous sodium hydroxide (8 M, 0.09 mL) in tetrahydrofuran (1.8 mL) was stirred for 24 h at reflux. The reaction mixture was concentrated in vacuo. To the residue was added tetrahydrofuran (3.0 mL) and ethyl chloroformate (74.3 μL, 0.780 mmol) at 0° C. After being stirred for 1.5 h at room temperature, the reaction mixture was cooled down to 0° C. And then aqueous ammonia solution (28%, 150 μL) was added. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with ethyl acetate to give the title compound as a colorless solid (60.1 mg, 0.133 mmol, 37%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C:14]3([C:30]([N:32]4[CH:37]5[CH2:38][CH2:39][CH:33]4[CH2:34][CH:35]([N:40]4[C:44]([CH3:45])=[N:43][N:42]=[C:41]4[CH:46]([CH3:48])[CH3:47])[CH2:36]5)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C:14]3([C:30]([N:32]4[CH:33]5[CH2:39][CH2:38][CH:37]4[CH2:36][CH:35]([N:40]4[C:44]([CH3:45])=[N:43][N:42]=[C:41]4[CH:46]([CH3:47])[CH3:48])[CH2:34]5)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:51])[CH3:52]
Reactant: C=C(C)[C@@H]1CCC2(C(=O)N3C4CCC3CC(n3c(C)nnc3C(C)C)C4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CCC2(C(=O)N3C4CCC3CC(n3c(C)nnc3C(C)C)C4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 22, 0.2 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about for about 6 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25-1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, 1H); 4.60 (s, 1H); 4.74 (s, 1H); ES Mass: [M+] 672 (100%), [M+1] 673; HPLC: 95.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[CH:4][C:3]=1[F:17].[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[CH:4][C:3]=1[F:17]
Reactant: Fc1cc(/C=C/c2nc(CCl)co2)ccc1Cl
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)c(F)c3)n2)cc1
Yield: 62.9 %

Procedure:
Using 2-[(E)-2-(4-chloro-3-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (291 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) and 65% sodium hydride (39.5 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (333 mg) as colorless needle crystals.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:13]([CH2:19][C:20]#[N:21])(=O)[C:14]([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:13]1[CH:19]=[C:20]([NH2:21])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COC(=O)c1ccc(NN)cc1
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
Methyl 4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).