Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)([OH:3])=O.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(P(=O)(OCC)OCC)#N>CN(C=O)C>[C:21]([NH:25][C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=[O:3])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CC(C)(C)N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 144 mg (0.50 mmol) of 6-carboxy-4-(3-chloro-anilino)-7H-pyrrolo[2,3-d]pyrimidine (cf. Example 42) and 116 μl (1.1 mmol) of tert.-butylamine in 5 ml of DMF are added 114 μl (0.75 mmol) of diethyl cyanophosphonate (Aldrich; Milwaukee/USA). After 4 h, the reaction mixture is poured onto ice water, stirred for 30 min and finally filtered. The residue is redissolved in isopropanol, treated with charcoal and filtered. Concentration in vacuo and washing with dichloromethane/diethyl ether yields the title compound; HPLC: tRet (Grad20)=11.4; FAB-MS: (M+H)+ =344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11]Cl)[C:6]=2[CH:13]=1.[CH3:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11][NH:15][CH3:14])[C:6]=2[CH:13]=1
Reactant: ClCC1=CCOc2ccc(Cl)cc21
Reactant: CN
Product: CNCC1=CCOc2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
500 ml of 33% ethanolic methylamine are added dropwise under ice-water cooling to 105 g 6-chloro-4-chloromethyl-2H-1-benzopyrane. Reaction is continued for 8 hours at room temperature, the mixture concentrated by evaporation and the residue taken up in dichloromethane. The mixture is washed with 500 ml each of 1 N NaOH and water, dried over MgSO4 and concentrated by evaporation. Distillation of the residue yields the title product b.p. 116°-120°/13.3 pascal.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (1.0 g, Example 1 part c)), methyl acrylate (0.95 ml), tri-o-tolylphosphine (0.128 g), palladium acetate (0.047 g) and triethylamine (4 ml) in acetonitrile (20 ml) were stirred in a pressure tube at 70° C. for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by flash silica chromatography eluting with a gradient of 0-1% ethanol in dichloromethane to give the sub-title compound as a brown foam (0.90 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34]N)[CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: COC(=O)c1cccc(NN)c1
Product: COC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-hydrazino-benzoic acid methyl ester according to example 43 gave the desired product. MS: M=451.0 (M+H)+
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.Cl.Cl.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([NH2:25])=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]2)[N:11]=1.O1CCCC1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.CCOC(C)=O>[NH2:9][C:10]1[N:11]=[C:12]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:27]2)[CH:13]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([NH2:25])=[N:21][NH:22]3)=[CH:18][CH:17]=2)[N:15]=1
Reactant: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC(N)C2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC(NC(=O)c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
Sodium bicarbonate (145 mg, 1.73 mmol) was added to a solution of 6-[2-amino-6-(3-amino-1-piperidinyl)-4-pyrimidinyl]-1H-indazol-3-amine trihydrochloride (150 mg, 0.346 mmol) in water (1.5 mL) with stirring. Tetrahydrofuran (THF) (1.5 mL) was added, the mixture was cooled in an ice bath, and benzoyl chloride (0.044 mL, 0.380 mmol) was added dropwise with stirring. The mixture was then warmed to room temperature and stirred for 2 hours. LCMS showed starting material remaining, product, and bis-benzoylation. An additional 40 uL of benzoyl chloride and 145 mg of NaHCO3 were added, and the mixture was stirred for 1 hour. HPLC showed complete conversion to multi-benzoylated product. The reaction was diluted with EtOAc, washed with water, dried (Na2SO4), filtered and evaporated. The crude was suspended in CH3OH (8 mL), 1 mL of concentrated aqueous HCL was added, and the mixture was stirred 3 days at 65° C. HPLC showed conversion to the desired product. The mixture was concentrated to ˜2 mL, then diluted with CH3CN (˜8 mL) and heated. Additional CH3CN was added to the hot solution until turbid. The mixture was allowed to cool slowly to room temperature with strring over 2 hours. The precipitate was collected by filtration, washed with CH3CN, then Et2O and finally hexanes. Drying afforded the title compound (156 mg) dihydrochloride as an off-white solid. A 100 mg portion was purified further by Gilson automated reverse phase HPLC (Gemini Phenomenex C18 5u, 100×300 mm), eluting with 5-90% CH3CN-water+0.1% NH4OH) to give the title compound (55 mg) as a white solid. LC-MS (ES) m/z=429 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.60 (m, 1H), 1.60-1.74 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.03 (m, 1H), 2.87-3.00 (m, 2H), 3.83-3.95 (m, 1H), 4.27-4.39 (m, 1H), 4.49 (bs, 1H), 5.38 (s, 2H), 6.12 (s, 2H), 6.64 (s, 1H), 7.46 (t, J=7.3 Hz, 2H), 7.50-7.54 (m, 1H), 7.54-7.61 (m, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.1 Hz, 2H), 7.94 (s, 1H), 8.39 (d, J=7.6 Hz, 1H), 11.52 (s, 1H).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([F:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:22])=[C:40]([F:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenylethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[CH2:24]([O:23][C:21]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CNCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon at 0° C., to a solution of ethyl 1,4-dibenzylpiperazine-2-carboxylate (10 g) in dichloroethane (40 mL) a solution of 1-chloroethyl chloroformate (4.73 mL) in dichloroethane (14 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred for 15 minutes at 0° C., and then heated to reflux overnight. The solvent was evaporated and the crude material was dissolved in ethanol and heated at reflux overnight. The solvent was evaporated and the residue was dissolved in water and extracted with diethyl ether (×2) and CH2Cl2 (×2). A saturated solution of NaHCO3 was then added to the water phase, and the inorganic phase was extracted with CH2Cl2 (×2). The organic layers were then combined, washed with brine, dried (Na2SO4), filtered and concentrated to give 1-benzyl-piperazine-2-carboxylic acid ethyl ester as crude product, MS: 248.9 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35](O)=[O:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)=[O:22])[CH:17]([C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:36])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Product: O=C(C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1)N1CCOCC1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with morpholine to give 4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 60% yield, m.p. 235-237 ° C.;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]1[CH:7]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:8][C:9]1[CH:17]=[C:16]([CH3:18])[C:15]2[C:11](=[CH:12][N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:14]=2)[CH:10]=1
Reactant: Cc1c[nH]c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 1-(4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (38.4 mg, 0.079 mmol), 3-fluoro benzylbromide (10.8 μL, 0.083 mmol, 1.05 equiv), and potassium carbonate (22.0 mg, 0.16 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 31.0 mg (64%). 1H-NMR (CD3OD, 300 MHz) δ −0.02 (s, 9H), 0.87-0.98 (m, 2H), 1.31 (s, 9H), 2.23 (s, 3H), 2.47 (s, 3H), 3.08-3.18 (m, 2H), 3.56-3.71 (m, 2H), 4.89-5.13 (m, 3H), 5.72 (s, 1H), 6.83-7.14 (m, 2H), 7.21 (s, 1H), 8.20 (s, 1H). Mass spec.: 594.47 (MH)+.
Reaction SMILES: C(O[C:4](=[NH:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[CH:19]([NH:21][NH2:22])=O>O1CCOCC1>[NH:21]1[CH:19]=[N:18][C:4]([CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]2)=[N:22]1
Reactant: NNC=O
Reactant: CCOC(=N)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc[nH]n2)CC1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 4-(ethoxy(imino)methyl)piperidine-1-carboxylate (51 g, 198.95 mmol) in dioxane (500 mL), was added formohydrazide (17.92 g, 298.43 mmol). This solution was left to stir at 40° C. overnight under N2 resulting in precipitation of a white solid (hydrazide intermediate). The reaction mixture was then heated to 80° C. for 6 h, cooled to room temperature and concentrated. The residue was dissolved in 500 mL of CH2Cl2 and 300 mL of water was added. The phases were decanted and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl 4-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (46.0 g, 92%) as a white solid: 1H NMR Spectrum; (CDCl3) 1.47 (9H, s), 1.76 (2H, m), 1.98-2.11 (2H, m), 2.91 (2H, s), 2.97-3.08 (m, 1H), 4.06-4.23 (2H, m), 8.05 (1H, s); Mass Spectrum [M+H]+=no mass ion.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:52])[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH:9]=[CH:8][C:7]=1[OH:51].Cl>CO>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:7]([OH:51])=[C:6]([CH:11]=2)[C:5]([OH:52])=[O:4])[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(O)c(C(=O)O)c1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
Add 2 N sodium hydroxide solution (2 mL) to a solution of (S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-2-hydroxy-benzoic acid methyl ester (0.100 g, 0.139 mmol) in methanol (5 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (0.076 g, 78%). 1H NMR (CDCl3, 300 MHz) δ 1.23-1.32 (m, 2H), 1.51-1.52 (m, 2H), 1.94-2.05 (m, 1H), 2.25 (s, 3H), 2.65-2.71 (m, 1H), 2.95-3.04 (m, 1H), 4.10-4.21 (m, 5H), 4.76-5.03 (m, 2H), 5.50-5.61 (m, 1H), 6.68-6.89 (m, 2H), 7.31-7.40 (m, 2H), 7.49-7.62 (m, 2H), 7.70 (s, 1H), 7.98 (s, 1H), 10.43 (s, 1H); ESI MS m/z 703 [C31H27F9N6O3+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:16][CH2:15][N:14]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:16][CH2:15][N:14]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:11]
Reactant: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(C=O)C1
Reaction time: 0.5 h

Procedure:
At −78° C., to a solution of Oxalyl Chloride (0.24 mL, 2.75 mmol) in DCM (4 mL), DMSO (0.43 mL, 6.04 mmol) was added. The reaction solution was stirred at the same temperature for 30 min and then a solution of tert-butyl 2-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate 125 (580 mg, 1.8 mmol) in DCM (2 mL) was added. The reaction mixture was stirred at −78° C. for 30 min, followed by the addition of Et3N (1.1 mL, 7.32 mmol). The reaction mixture was warmed up to r.t overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. After removal of solvent, the crude product of tert-butyl 2-formyl-4-(2-methoxyphenyl)piperidine-1-carboxylate 126 was obtained without further purification. LC/MS RT (5 min method)=2.406 min. Mass observed: 264.1 (M-Buthyl+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH3:22])([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C:9]=2[C:23]=1[CH3:24])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:22])[CH2:10][C:9]=2[C:23]=1[CH3:24])[CH3:2]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To tetrahydrofuran (20 ml) were added 5-acetylamino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl)ethyl]-2,3-dihydrobenzofuran (1.2 g, 3.4 mmol) and lithium aluminum hydride. The mixture was heated under reflux for hours. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1) to obtain the desired compound (0.82 g, yield: 71.2%) as oil.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (1.0 g, 3.7 mmol) and 1-bromopentadecane (6.55 g, 22.5 mmol), alcohol 56 was obtained as a colorless oil (800 mg, 45% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[Na].[CH2:29](N(CC)CC)C.S(Cl)(Cl)=O>ClCl.CO>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[C:5]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:4]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(-c2ccc(C(=O)O)cc2)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CCN(CC)CC
Agent: ClCl
Agent: [Na]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a suspension of 4-[1-methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt (20 mg, 0.06 mmol) [See Ex. 5 above] in CH2 Cl2 (2 mL.) was added triethylamine (24 mL, 0.17 mmol), followed by thionyl chloride (10 mL, 0.14 mmol). The reaction mixture was stirred at rt for 30 min, at which time MeOH (0.5 mL) was added. The mixture was stirred at rt for an additional 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0-1% MeOH/CHCl3 and recrystallized from EtOAc to afford the title compound as an off-white crystalline solid (1.6 mg, 8%): mp 208°-209° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH:35]12[O:41][CH:40]1[CH2:39][CH2:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C@@H:39]3[CH2:38][CH2:37][CH2:36][CH2:35][C@H:40]3[OH:41])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: C1CCC2OC2C1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in N,N-dimethylacetamide (20 mL) were added 7-oxabicyclo[4.1.0]heptane (0.66 g) and cesium carbonate (1.5 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.76 g, 62%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Isopropyl alcohol (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 30 minutes. The mass was then filtered and the solid was washed with isopropyl alcohol (10 mL). The wet solid was dried at about 75° C. to a constant weight to yield 6.2 g of the title compound. Purity by HPLC: 98.31%.