Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21](=[NH:25])OCC)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[N:25]=[CH:1][NH:3][N:4]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: NNC=O
Reactant: CCOC(=N)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nc[nH]n1
Yield: 32.6 %

Procedure:
Formylhydrazine (120 mg) was added to a solution of ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (295 mg) [see Preparation 41] in toluene (5 ml) and 1,4-dioxane (5 ml). The reaction mixture was stirred at reflux for 26 hours after which time the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1,2,4-triazol-3-yl)piperidine (95 mg) as an off-white foam.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C>[C:6]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 2 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (105 mg, 0.247 mmol), trimethylsilyl acetylene (0.105 mL, 0.741 mmol), copper(I) iodide (4.7 mg, 0.025 mmol) and Pd(PPh3)2Cl2 (8.7 mg, 0.012 mmol) was added triethylamine (1.0 mL) and anhydrous DMF (0.25 mL). After 16 hours, the mixture was diluted with diethyl ether (50 mL) and quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude solid was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide as a tan solid. 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide (70.0 mg, 0.158 mmol) was dissolved in THF (1.0 mL) and treated with a 1 M solution of TBAF in THF (0.16 mL, 0.16 mmol) at room temperature. The solution was stirred for 2 hours and then diluted with diethyl ether (10 mL) and quenched with water (10 mL). The aqueous layers were extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes to afford the title compound as a white solid.
Reaction SMILES: [CH:1]12[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]1[CH2:9]3)[CH:6]1[CH:2]2[C:3](=[O:14])[O:4][C:5]1=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:3]([CH:2]1[CH:1]2[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]2[CH2:9]3)[CH:6]1[C:5]([OH:4])=[O:13])=[O:14]
Reactant: CO
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Product: COC(=O)C1C2C=CC(C3CC23)C1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (prepared as described in Example 51a, 0.86 g, 4.50 mmol) was dissolved in methanol (20 mL). The reaction was stirred at 25° C. for 72 h. The mixture was concentrated to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) afforded the desired product, rac-(1S,2S,4R,5R,6S,7R)-7-(Methoxycarbonyl)tricyclo [3.2.2.02,4]non-8-ene-6-carboxylic acid (0.94 g, 4.23 mmol, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.06-0.17 (2H, m), 1.26-1.38 (2H, m), 2.74-2.85 (2H, m), 3.15-3.19 (2H, m), 3.67 (3H, s), 5.85-5.86 (2H, m). LC-MS (ESI) calcd for C12H14O4 222.24, found 223.5 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([N:16]2[CH:17]=[C:13]([C:12]3[N:11]([CH3:18])[N:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:14]=[CH:15]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 120 °C
Yield: 52.9 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (486 mg, 2.00 mmol), methyl 4-fluorobenzoate (308 mg, 2.00 mmol) and potassium carbonate (553 mg, 4.00 mmol) in DMF (10 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (399 mg, 53%) as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16]1[C:20]2[CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][C:25]([C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][S:16][C:20]=2[CH:21]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NCc1cccc(Oc2ccccc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Oc2ccccc2)c1)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 3-phenoxybenzylamine described in Preparation Example 4 (33 mg, 0.167 mmol) and benzothiazole-6-carboxylic acid (30 mg, 0.167 mmol) in tetrahydrofuran (1 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (89 mg, 0.20 mmol) and triethylamine (28 μl, 0.20 mmol), and the solution was stirred at room temperature for 17 hours. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (37 mg, 62%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([CH:3](C(OCC)=O)[C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20]CC)=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24])#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([CH2:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([OH:20])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:16][CH2:17]2)=[CH:6][C:5]=1[F:24])#[N:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Temperature: 25 °C

Procedure:
100 g of the compound from Example 1, 230 ml of acetic acid, 200 ml of water and 20 ml of sulphuric acid are boiled for 5 hours. After cooling to room temperature, water is added. The precipitated solid is isolated, washed with water and dried.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[C:11]=1[F:18])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>C1COCC1>[F:18][C:11]1[C:12]([F:17])=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane (6.5 g, 24 mmol) in THF (24 mL) was added tetrabutylammonium fluoride (24 mL of a 1M solution in THF, 24 mmol). After stirring at ambient temperature for 1 hour, the mixture was poured into water, acidified with 1M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 to 2:1 hexane-ethyl acetate), affording (2,3-Difluoro-4-methyl-phenyl)-methanol as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:42])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH:25]=[CH:24][N:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:43].O1CCOCC1>CC#N>[ClH:43].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:42])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)[CH:25]=[CH:24][N:23]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Yield: 77 %

Procedure:
tert-Butyl 4-(2-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-4-yloxy)piperidine-1-carboxylate from Step 3 (280 mg, 0.48 mmol) was stirred in 4N HCl/1,4-Dioxane (10 mL) for 2 h at rt. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with CH3CN (20 mL) and evaporated under reduced pressure. The residue was taken up in CH3CN/Et2O (1:5, v/v), sonicated at rt for 15 min, and filtered to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride as a yellow solid (190 mg, 77% yield). LC-MS (ESI) m/z 479 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.69 (s, 1H), 9.36 (br. s., 1H), 9.07 (br. s., 1H), 8.60 (d, J=5.84 Hz, 1H), 7.97 (br. s., 1H), 7.83 (d, J=8.85 Hz, 2H), 7.46 (d, J=9.04 Hz, 2H), 7.39 (dd, J=2.17, 5.75 Hz, 1H), 6.51 (s, 1H), 5.07 (br. s., 1H), 4.50 (br. s., 1H), 3.25 (br. s., 2H), 3.13 (d, J=3.58 Hz, 2H), 2.20 (d, J=14.32 Hz, 2H), 1.93 (d, J=9.04 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:23])[C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].[Na+]>>[F:23][C:7]1[C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Yield: 89.6 %

Procedure:
To a solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (500 mg, 1.17 mmol) in IMS (10 mL) was added sodium hydroxide (1.75 mL, 1M aqueous solution, 1.75 mmol), the reaction mixture heated at 65° C. for 45 min. The reaction mixture was concentrated in vacuo and the residue taken up in water. 1N HCl was added to adjust to pH 1. The precipitate formed was filtered off and dried in vacuo to give the title compound (435 mg, 90%). LCMS (method B): RT=3.47 min, [M+H]+=416.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C@:15]12[CH2:23][N:22]([C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:21](=[O:32])[C@@H:20]1[CH2:19][CH:18]=[CH:17][CH2:16]2)=[O:14])(C)(C)C>ClCCl>[O:32]=[C:21]1[N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[CH2:23][C@@:15]2([C:13]([OH:14])=[O:12])[C@H:20]1[CH2:19][CH:18]=[CH:17][CH2:16]2
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC=CC[C@H]2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CC=CC[C@H]2C1=O
Yield: 81.9 %

Procedure:
Trifluoroacetic acid (18.0 mL) was added to a solution of [(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]carboxylic acid tert-butyl ester (2.04 g, 5.99 mmol) in dichloromethane (18.0 mL) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3). A 1 mol/L sodium hydroxide solution (15.0 mL) was added to the resulting residue under ice-cooling, and the mixture was washed with diethyl ether (40 mL×2). The aqueous layer was made acidic with 1 mol/L hydrochloric acid (20 mL) under ice-cooling. Then, the precipitated crystals were collected by filtration and washed with 0.5 mol/L hydrochloric acid, ethyl acetate, and diethyl ether. The resulting crystals were dried under reduced pressure at 50° C. overnight to give 1.40 g of the title compound as white crystals. The aqueous layer of the filtrate was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with water (150 mL) and brine (150 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 250 mg of the title compound as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[NH4+:22].[OH-]>C(O)C>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:18]=1)[C:12]([NH:11][C:10]1[C:5]([C:3]([NH2:22])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1)=[O:21]
Reactant: [NH4+]
Reactant: COC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic acid methyl ester 102 (2.6 g, 7.34 mmol) and NH4OH (15 mL) in ethanol (50 mL) was heated at reflux for 10 min. Then, the reaction mixture was cooled at room temperature and the precipitate was filtered off, washed with ethanol and ether to give 2.1 g of the title product 103 as a white powder (LCMS analysis).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]([CH3:22])[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]([CH3:22])[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1)[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)cn1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)cn1C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
To a mixture of {3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]phenyl}methanol (1.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.64 g), tributylphosphine (0.95 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.78 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[Cl:31])[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reactant: O=Cc1ccccc1Cl
Product: CN(Cc1ccccc1Cl)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 2-chlorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=528.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[O:30]C(C)(C)C)=[O:17])[CH2:11][CH2:10][CH:9]([O:12][C:13](=[O:15])[CH3:14])[CH2:8]1)[CH3:6])(=[O:3])[CH3:2]>Cl.O1CCOCC1>[C:13]([O:12][CH:9]1[CH2:10][CH2:11][C:7]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][C:21]=2[OH:30])=[O:17])[CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC1CCC(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)(C(C)OC(C)=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OC1CCC(C(=O)NCc2cc(C(F)(F)F)ccc2O)(C(C)OC(C)=O)C1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
1-[3-(Acetyloxy)-1-({[2-tert-butoxy-5-(trifluoromethyl)benzyl]amino}carbonyl)cyclopentyl]ethyl acetate (7.0 g, 14.4 mmol) was dissolved in anhydrous 4N HCl in dioxane (40 mL) and stirred at rt for 65 min. The reaction mixture was then concentrated to give 3-[1-(acetyloxy)ethyl]-3-({[2-hydroxy-5-(trifluoromethyl)benzyl]amino}carbonyl)cyclopentyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCCN
Solvent: CCO
Product: CCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and propylamine in ethanol. EI-MS m/e (%). 243 (M+, 44), 242 ([M—H]+, 28), 228 ([M—CH3]+, 16), 214 ([M—C2H5]+, 100), 201 ([M—C3H6]+, 70).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[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: CCCCCCCCCCCC(=O)Cl
Reactant: C1CCNCC1
Product: CCCCCCCCCCCC(=O)N1CCCCC1
Yield: 61.9 %

Procedure:
In a manner similar to that described in Example 1, dodecanoyl chloride (21.88 g, 0.1M) was treated with piperidine (8.52 g, 01M). Work up and distillation gave 16.55 g (62%) of the product, b.p. 185/2 mm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][Si](C)(C)C)=[CH:30][CH:29]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:12]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=3)[CH2:13][CH2:14][CH:15]2[C:16]2[CH:17]=[CH:18][C:19]([C:22]#[CH:23])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(C#C[Si](C)(C)C)cc3)CCC2c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C2CCC(c3ccc(C#C)cc3)N2c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolved the product of Example 105A (322 mg, 0.588 mmol) in anhydrous THF (5 mL) under nitrogen, added 1M TBAF in THF (1.322 mL, 1.322 mmol), and stirred at 25° C. for 30 min. The reaction darkened immediately upon addition and remained a brown color throughout the reaction. Removed solvent by rotary evaporation, dissolved the residue in Et2O (50 mL), washed with H2O (2×25 mL) and brine (25 mL), dried the organic phase over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to a light tan foam (289 mg). Purified by flash chromatography (silica gel, 3.8 cm×14 cm, 20% CH2Cl2/hexanes) to the title compound as a light yellow foam (176 mg, 74%) as a mixture of stereoisomers. MS (ESI+) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Br:43]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}-benzyl alcohol (3.52 g) was dissolved in 60 ml of dichloromethane. After addition of 3.77 g of triphenylphosphine and 5.17 g of carbon tetrabromide, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=4:1) to provide 3.96 g of the objective compound as colorless crystals. M.p. 101-102° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCCCBr)cc1
Yield: 86.2 %

Procedure:
A solution of 6.56 g (29.4 mmol) of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester dissolved in 250 ml of acetone was treated with 12.2 g (88.1 mmol) of K2CO3 and 13.4 ml (88.1 mmol) of 1,6-dibromohexane. The suspension was heated under reflux overnight, cooled, filtered and concentrated. Purification by flash chromatography on silica gel with toluene/EtOAc (95:5) as eluent yielded 9.79 g (86%) of [4-(6-Bromo-hexyloxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 386 (MH+, 1Br).