Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:24])[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:19]4[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:25][CH3:26].C[C:28]([CH3:30])=O.C(Cl)Cl.CC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:24])[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:19]4[CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:25][CH3:26].[NH:11]1[CH2:30][CH2:28][NH:18][CH2:17][CH2:12]1
Reactant: CC(C)=O
Agent: COc1ccnc(C[S+]([O-])c2nc3cc(-n4cccc4)ccc3[nH]2)c1C
Solvent: ClCCl
Product: C1CNCCN1

Procedure:
A single crystal X-ray diffraction study of racemic ilaprazole, Form F was done using crystals obtained from a acetone/methylene chloride solution. A solution of ilaprazole (˜35.8 mg) and piperazine (˜10.4 mg) was prepared in a solvent mixture of acetone (2.0 mL) and methylene chloride (0.5 mL) at room temperature. Hexanes (5.0 mL) were added to provide a turbid solution. The vial was sealed and the solution was left, undisturbed, at ambient conditions. Racemic ilaprazole, Form F crystals were observed after six days were subsampled from the parent sample.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[C@H:3]([NH:17]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:17][C@H:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:8][CH:9]=1)[C:2]([CH3:26])([OH:1])[CH3:25]
Reactant: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(C)(C)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)COc1ccc([C@@H](N)C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of t-butyl (1R)-2-hydroxy-2-methyl-1-(4-(2-methylpentyloxy)phenyl)-propylcarbamate (340 mg, 0.930 mmol) in dichloromethane (1 mL) was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was transferred to a separatory funnel containing saturated aqueous K2CO3 solution. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated to afford (1R)-1-amino-2-methyl-1-(4-(2-methylpentyloxy)phenyl)propan-2-ol.TFA (350 mg, 99% yield) as a colorless oil which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 3.78 (dd, J=9.1, 5.8 Hz, 1H), 3.73 (s, 1H), 3.68 (dd, J=8.9, 6.7 Hz, 1H), 1.86-1.97 (m, 1H), 1.27-1.51 (m, 4H), 1.17 (s, 3H), 1.01 (s, 3H), 0.99 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis/trans-Ethyl 4-(ethyloxy)cyclohexanecarboxylate (D2, 21 g, 105 mmol) was dissolved in MeOH-THF (100 mL-100 mL) and NaOH (5 eq., 0.5 mol, 40 mL, 12.5 N aqueous solution) was slowly added at room temperature. The mixture was stirred at room temperature overnight. The THF/MeOH was then evaporated and the crude was washed with Et2O. The aqueous phase was acidified and extracted with EtOAc (2×); organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound as a pale-yellow oil, 17.3 g, 96%.
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29]OS(C)(=O)=O)[CH2:11][O:10][C:9](=[O:35])[C:8]=2[C:7]([CH3:36])=[C:6]([O:37][CH3:38])[CH:5]=1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CO>[OH:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:11][O:10][C:9](=[O:35])[C:8]=2[C:7]([CH3:36])=[C:6]([O:37][CH3:38])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COS(C)(=O)=O)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Reactant: C1COCCN1
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)OC[C@H](CN1CCOCC1)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of 46 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethylpropyl)silanyloxy]-14-methoxy-13-methyl-4-(3-methyl[1,2,4]oxadiazol-5-yl)-9-(methylsulfonyloxymethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one in a mixture of 0.25 ml of morpholine and 0.25 ml of methanol was stirred at 20° C. for 18 h. The solution was evaporated in vacuo and the residue was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield 12 mg of (4R,9S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-9-(morpholin-4-ylmethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([C:24]5([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:41]I>CN(C)C=O>[CH:1]1([N:6]([CH3:41])[C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([C:24]5([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4cccc(NC5CCCC5)c4)nc23)CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(-c2cnc3c(n2)c(C(=O)C2(C)CCCCC2)cn3COCC[Si](C)(C)C)c1)C1CCCC1
Reaction time: 14 h
Yield: 15 %

Procedure:
To a solution of [2-(3-Cyclopentylamino-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone in dimethyl formamide was added sodium hydride (60% dispersion in mineral oil, 9 mg, 0.218 mmol) under argon. The reaction mixture was stirred at room temperature for 15 minutes before the addition of methyl iodide via syringe. The reaction was stirred for 14 h before quenching with water and extracting 3 times with dichloromethane. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. Preparative thin layer chromatography (25% EtOAc/hexanes) afforded 0.0152 g (15% yield) of [2-[3-(Cyclopentyl-methyl-amino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone as a yellow oil. MS (E/I): 547 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[F:12]C(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([F:12])=[C:4]2[N:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C)n2nccc2n1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)n2ncc(F)c2n1
Temperature: 0 °C

Procedure:
A mixture of 5,7-dimethyl pyrazolo[1,5-a]pyrimidine [1.47g (10 mmoles)], trifluoroacetic anhydride (2.0 ml), and boron trifluoride etherate (2.0 ml) in CH2Cl2 (30 ml) was heated at reflux for 24 hours. At the end of this time the red solution was cooled and added to an ice cold solution of NaOH (30 ml, 2N). The organic layer was separated and the alkaline layer extracted with CH2Cl2 3(20 ml). The combined CH2Cl2 extracts were washed with water 2(20 ml) and dried over Na2SO4. The CH2Cl2 extract was evaporated and the residue covered with n-petane qnd chilled. The yellow white crystalline plates were separated by filtration, and recrystallized from n-heptane to yield an analytically pure product; mp 129°-30°.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]ncc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.301 g, 1.09 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (0.293 g, 1.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding aqueous Na2CO3. The organic layer was separated, washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (SiO2, 30% EtOAc in hexanes) to give the desired product. tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.258 g, 67%) as a foamy white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 8.40 (s, 1H), 4.63 (s, 2H), 3.67 (m, 2H), 3.28 (m, 2H), 1.44 (s, 9H); LCMS [M+H]: 353.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C([O-])(O)=O.[Na+].[NH2:36][C:37]1[C:38]2[N:39]([N:44]=[N:45][N:46]=2)[N:40]=[C:41]([SH:43])[CH:42]=1.Cl>O>[NH2:36][C:37]1[C:38]2[N:39]([N:44]=[N:45][N:46]=2)[N:40]=[C:41]([S:43][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:42]=1
Reactant: Nc1cc(S)nn2nnnc12
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(N)c4nnnn4n3)CS[C@H]12)c1csc(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer), (0.456 g, 0.001 mole) and NaHCO3 (0.143 g, 0.0017 mole) in water (10 ml), 8-amino-6-mercapto-tetrazolo[1,5-b]pyridazine (0.118 g, 0.0007 mole) was added. A slow stream of nitrogen was passed through the solution, and the mixture was heated at 50° C. for 12 hours, while keeping the pH at 6.8. After cooling, the solution was acidified with 10% HCl, the precipitate collected by filtration, washed with water and then with ethanol. There was thus obtained 0.215 g of compound (2) which was shown by NMR, TLC and IR, to be identical to the product described in Example 1, apart a minor contaminant of the anti-isomer. By using the same method, the following compounds were prepared:
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([C:52]1[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)[CH2:50][OH:51].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][CH2:50][C@@H:49]([NH:48][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=1)=[O:23])[C:52]1[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: COc1ccc([C@H](N)CO)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc([C@@H](CO)NC(=O)c2cc(C(=O)N(C)CC(C)C)cc(-c3ccc(C)cc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (41 mg, 0.22 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.11 mmol), CH2Cl2 (3 mL) were added (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (27 mg, 0.16 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (28 pt, 0.16 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1)=[O:10]
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccsc3S(=O)(=O)C2)no1
Temperature: 5 °C
Yield: 56.2 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (3.1 g, 0.012 mole), 3-amino-5-methylisoxazole (1.5 g, 0.015 mole) and xylene (120 ml) is refluxed for 1.5 hrs. in a Soxhlet apparatus, the thimble of which contains 15 g of Linde type 4A molecular sieve. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline precipitate is collected. The filtrate is refluxed for two additional hours and then cooled to give a second crop. The two fractions are combined and recrystallized from CH2Cl2 --CHCl3 mixture to give a off-white crystalline solid (2.2 g, 56%), m.p. 209°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCI
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-pentyl iodide 0.79 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 15 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[C:5]=2[CH2:3][OH:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Alternate procedure: Cool a solution of 5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole-4-carboxylic acid methyl ester (62.4 g, 200 mmol) in dichloromethane (400 mL) to 0° C. Add diisobutylaluminum hydride (440 mL, 1.0 M, 440 mmol) while maintaining the temperature between −5° C. and 0° C. Stir the resulting mixture for 30 min. Warm to 15° C. to 25° C. and stir for 3 h. Add the reaction solution to 2.0 M HCl (800 mL) at ˜8° C. to 10° C. Stir for 30 minutes Separate the phases and extract the aqueous phase with dichloromethane (200 mL). Wash the combined organic phases with water (3×100 mL). Concentrate the organic phase to 180 mL total volume. Add heptane (350 mL). Filter the resulting solid to afford 51.5 g (90%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]#[N:12])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:13]([OH:15])[CH3:14].[ClH:16]>CCOCC>[ClH:16].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:10])[C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCO
Reactant: N#CC(O)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C(O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 1-(3-bromo-4-fluorophenyl)-1-cyanomethanol (47.5 g, 206 mmol) and ethanol (10.9 g, 237 mmol) in ether is cooled with an ice bath and treated dropwise with HCl (258 mL of a 1.0 M solution in diethyl ether, 258 mmol) over a period of 40 min., stirred at ice-bath temperature for 2 h, stored at 0° C. for 6 days, warmed to room temperature, diluted with hexanes and filtered. The filtercake is dried to afford the title compound as a white solid, 39.8 g (62% yield), identified by NMR and mass spectral analyses. The title compound is a mixture of E and Z isomers. 1H NMR (300 MHz, CD3OD) δ 7.78 (m, 1H), 7.49 (m, 1H), 7.28 (m, 1H), 5.54 and 5.17 (2m, 1H), 4.45 and 4.15 (2m, 2H), 1.38 and 1.20 (2t, 3H); ESI MS m/z 261 [C10H11BrFNO2+H]+
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCc1cc(F)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.72 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.79 (1H, d, J=2.0 Hz), 6.89-7.00 (2H, m), 7.36-7.40 (2H, m), 7.59 (1H, d, J=2.0 Hz), 7.98 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:12][CH2:11][CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCO
Product: CCOCc1ccc(Br)cc1

Procedure:
A solution of 1.00 g of 4-bromobenzyl bromide in 20 ml EtOH is stirred 5 h under reflux. The solvent is evaporated to obtain 766 mg of 1-bromo-4-ethoxymethyl-benzene as a yellow oil, MS (ESI) 216.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([CH:23]([NH2:30])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH:23]([NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NC(c1cccnc1)C1CC1
Product: CCc1cc(-c2cncc(C(=O)NC(c3cccnc3)C3CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (cyclopropyl-pyridin-3-yl-methyl)-amine to afford the title compound. MS: m/e=389 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2NN=C(N)N=2)[CH2:28]C[CH2:26]1>>[CH:1]1([C:2]2[N:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:28][CH2:25][CH2:26]1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Nc1n[nH]c(C2CCC2)n1
Product: O=Cc1ccc(-c2nc3nc(C4CCC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-cyclobutyl-1,2,4-triazol-3-amine in the first step.
Reaction SMILES: [C:1]1([CH:9]=O)[C:2]([CH:7]=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C@@H:12]([CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14]>C(#N)C>[CH:17]1([CH2:16][C@H:12]([N:11]2[CH2:9][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:7]2=[O:8])[C:13]([OH:15])=[O:14])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=Cc1ccccc1C=O
Reactant: N[C@@H](CC1CCCC1)C(=O)O
Solvent: CC#N
Product: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 4 °C
Yield: 84.4 %

Procedure:
A solution of benzene-1,2-dicarbaldehyde (1.9 g, 14 mmol) and (S)-2-amino-3-cyclopentyl-propionic acid (2.0 g, 13 mmol) in acetonitrile was heated to reflux for 17 h. The solution was cooled to 4° C. for 3 h during which time a precipitate formed. The mixture was filtered and the solid washed with cold acetonitrile and dried under vacuum to give (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (3.0 g, 86%) as a white solid: LR-ES(+) m/e calcd for C16H19NO3 [M+H]+ 274.15, observed 274.1; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-2.29 (m, 11H), 4.23-5.12 (m, 3H), 7.20-7.99 (m, 4H), 13.00 (s, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([SH:15])[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3][CH3:4]>[Zn].C(O)(=O)C>[NH2:12][C:11]1[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([CH3:16])=[N:9][C:10]=1[SH:15]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCNc1c(N)c(S)nc(C)c1C(=O)OCC

Procedure:
6.2 g. of 4-butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.02 Mol.) are dissolved in 25 ml. of acetic acid at reflux temperature with stirring. Zinc dust is added cautiously in small portions until the solvent is colorless. The inorganic precipitate is then filtered off, the solvent is removed and the residue is dissolved in 10 ml. of methanol. The product 5-amino-4-butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester precipitates after the addition of aqueous ammonia, yield 3.6 g. (64%), m.p. 103°-105° (ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].B>C1COCC1>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: N#Cc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Yield: 46.3 %

Procedure:
In a 100 mL round-bottomed flask was added 4-(2-(trifluoromethoxy)phenylsulfonyl)benzonitrile (900 mg, 2.75 mmol) in THF (Volume: 25 mL) to give a colorless solution. Borane (1 molar in THF, 6.87 mL, 6.87 mmol) was added and the mixture heated to reflux and monitored by TLC. TLC appeared to show little reaction after 3 hours, so heated overnight. TLC did not change so added 2 additional equivalents of borane and refluxed for an additional two hours. The reaction was then cooled and slowly quenched with methanol. The reaction was diluted with ethyl acetate and poured into a separatory funnel. The organic layer was washed with 2M NaOH, water, and saturated, aqueous sodium chloride. The organic was separated, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 927.8 mg of crude product. Material purified on Biotage to give 422.0 mg of product (46% yield).