Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@H:5]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O1CCCC1.[OH-].[Na+]>CO>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][C@H:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:35])=[O:2])=[O:14])[N:16]=1)#[N:34]
Reactant: COC(=O)C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
3-(S)-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-3-pyridin-3-yl-propionic acid methyl ester (25 mg, 0.0533 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL.) Sodium hydroxide solution (2 mL, 2M) was added and the reaction was permitted to stir overnight at room temperature. After 18 hours, the pH was adjusted to 4 and reaction lyophilized. The crude product was purified by HPLC to provide the title compound in 68% yield. LC-MS ESI+: 455 (M+1)+; ESI−: 453 (M−1)−.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C=O)C>>[C:25]([C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: COc1cc(NC(=O)Cn2cnc3cccc(Br)c32)cc(OC)c1
Product: COc1cc(NC(=O)Cn2cnc3cccc(C#N)c32)cc(OC)c1

Procedure:
To a solution of 2-(7-bromo-1H-benzoimidazol-1-yl)-N-(3,5-dimethoxyphenyl)acetamide (Example 52) (50 mg, 0.13 mmol) in dry DMF (0.64 mL) copper(I) cyanide (23 mg, 0.26 mmol) was added. The mixture was irradiated in a microwave oven at 200° C. for 60 min. The reaction mixture was partitioned between ethyl acetate and water. The organic extract was concentrated and the residue was purified by preparative HPLC to yield the title compound, 20 mg (46%). MS (ESI) m/z: 337.2 [M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.69 (s, 6 H) 5.39 (s, 2H) 6.23 (t, J=2.3 Hz, 1H) 6.80 (d, J=2.0 Hz, 2 H) 7.37 (t, J=7.8 Hz, 1H) 7.74 (d, J=7.1 Hz, 1H) 8.05 (dd, J=8.1, 1.0 Hz, 1H) 8.40 (s, 1H) 10.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:11][CH2:12][N:13]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[CH2:14][CH2:15]2)[N:7]=1
Reactant: Nc1nc(C#CC2(O)CCNCC2)cn2nc(-c3ccco3)nc12
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(C#CC2(O)CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-piperidin-4-ol (22 mg,0.068 mmol) and 2,4,6-trifluoro-benzaldehyde (11 mg, 0.068 mmol) in CH2Cl2 (2 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol) and acetic acid (6 uL, 0.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of silica-gel, washed with ethyl acetate. The eluant was concentrated. The residue was isolated by reversed phased HPLC eluting with a water/acetonitrile gradient to yield 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-1-(2,4,6-trifluoro-benzyl)-piperidin-4-ol (1 mg, 3%). 1H NMR (300 MHz, DMSO): δ 7.92 (br s, 1H), 7.70 (m, 3H), 7.41 (s, 2H), 7.14 (s, 1H), 6.72 (s, 1H), 4.43 (s, 2H), 3.80 (m, 4H), 2.12-1.96 (m, 4 H). MS: m/z: 469 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)[NH2:7].CCN(C(C)C)C(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[ClH:1].[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNCc1cc(N)cc(F)c1O[C@@H]1CCOC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(N)cc(F)c1O[C@@H]1CCOC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To 38B (200 mg, 0.639 mmol) and DIEA (0.445 ml, 2.55 mmol) in DMF (10 mL), was added N-(benzyloxycarbonyloxy) succinimide (167 mg, 0.671 mmol). The mixture was stirred at rt for 1 h, then quenched with H2O. The mixture was extracted with EtOAc (3×) and the organic layer was washed with 1N HCl, sat. NaHCO3, brine, and dried over Na2SO4. The crude was purified by flash column chromatography (0-60% EtOAc/hexanes) to give 38C (182 mg, 0.486 mmol, 76% yield). MS (ESI) m/z: 375.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:22]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH2:28][CH2:29]2)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of trans-4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (8.5 g, 32.8 mmol) in DCM (100 mL) 1,1-carbonyldiimidazole (4.87 g, 30.1 mmol) was added and the reaction was left stirring for 2 hours. Then isobutyryl-piperazine (6.95 g, 27.3 mmol) was also added and the reaction was left stirring for 16 h at room temperature. The mixture was diluted with 50 mL of H2O, the organic phase collected and the solvent removed under reduced pressure. The residue was washed with 1N NaOH solution and the precipitate was filtered, affording 8.7 g (21.9 mmol) of [4-(4-Isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester. The product obtained was dissolved in 100 mL of DCM and H2SO4 (2.92 mL, 54.9 mmol) was added. The reaction was stirred for 18 hours and the mixture was washed with 50 mL of 15% NaOH solution, the organic phase was collected and concentrated under reduced pressure. 3.85 g of the titled product were obtained (yield=48%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1cccc(Br)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a suspension of sodium hydride (3.52 g, 88 mmol) in DMF (40 ml), was added pyrazole (3.0 g, 44 mmol) in portions. After stirring at room temperature for 30 minutes, 1-bromo-3-fluorobenzene (9.3 g, 53 mmol) in DMF (20 ml) was added dropwise and the resulting mixture was stirred for 2 hours at 130° C. The mixture was cooled and quenched by the addition of a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using normal phase chromatography, eluting with petroleum ether containing 10% ethyl acetate to give 1-(3-bromophenyl)-1H-pyrazole (4.7 g) as yellow solid.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:29]2[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:34][C:31]1[S:32][CH:33]=[C:29]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:30]=1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A mixture of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) and concentrated hydrochloric acid (0.404 ml) in methanol (10.5 ml) was warmed at 33°-35° C. for 1.5 hours. The mixture was poured into ice-water, adjusted to pH 7.5 with saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (786 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C:7](=[O:16])[NH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[NH:8][C:7](=[O:16])[C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(=O)[nH]c(Cl)nc2c1OC

Procedure:
Equimolar amounts (0.10 mole) of 7,8-dimethoxy-2,4-(1H,3H)-quinazolinedione and phosphorous oxychloride are stirred at room temperature overnight and the volatiles evaporated in vacuo to afford a residue of 2-chloro-7,8-dimethoxy-4(3H)-quinazolineone which is purified by washing with aqueous sodium bicarbonate, extraction with chloroform and evaporation of solvent. To the residue is added a solution of 0.10 mole of 3-methylpiperidine in 300 ml. of isoamyl alcohol and the mixture heated at reflux for three hours, the solvent is then evaporated in vacuo to afford 2-(3-methylpiperidin-1-yl)-7,8-dimethoxy-4(3H)-quinazolineone hydrochloride. To this is added 150 ml. of phosphorous oxychloride and the resulting mixture is heated at reflux for two hours. The liquids are evaporated to give a residue of 2-(3-methylpiperidin-1-yl)-4-chloro-7,8-dimethoxyquinazoline hydrochloride. The product is dissolved in dilute aqueous sodium bicarbonate, extracted with chloroform, dried (Na2SO4) and the solvent evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:20])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:11]([CH3:28])[CH2:10]2)[C:38](=[O:40])[CH3:39])=[CH:4][CH:3]=1
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of (2S,4R)-[4-(4-chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone (250 mg, 0.636 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol) followed by acetyl chloride (90 uL, 1.27 mmol). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg, 71%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=O)=[CH:12][CH:13]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: COc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc(C)cc1
Yield: 54.1 %

Procedure:
When the above experiment was repeated using 17.5 grams of sulfuric acid in the electrolyte, there was observed a current yield of 44.0% with a 51.8% selectivity to anisaldehyde. In addition, the current efficiency was 84.9%. Again, when the experiment was repeated using 32 grams of sulfuric acid, the oxidation of p-methoxytoluene resulted in a current yield of 54.1%, a 54.1% selectivity to the aldehyde and a 100% current efficiency.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.CCOC(C)=O.O.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)#[N:23]
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.3 g, 1.0 mmol) in DMF (5 mL) was added Zn(CN)2 (0.12 g, 1.0 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The reaction mixture was allowed to stir at 80° C. for 3.5 h. After being allowed to cool to rt, EtOAc (20 mL) and H2O (20 mL) were added, the organic solution was separated, and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, washed with H2O and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to provide 8-cyano-3,4-dihydro-1H-1-benzazepine-2,5-dione (140 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5](NC)[N:4]=1.[C:12](OC(=O)C)(=[O:14])C>[Zn]>[CH3:12][O:14][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1
Reactant: CNc1nc(C)nc(OC)n1
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Product: COc1nc(C)nc(OC)n1

Procedure:
Provided herein is a novel and useful process for preparing 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine that broadly comprises the steps of (a) reacting zinc bis(imino-bis-carbimic acid methyl ester) with acetic anhydride to give 2,4-dimethoxy-6-methyl-1,3,5-triazine and (b) reacting the 2,4-dimethoxy-6-methyl-1,3,5-triazine, formed in step (a), with methylamine to give 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[OH-].[Na+].O.S(OC)(O[CH3:20])(=O)=O>CCOCC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:20])=[C:6]([Cl:11])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(OC)c(Cl)c1

Procedure:
To a cooled solution of 14.5 g. (0.078 mol.) of 3-chloro-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) of sodium hydroxide in 100 ml. of water was dropwise added 9.8 g. (7.3 ml., 0.079 mol.) of dimethyl sulfate. The reaction mixture was refluxed for two hours. After cooling, ether was added and the layers were separated. The organic phase was washed with water, dilute sulfuric acid and water, dried (Na2SO4) and concentrated in vacuo to give 3-chloro-4-methoxybenzoic acid methyl ester, m.p. 72°-74°.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].CC(O)C.[CH2:17]([NH2:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:17]([NH:33][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
A 2 L two neck round bottom flask equipped with condenser was charged with D(+) glucose (60 g, 0.333 moles), 2-propanol (900 mL), hexadecylamine (81 g, 0.334 moles) and deionized water (300 mL). The reaction was stirred and heated to 50°-55° celsius for 1 hour to obtain a homogeneous solution. The reaction was then allowed to run overnight at room temperature. The reaction precipitated out after 2-3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[C:5]([Cl:10])=[CH:4][N:3]=1.Cl.[NH2:12][OH:13]>CC(O)C.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:12][OH:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1cc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: ON=Cc1cc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of lithium di-isopropylamide was prepared by the addition of 100 ml of 1.5 molar (M) butyllithium (in a hexane solution) to 14.2 g of di-isopropylamine in 100 ml of THF at less than -30° C. After stirring for 20 minutes the solution was cooled to below -70° C. and a solution of 20.8 g of 2,5-dichloropyridine in 56 ml of THF was added at such a rate that the temperature was maintained at below -70° C. After the addition was complete, the reaction temperature was stirred at below -70° C. for 30 minutes. A solution of 13.2 g of DMF in 30 ml THF was added at the same temperature and stirred for an additional 30 minutes. The reaction mixture was allowed to warm to room temperature then poured into a mixture containing 250 g of ice and 45 ml of concentrated HCl and stirred for 15 minutes. The acidic solution was neutralized to about pH 6-7 with 3 normal (N) NaOH. The organic layer was separated and the aqueous layer extracted with ethyl ether. The organic solutions were combined, washed with saturated NaCl solution, dried and evaporated to dryness to give about 22 g of 2,5-dichloro-4-pyridinecarboxaldehyde. This aldehyde was dissolved in 100 ml of 2-propanol, mixed with 13.8 g of hydroxylamine hydrochloride and 20 drops of concentrated HCl and heated on a steambath for 1 hour. The mixture was then poured onto 200 g of ice, stirred well and filtered leaving a solid residue. The solid was vacuum dried to give 22.8 g (85%) of the desired 2,5-dichloro-4-pyridinecarboxaldehyde oxime ##STR6##
Reaction SMILES: [OH-:1].[Na+].OO.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[C:28]([F:31])([F:30])[F:29])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1.O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:1])=[CH:22][C:21]=3[C:28]([F:31])([F:29])[F:30])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1
Reactant: [OH-]
Reactant: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C#N)cc2C(F)(F)F)n1C
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C(N)=O)cc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1M aqueous sodium hydroxide solution (0.73 ml) and a 30% hydrogen peroxide solution (0.1 ml) were added to a solution of 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzonitrile (50 mg) in ethanol (3 ml) in an ice bath, followed by stirring at room temperature for 3 hours, and a 1M aqueous sodium hydroxide solution (0.42 ml) was added thereto, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate (1 ml) was added to the residue and the precipitated solid was washed with ethyl acetate and then diethylether to obtain, as a white solid 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzamide (29.2 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]C(C2OCCO2)C)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[O:32]1CCO[CH2:34][CH2:33]1.Cl>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][C:33](=[O:32])[CH3:34])[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)C1OCCO1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)=O

Procedure:
A suspension of 8 g. of 5-chloro-2-[4-(1,3-dioxolan-2-yl)pentyl]-3-phenylisoindole-1-carboxylic acid ethyl ester in a mixture of 40 ml. of dioxane and 10 ml. of water is treated with 2 ml. of concentrated hydrochloric acid and then boiled at reflux for 3 hours. The solution obtained is concentrated to dryness under reduced pressure and the residue partitioned between water and methylene chloride. The organic phase is washed with a 2-N sodium carbonate solution and then with a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed, and there is obtained 5-chloro-2-(4-oxopentyl)-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 93°-94° C. Crystallization from ether/hexane yields colorless crystals; melting point 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:25]=[CH:26][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:24][CH2:23]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (15 ml) was added 1-(4-chlorobenzyl)-piperazine (0.115 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.55 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.148 g, 70%); 1H-NMR (500 MHz, DMSO-d6) 3.05 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 7.02 (s, 2H, NH2), 7.34 (d, J=8.52 Hz, 2H) and 7.38 (d, 2H) (3,5-ArH and 2,6-ArH), 8.16 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.92 min—426, 428, 430 [(M+H)+, BrCl isotopic pattern].