Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=591.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-N,N-dimethylacetamide.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[N:20]=[C:19]([C:21]#N)[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl.[O:24]1CCCC1>C(OCC)(=O)C>[C:11]([C:15]1[N:20]=[C:19]([CH:21]=[O:24])[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cccc(C#N)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(C=O)n1
Reaction time: 1.5 h

Procedure:
Diisobutylaluminum hydride (1.02 mol/L toluene solution, 23.5 mL, 24.1 mmol) was added to a solution of 6-tert-butylpyridine-2-carbonitrile obtained (2.57 g, 16.0 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at −78° C., and the mixture was stirred for 1.5 hr while cooling in ice. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate and stirred at room temperature for 45 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=4:1) to afford the title compound as a yellow oil (1.71 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].O.[OH-].[Na+]>OS(O)(=O)=O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH:12]([C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(CSc1nc2ccccc2[nH]1)C(=O)O

Procedure:
47.4 g of 2-mercaptobenzimidazole are reacted in the same manner as in Example 10 with 40.7 g of itaconic acid in 150 ml of 70% H2SO4 at 40°-43°. After dilution with water, sodium hydroxide solution is added until pH 4 is reached, the product being precipitated as the dihydrate. Anhydrous 3-(benzimidazol-2-ylthio)-propane-1,2-dicarboxylic acid, melting at 165°-168°, is obtained from the dihydrate by recrystallisation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:7])[OH:6].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:6])[OH:7])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCC[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of water is cooled to 5° , and the pH adjusted to 9.5 with 2 molar sodium hydroxide solution. To this mixture is added 6.8 g of benzyl chloroformate whilst maintaining the pH and temperature. After the addition is complete the mixture is stirred for 3 hours at pH 9.5 at room temperature and left to stand overnight. The mixture is then extracted with 100 ml of ether and the aqueous layer stirred at 5° with an equal volume of chloroform. The mixture is acidified to pH 2, the chloroform layer separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The oily product is triturated with ether to give a white solid, 3-(N-benzyloxycarbonylamino)propylphosphinic acid, m.p. 53-55°, 31P-NMR : δ=+36.6 ppm (CDCl3).
Reaction SMILES: [CH3:1][NH2:2].CO.Cl[C:6]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:23][CH3:24])=[O:22])[CH:9]=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29]>O>[CH3:1][NH:2][C:6]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:23][CH3:24])=[O:22])[CH:9]=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C(F)(F)F)c(Cl)n1
Reactant: CN
Solvent: CO
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C(F)(F)F)c(NC)n1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A 40% methylamine--methanol solution (10 ml) was added to (E)-2-[2-(6-chloro-5-trifluoromethylpyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (402 mg), and the mixture was stirred at 100° C. for 17 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (379 mg). mp. 66°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:39](=[O:50])[CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:47]([N:44]4[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)=[O:50])[CH2:46][CH2:45]4)=[O:48])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCN(CC(=O)N2CCOCC2)CC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (90 mg, 0.24 mmol) (from Example 25a supra) in tetrahydrofuron (3 mL) was added triethyl amine (60 mg, 0.60 mmol) (Aldrich), followed by the addition of 4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl chloride (99 mg, 0.36 mmol) (from Example 48a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-{1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-piperidine-3-yl}-1,3-dihydro-indol-2-one as a white solid. (Yield 70 mg, 47.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH2:14]([C:21]1[C:22](=[O:31])[NH:23][C:24](N[N+]([O-])=O)=[N:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:24]2[NH:23][C:22](=[O:31])[C:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:26][N:25]=2)=[N:6][CH:7]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccccc1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccccc2)c(=O)[nH]1
Yield: 50.6 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-benzyl-2-nitroamino-4-pyrimidone (0.74 g) were refluxed in pyridine (3 ml) for 4 hours. The solvent was removed in vacuo and the residual oil partitioned between chloroform and water at pH 5. The chloroform extracts were dried over magnesium sulphate and evaporated to an oil. Recrystallisation from ethanol/ethyl acetate gave 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-benzyl-4-pyrimidone (0.65 g) m.p. 138°-9° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][CH2:9]C(O)=O)=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C([N:22](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Cl:16][CH2:15][CH2:14][N:13]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][CH2:9][NH2:22])=[CH:1][CH:2]=1)[CH2:17][CH2:18][Cl:19]
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Chlorambucil (0.30 g; 0.99 mmol) was suspended in 2 ml of acetone. The resultant mixture was stirred under a nitrogen gas atmosphere and ice-cooling, to which 0.17 ml (1.22 mmol; 1.2 equivalents) of triethylamine and 0.11 ml (1.22 mmol; 1.2 equivalents) of ethyl chloroformate were added successively. Twenty minutes later, a solution of 0.13 g (2.0 mmol; 2.0 equivalents) of sodium azide in 2 ml of water was added dropwise. The resulting mixture was stirred, as was, for 1 hour, to which ice was added to terminate the reaction. The thus-obtained mixture was extracted three times with 20 ml portions of benzene. The benzene layers were combined, dried over sodium sulfate and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was added with 9 ml of 8N hydrochloric acid, followed by heating for 15 minutes at 100° C. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water. The thus-obtained mixture was adjusted to pH 12 with concentrated aqueous ammonia, followed by extraction with ethyl acetate. The extract was dried and concentrated, whereby 0.21 g of the title compound was obtained as a crude yellow oil of high viscosity. This reaction product was provided for use in the next reaction without purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([OH:19])[CH2:10][O:11][Si](C(C)(C)C)(C)C)(C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:7][C@H:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([OH:19])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H](c1ccccc1)[C@H](O)CO
Reaction time: 2 h

Procedure:
To a solution of 300 mg of tert-butyl[(1R,2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate and 5 ml of methanol was added 5 ml of a 4 M hydrogen chloride/dioxane solution, followed by stirring for 2 hours. The solvent was evaporated under reduced pressure to obtain 171 mg of (2S,3R)-3-amino-3-phenylpropane-1,2-diol hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH2:26]>CC(O)C>[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH:26][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: NC[C@H](O)CO
Solvent: CC(C)O
Product: COc1ccc2nc(NC[C@H](O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product (17 mg, 22%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>C1COCC1>[CH2:19]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC1c2ccccc2-c2ccccc21
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of fluorene (33.2 g, 0.20 mol) in 300 mL THF at −78° C., n-butyllithium (2.5 M, 80 mL) was added dropwisely. The mixture was stirred at −50° C. for 45 minutes, and then cooled to −78° C. again and n-hexylbromide (33.0 g, 0.20 mol) in THF (25 mL) was added dropwise to the mixture. The solution was allowed to warm up to room temperature and stirred for 5 h. The mixture was then poured into water and extracted with ether. The organic extracts were washed with brine and dried over magnesium sulfate, and purified by silica gel column with hexane to give pure compound 2 (38 g, yield 76%).
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:7][N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:34](F)=[CH:35][C:36]([F:59])=[C:37]([S:39]([N:42]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH3:58])[C:43]2[S:44][CH:45]=[N:46][N:47]=2)(=[O:41])=[O:40])[CH:38]=1>CS(C)=O.C(OCC)(=O)C>[Cl:32][C:33]1[C:34]([O:19][C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:7]=2)=[CH:35][C:36]([F:59])=[C:37]([S:39]([N:42]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH3:58])[C:43]2[S:44][CH:45]=[N:46][N:47]=2)(=[O:40])=[O:41])[CH:38]=1
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol (Preparation 868, 2.069 g, 5.791 mmol) in dimethyl sulfoxide (34 mL) was added potassium carbonate (1.66 g, 12.0 mmol). After stirring for 10 minutes, 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 2.67 g, 5.78 mmol) was added. After stirring at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by automated flash column chromatography using a 0-100% ethyl acetate/hexanes gradient and a 40 g column gave the title compound (3.20 g, 69%) as a clear oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C.C(OCC)(=O)C>CC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17][CH2:18][C:19]([OH:23])=[O:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OCCCO)c1ccc(CC(C)C)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCC(OCCC(=O)O)c1ccc(CC(C)C)cc1
Reaction time: 0.17 h

Procedure:
Chromium(VI) oxide was dissolved in an aqueous solution of sulfuric acid, and diluted with water to give a Jones reagent. To a solution of 3-[1-(4-isobutylphenyl)pentyloxy]propanol in acetone was added the obtained Jones reagent at room temperature until an orange-brown color persisted. After 10 minutes, 2-propanol was added to the reaction mixture. Ethyl acetate was added thereto, and the mixture was washed with water and brine, dried over magnesium sulfate and concentrated. Silica gel column chromatography of the concentrate afforded the object compound.
Reaction SMILES: C([Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.C(O)=O.[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]([C:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][N:54]=3)=[O:52])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>>[OH:28][C@H:27]([CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=1)[CH2:29][NH:33][CH2:34][CH:35]1[CH2:36][CH2:37][N:38]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]([C:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][N:54]=3)=[O:52])=[CH:46][CH:45]=2)(=[O:42])=[O:43])[CH2:39][CH2:40]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)c3n[nH]c4ccccc34)cc2)CC1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1n[nH]c2ccccc12
Yield: 13.4 %

Procedure:
Prepared from t-butyl-[4-(2S)-oxiranylmethoxy-phenoxy]-diphenylsilane (0.623 g, 1.54 mmol), (1H)-Indazole-3-carboxylic acid [4-(4-aminomethyl-1-piperidinyl-sulfonyl)-phenyl]-amide formate salt (0.71 g, xx mmol) and diisopropylethyl amine (0.41 mL) according to the procedure used for example 37 to give 0.12 g of the title compound as a white solid.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClN1C(=O)CCC1=O.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:25][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][N:29]=2)[CH3:27])=[O:24])=[CH:18][CH:17]=1)([CH3:15])=[CH2:14]>>[CH3:2][C:1]1[CH2:15][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:25][C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[CH:30][N:29]=3)[CH3:27])=[O:24])=[CH:20][CH:21]=2)([CH3:14])[O:4][N:3]=1
Reactant: CC=NO
Reactant: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Agent: O=C1CCC(=O)N1Cl
Product: CC1=NOC(C)(c2ccc(CC(=O)N[C@H](C)c3ccc(OCC(F)(F)F)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of acetaldoxime (14.1 mg, 0.238 mmol) was added N-chlorosuccinimide (31.8 mg, 0.238 mmol). The resulting mixture was stirred at room temperature for 3 h. 2-(4-Isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (90 mg, 0.24 mmol) was added, followed by the TEA (0.099 ml, 0.71 mmol), the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(3,5-dimethyl-4,5-dihydro-isoxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a white solid (23.8 mg, 23%). 1H NMR (CDCl3, 400 MHz). δ 8.299 (dd, J=2.75, 5.31 Hz, 1H); 7.407 (t, J=2.93 Hz, 1H); 7.361 (dd, J=1.28 Hz, J=8.42 Hz, 4H); 7.243 (d, J=2.20 Hz, 1H); 7.222 (d, J=2.38 Hz, 1H); 5.122 (quintet, J=7.14 Hz, 1H); 4.436 (m, 2H); 3.550 (s, 2H); 3.063 (m, 2H); 1.965 (t, J=1.10 Hz, 3H); 1.684 (d, J=1.10 Hz, 2H); 1.466 (d, J=6.96 Hz, 3H); MS (ES): m/z 436.2 (M+H). FLIPR alpha1I IP=41 nM.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:14](O)[CH2:15][CH2:16]CC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCCCC)(=O)C>[C:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCOC(=O)C(O)c1ccccc1
Reactant: CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCOC(C)=O
Product: CCCCCOC(=O)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
A 100 mL three-neck flask, equipped with a magnetic stir bar, a Claisen adapter with a thermocouple and a subsurface nitrogen inlet, and a short path condenser, was charged with 7.94 grams of ethyl mandelate, 40 mL of 1-pentanol, and 0.75 gram of p-toluenesulfonic acid. The reaction was stirred at 120°-132° C. for 4.0 hours with a nitrogen sweep. The reaction mixture was taken up in butyl acetate, extracted with dilute aqueous sodium hydroxide, washed three times with water, dried over magnesium sulfate, and filtered. Solvent was removed by rotary evaporation to yield 8.3 grams of a straw-colored liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](I)[CH3:10]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Oc1cccc(F)c1
Product: CCOc1cccc(F)c1

Procedure:
3-fluoro-phenol and ethyl iodide were reacted to form 3-fluoro-ethoxy benzene with a refractive index of nD25 =1.4823 which was reacted with nitric acid to obtain 2-ethoxy-4-fluoronitro benzene with a melting point of 28°~30° C. which was reacted to obtain 0-(4-nitro-3-ethoxy-phenyl)-hydroxylamine melting at 97°~98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a 250 mL round-bottomed flask was added chloroform (60 mL) along with 2,4-dimethoxybenzoic acid (2.0 g, 10.98 mmol). The solution was cooled to 0° C. and bromine (0.566 mL, 10.98 mmol) was added dropwise over 5 minutes. The solution was allowed to warm to room temperature and stirred overnight. The resulting solid was filtered, washed with cold chloroform and dried under vacuum to give 2.49 g (8.6 mmol, 78% yield) of 5-bromo-2,4-dimethoxybenzoic acid as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1.0 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 3.95 (s, 3H), 6.78 (s, 1H), 7.86 (s, 1H). LCMS Rt=1.453 min., m/z 262.99 (M+H), 93% purity.
Reaction SMILES: [CH2:1]([NH:8][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.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][C:37](=O)[CH2:36]1)=[O:34])[CH3:31]>C(O)(=O)C.C1COCC1>[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][CH:37]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:36]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
Dibenzyl amine (0.150 g, 0.77 mmol) and sodium triacetoxyborohydride (0.300 g, 1.4 mmol) were added to a solution of 3-oxo-cyclobutanecarboxylic acid ethyl ester (0.100 g, 0.700 mmol) and acetic acid/THF (10%, 4.4 mL), stirred at room temperature for 72 hours and concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with water, saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo to give crude product. Purification by flash chromatography (silica, 1:9-3:7 EtOAc:hexanes) provided the title compound (0.180 g, 73% yield, 10:1 cis:trans ratio) as a solid.