Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].Cl.[NH2:33]O.Cl>CO.CO.O.C(OCC)(=O)C.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
A solution of trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (0.4 g, 0.96 mmol) in methanol (3 mL) was added dropwise to a solution of NaOH (0.042 g, 1.06 mmol) in methanol/water (3 mL/0.2 mL) at −30° C. After stirring for 10 min a solution of hydroxylamine hydrochloride (0.134 g, 1.93 mmol) and NaOH (0.077 g, 1.93 mmol) in methanol/water (5 mL/5 mL) was added at −30° C. Stirring was continued for 30 min at −30° C. The solution was added dropwise to 6 M HCl at 80° C. Stirred 30 min at 80° C. The reaction mixture was dissolved between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Acidic reversed phase chromatography, gradient 35% to 75% acetonitrile. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (205 mg, 55.4%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.63 (d, 2H), 1.98 (d, 2H), 2.81-3.14 (m, 4H), 3.55 (d, 3H), 4.21 (d, 1H), 4.63 (d, 1H), 5.63 (s, 1H), 7.22-7.37 (m, 2H), 7.54 (d, 2H). MS m/z 385 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:26].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:26]
Reactant: CC1Oc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a 40 mL vial containing tert-butyl 4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yloxy)piperidine-1-carboxylate 394D (0.223 g, 0.615 mmol) was added 50% solution of TFA in DCM (2.0 mL, 12.98 mmol) to give a clear brown solution. The reaction was monitored by HPLC. At 0.5 hr, the reaction was pulled and concentrated in vacuo, affording the product as a clear, brown oil (0.161 g, 100% yield). ESI-MS: m/z 263.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:12][S:11][CH2:10]1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:14]2[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:12][S:11][CH2:10][CH:9]12
Reactant: Cc1ccccc1C=C1CSCC(=Cc2ccccc2C)C1=O
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3C)CSCC2C1c1ccccc1C
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A mixture of 6.7g of tetrahydro-3,5-bis-[(2-methylphenyl)methylene]-4H-thiopyran-4-one and 1.6g of n-propyl hydrazine in 250ml of methanol is heated at reflux temperature for 4 hours and allowed to cool to room temperature over a 16hour period. The precipitate that forms is collected by filtration and chromatographed on a neutral alumina column (Activity I). The fractions eluted with 10-20 % ether/hexane are combined and recrystallized from methanol/water to give 1.6g of the title compound, melting point 110°-112.5°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9]N=C1CCCCC1=O.OS(O)(=O)=O.[C:23]([O-:26])(O)=O.[Na+]>CC#N>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]2[C:4]([C:2]3[CH2:3][CH2:4][CH2:5][C:23](=[O:26])[C:7]=3[NH:9]2)=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C1CCCCC1=NNc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(Cl)c(Cl)ccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 2-(2-(2,3-dichlorophenyl)hydrazono)cyclohexanone (1.6 g, 5.9 mmol) in MeCN (10 mL), H2SO4 (0.6 mL, 0.01 mmol, 1.6M solution) was added and the reaction mixture was stirred at 80° C. for 16 h, cooled to room temperature, basified with NaHCO3 and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound as a solid (0.90 g, 60%). 1H NMR (200 MHz, DMSO-d6, δ in ppm) 12.13 (bs, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 2.99 (t, J=8.4 Hz, 2H), 2.62-2.2.56 (m, 2H), 2.21-2.12 (m, 2H).
Reaction SMILES: [CH2:1]1[O:9][C:4]([CH2:7][CH3:8])([CH2:5]Br)[O:3][CH2:2]1.[I-:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]1[O:9][C:4]([CH2:7][CH2:8][I:10])([CH3:5])[O:3][CH2:2]1
Reactant: CCC1(CBr)OCCO1
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(CCI)OCCO1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of 4 bromo-2-butanone ethylene ketal (16.4 mmol, 3.2 g) in acetone (30 mL) was treated with sodium iodide (24 mmol, 3.7 g) and sodium carbonate (50 mmol, 5.1 g) and was reluxed overnight. The resulting mixture was filtered, washed with acetone (10 mL) and evaporated to dryness to a white solid. The residue was triturated with a mixture of 1:1 ether:pet ether (20 mL), stirred 30 min., filtered and evaporated to give 3.74 g (94%) of a pale yellow oil. LR-ES (C13H22O4): 243 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: Nc1cccnc1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCCCl)Nc1cccnc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
1-Chloro-2-isocyanato-ethane (560 mg, 5.31 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (500 mg, 5.31 mmol) in toluene (10 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 1.0 g (98% yield) of 1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[C:25]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCCc2c1cccc2-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 50 mL Schlenk tube was charged with 5-bromo-3,4-dihydronaphthalen-1(2H)-one (5-bromo-1-tetralone [Aldrich], 488 mg, 2.17 mmol), which was dissolved in toluene (2.5 mL) under a nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (0) (70 mg, 0.06 mmol) was added to the flask followed by more toluene (2.5 mL). Aqueous sodium carbonate (2.0 M, 2 mL, 4 mmol) was added, followed by a solution of 3-trifluoromethylphenyl boronic acid (489 mg, 2.57 mmol) in ethanol (2.5 mL). A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then the flask was sealed and heated in a 110° C. oil bath overnight. The resulting mixture was cooled to room temperature. Aqueous hydrogen peroxide solution (30%, 0.3 mL) was added and the mixture was stirred for 1 h. The reaction was then diluted with water (25 mL) and extracted with ethyl ether or EtOAc (3×75 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→40% EtOAc/hexanes, gradient), to afford 628 mg (99%) of 5-(3-(trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]=O)[O:11][C:10]=2[CH:16]=1)[CH2:4][CH3:5])[CH3:2].[C:17]([CH:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][O:21][C:20]1=[O:30])#[N:18].[NH4+].[Cl-]>N1C=CC=CC=1>[C:17]([C:19]1[C:20](=[O:30])[O:21][C:22](=[CH:14][C:12]2[O:11][C:10]3[CH:16]=[C:6]([N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=[CH:8][C:9]=3[CH:13]=2)[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:18]
Reactant: CCN(CC)c1ccc2cc(C=O)oc2c1
Reactant: N#CC1C(=O)OC=C1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CCN(CC)c1ccc2cc(C=C3OC(=O)C(C#N)=C3c3ccccc3)oc2c1
Temperature: 80 °C

Procedure:
To 5 mL of pyridine in a 15 mL round-bottom flask was added 217 mg (1 mmol) of the compound of Example 2 and 172 mg (1 mmol) of 3-cyano-4-phenyl-2-furanone. The solution was heated at 80° C. for one hour, colled and poured into 20 mL dilute NH4Cl. The resulting mixture was extracted 2X with 20 mL 3:2 hexanes Et2O and the combined organic extracts were washed once with 10 mL of water, The organic phase was dried (MgSO4) and the solvent removed by rotary evaporation. The resulting solid was purified by flash chromatography (7:2 cyclohexane/EtOAc; SiO2, 1 ×12") to yield 292 mg of dye. Anal. calcd. for C24H20N2O3 : C, 74.2; H, 5.4; N, 7.5. Found: C, 74.0; H, 5.2; N, 6.9.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[S:19][CH:18]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>ClCCl>[C:26]([O:30][C:31](=[O:32])[NH:33][CH2:34][C:35]([NH:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[S:19][CH:18]=1)=[O:36])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1csc2ncccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1csc2ncccc12
Yield: 85.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (11 g) was added with stirring to a solution of 3-aminothieno[2,3-b]pyridine (8 g) and N-(tert-butoxycarbonyl)glycine (10 g) in 200 mL of dichloromethane. After one hour the reaction mixture was filtered to remove the separated 1,3-dicyclohexylurea and evaporated to an oil. Crystallization from ethyl ether afforded 14 g of a solid, m.p. 190°-192° C. Recrystallization of 3 g from acetonitrile afforded 2.4 g of crystals, m.p. 192°-194° C. Final recrystallization from acetonitrile afforded 2.0 g of crystals, m.p. 194°-196° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([O:18][CH2:19][CH2:20][OH:21])([C:16]#[N:17])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:22][OH:23]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13]([O:18][CH2:19][CH2:20][OH:21])([C:16](=[NH:17])[NH:22][OH:23])[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(C#N)(OCCO)CC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CCC(OCCO)(C(=N)NO)CC1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyloxy)methyl)-1-(2-hydroxyethoxy)cyclohexane carbonitrile (3.44 g, 10.97 mmol) and 50% aq. hydroxylamine (0.725 g, 10.97 mmol) in ethanol (17 mL) was heated at 80° C. (oil bath temp) for 6 h. The mixture was concentrated to dryness in vacuo and the residual solid triturated with ethanol to obtain the title compound, 4-((tert-butyldimethylsilyloxy)methyl)-N-hydroxy-1-(2-hydroxyethoxy)cyclohexanecarboximidamide (3.30 g, 9.52 mmol, 87% yield) as a tan crystalline powder: HPLC: retention time=1.96 min (area percent=91%); LCMS: m/z 347 (M+H), 369 (M+Na); 1H NMR (500 MHz, CDCl3) δ ppm 0.02 (6H, s), 0.87 (9H, s),1.23 (1H, t, J=7.0 Hz), 1.25-1.34 (2H, m), 1.49-1.58 (2H, m), 1.57-1.63 (1H, m), 1.67-1.77 (2H, m), 2.05-2.16 (2H, m), 3.41-3.46 (4H, m), 3.69-3.72 (2H, m), 4.78 (2H, s), 7.95 (1H, brs); 13C NMR (126 MHz, CDCl3) δ ppm-5.22, 18.5, 25.0, 26.1, 32.0, 38.6, 62.1, 64.1, 66.9, 77.9, 154.7.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[N:9]=[C:8]([C:49]([F:52])([F:51])[F:50])[N:7]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.O>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:49]([F:51])([F:50])[F:52])[N:9]=[C:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:11]=1
Reactant: CC(=O)OCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reaction time: 0.75 h

Procedure:
To a solution of [6-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl)carbonyl]-2-(trifluoromethyl)pyrimidin-4-yl]methyl acetate (0.85 g, 1.15 mmol, from Step D) in THF (16 mL) at room temperature was added a solution of lithium hydroxide, monohydrate (0.072 g, 1.7 mmol) in water (4 mL). The reaction was stirred for 45 minutes, then was neutralized by the addition of 1N HCl and the product was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, decanted and concentrated to afford a yellow foam, which was used without further purification. Yield: 0.72 g (90%); LC-MS: 697.2 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.42 (d, 1H), 6.81 (d, 1H), 5.68 (s, 2H), 4.92 (s, 2H), 4.28-4.17 (m, 1H), 3.89-3.71 (m, 3H), 3.71-3.61 (m, 2H), 3.55 (dd, 2H), 3.47-3.34 (m, 3H), 3.33-3.21 (m, 1H), 2.68-2.53 (m, 1H), 1.93-1.68 (m, 2H), 1.60-1.41 (m, 2H), 0.92 (dd, 2H), −0.06 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([O-:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Na+].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 96.4 %

Procedure:
90 g Sodium gluconate were reacted as a 12% solution with sulfuric acid as in Example 5, but at 60° C. In this case, 78 g of gluconic acid and the corresponding amount of sodium sulfate were produced.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(NS(C)(=O)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cccc(C(=O)O)c1Cl

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (517 mg, 2.79 mmol) and pyridine (0.25 mL, 3.06 mmol) in 8 mL CH2Cl2 was added methanesulfonylchloride (0.24 mL, 3.06 mmol). After washing with 1M HCl, methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was isolated as a solid in quantitative yield. 1H NMR (400 MHz, CDCl3), δ 7.77 (dd, 1H, J=8.2, 1.6 Hz), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.33 (t, 1H, J=7.9 Hz), 7.16 (s, 1H), 3.91 (s, 3H), 2.99 (5, 3H); ESI-MS 262 (M−H). Methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylsulfonyl)amino]benzoic acid as a solid, which was used without further purification. ESI-MS 248 (M−H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[C:12]([CH:26]([OH:31])[CH2:27][CH2:28][CH2:29]O)=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[NH:16][C:15]=3[CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]>C(Cl)(Cl)Cl>[O:31]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:12]1[C:11]([O:10][C:9]2[CH:32]=[CH:33][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)=[CH:25][C:15]2[NH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)CCCO)cc1
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C2CCCO2)cc1
Reaction time: 8 h

Procedure:
P-toluenesulfonic acid monohydrate (20 mg) was added to a chloroform (4 ml) solution of 1-(6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)butane-1,4-diol (81 mg) obtained in (step 1), and the reaction liquid was stirred overnight with heating under reflux. The solvent was evaporated away under reduced pressure, and the reaction mixture was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[C:8]([O:12][C:13](=[O:16])[CH2:14]Br)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:6]([C:2]1[N:1]([CH2:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:16])[CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccnc1C=O
Temperature: 110 °C
Yield: 39 %

Procedure:
To a solution of 2-imidazole carboxaldehyde (1.00 g, 10.4 mmol) in DMF (1 mL) was added 1 eq. tert-butylbromoacetate, potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (850 mg, 4.03 mmol, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.6 (s, H), 7.23 (s, H), 5.15 (s, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([OH:24])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([O:24][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:7]1)=[O:5])[CH3:2]
Reactant: COCCCOc1cc(C)ccc1CBr
Reactant: CCOC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](OCc2ccc(C)cc2OCCCOC)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A suspension of the title C compound, (3R,4R)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid ethyl ester (150 mg, 0.45 mmol) and sodium hydride (60% dispersion in mineral oil, 30 mg, 0.68 mmol) in 10 mL of dry DMF is stirred for 10 min at 60° C. under argon. After cooling to room temperature, 1-bromomethyl-2-(3-methoxy-propoxy)-4-methyl-benzene (252 mg, 0.9 mmol) is added and the mixture further stirred for 3 h at 60° C. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative HPLC (Macherey-Nagel 250/4 nucleosil 100-10 C18 column, 20:80 CH3CN+0.1% TFA over 11 min, then 100% CH3CN+0.1% TFA for 5.5 min, 40 mL/min). To the combined fractions containing the desired product is added 1M aqueous sodium carbonate solution and the acetonitrile is removed under reduced pressure. The resulting aqueous suspension is extracted twice with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. MS 535.2 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 7.29 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][OH:12])[CH:7]=1.[CH:13]1[N:17]=[CH:16][N:15]([C:18](N2C=NC=C2)=[O:19])[CH:14]=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][C:18]([N:15]2[CH:14]=[CH:13][N:17]=[CH:16]2)=[O:19])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(-c2ccco2)on1
Solvent: ClCCl
Product: O=C(OCc1cc(-c2ccco2)on1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution 200 mg of (5-furan-2-yl-isoxazol-3-yl)-methanol in 6 mL of methylene chloride was added 216 mg of CDI. After stirring at room temperature for 4 hrs, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography to afford 282 mg of the title compound. (Yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17].C(N(CC)C(C)C)(C)C.[F:27][CH:28]([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([N:14]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:40])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(c2ccccc2Cl)CCC12CCCN2S(=O)(=O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(2-Chlorophenyl)-1,7-diazaspiro[4.4]nonan-6-one (20 mg, 0.00008 mol) was dissolved in DCM. To this solution was added N,N-diisopropylethylamine (DIPEA) (42 μL, 0.00024 mol) and 4-(difluoromethoxy)benzenesulfonyl chloride (21 mg, 0.000088 mol) at 0° C. The solution was allowed to gradually warm to RT while stirring for 18 h. LC-MS: 457.1 (M+1H)+.
Reaction SMILES: [C:1]1(=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].O.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O.C1C=CC=CC=1.C(O)C>[C:1]1(=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCCC1CCCCC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCCCC1CCCCC1=O

Procedure:
A solution of 232 g of 7-(cyclohexan-1-on-2-yl)heptanoic acid in 2500 ml. of ethanol is refluxed for 4.5 hours with 3.8 g of p-toluenesulfonic acid monohydrate. The solution is diluted with 200 ml. of benzene, and boiling is continued for 2 hours as 200 ml. of distillate is removed. The volume of the solution is concentrated to 500 ml. After dilution with 500 ml. of ether the solution is extracted with a solution prepared from 50 ml. of saturated sodium bicarbonate, 50 ml. of saturated sodium chloride, and 100 ml. of water. The extract is washed with saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm-1 (ester carbonyl) and 1715 cm-1 (ketone carbonyl).