Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(I)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, methyl 2-chloro-5-iodonicotinate (J. Org. Chem. 1989, 54, 3618, 594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by flash column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (2/1) to afford 644 mg (86%) of the title compound: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.3 Hz), 8.41 (1H, s), 7.09 (4H, d, J=6.2 Hz), 3.95 (3H, s); MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[O:18][C:17](=O)[CH:16]([CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:17][O:18]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CCCC1CCC(c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H]1CC[C@H](c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of 7.7 g (22.7 mmol) of the 6-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-3-propyltetrahydro-2-pyrone, 13.2 g (113.6 mmol) of triethylsilane, and 50 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. After termination of the reaction, 30 ml of water was added to the reaction solution and extracted with 50 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=9/1) to obtain 6.6 g of a crude trans-2-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-5-propyltetrahydropyran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([O:20][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:19]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(O)cc(F)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
A mixture of 3-[4-(3-fluoro-5-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (0.557 g, 1.75 mmol), 3-bromo-4-fluorobenzotrifluoride (0.425 g, 1.75 mmol) and 325 mesh potassium carbonate (0.29 g, 2.10 mmol) in dry DMSO (10 mL) is heated to 100° C. and stirred 2.5 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford 0.735 g (78%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C2H21O4F4Br 540, found 558 and 560 (M+NH4, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([C:18]([O:20]C)=[O:19])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:18]([OH:20])=[O:19])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)O
Yield: 96.6 %

Procedure:
A mixture of 51.9 g (0.15 mol) of dimethyl 3-(3,4-dichlorophenyl)-4,5-isothiazoledicarboxylate and 30 g (0.75 mol) of NaOH in 150 ml of water was held at reflux for 2 hours, was cooled, acidified with HCl, and was extracted with ether several times (total ether volume equals 1300 ml). The ether solution was dried (CaSO4) and concentrated to give 46.12 g of solid. A small sample was recrystallized twice from water and once from ether-dichloroethane to give pure product, m.p. 187.5 -188.5° with decomposition (fast).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]([CH3:16])[CH:6]=[CH:5]2.[Se](=O)=[O:18]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:14])[CH3:15])[N:8]=[C:7]([CH:16]=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)c(OC(C)C)cc2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1cc2nc(C=O)ccc2cc1F

Procedure:
To 6-fluoro-7-isopropoxy-2-methylquinoline (270 mg, 1.23 mmol) in dioxane/water (5 mL/0.05 mL) was added selenium dioxide (164 mg, 1.48 mmol) and the reaction was heated to reflux for 2 hours. After cooling and concentrating, the residue was purified by chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-7-isopropoxyquinoline-2-carbaldehyde as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:41]1[CH:46]=[CH:45][C:44]2[O:47][CH2:48][O:49][C:43]=2[CH:42]=1)[C@H:14]([N:16]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][C:21](=[O:29])[O:20]1)=[O:18])[CH3:15].[OH-:50].[Na+:51]>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:41]1[CH:46]=[CH:45][C:44]2[O:47][CH2:48][O:49][C:43]=2[CH:42]=1)[C@H:14]([N:16]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:17]([C@@H:19]([OH:50])[C@@H:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][C:21]([O-:20])=[O:29])=[O:18])[CH3:15].[Na+:51]
Reactant: [OH-]
Reactant: CCOC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CC(=O)[O-])[C@H](O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
120 mg of ethyl (2S,3S)-2-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was dissolved in a mixed solution of 5 ml of tetrahydrofuran and 2 ml of water, and 182 μl of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform/methanol=20/1→10/1) to obtain 33.0 mg (yield: 26%) of the above-identified compound as a colorless foam.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([CH3:26])=[N:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)cn1

Procedure:
The title compound, white solid (22.6 mg, 62.8%), MS (ISP) m/z=450.0 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 6-methylnicotinic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=2)[OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:32]=[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47](O)=[O:48])[C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[C:34](=[O:40])[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=1)[CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:48])=[O:32]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: COc1cc(CC[C@@H](O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cc(OC)c(OC)c(OC)c1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of alcohol 14 (650 mg, 1.5 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 382 mg, 1.5 mmol, followed by 1,3-dicyclohexylcarbodiimide (370 mg, 1.8 mmol), and 4-(dimethylamino)-pyridine (128 mg, 1.0 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-30% EtOAc/hexanes) to give (1R)-3-(3,4,5-trimethoxyphenyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (776 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.30-6.80 (m, 4 H), 6.37 (s, 2 H), 5.82 (t, J=6.1 Hz, 1 H), 5.33 (d, J=5.2 Hz, 1 H), 4.54 (s, 2 H), 3.85 (s, 6 H), 3.83 (s, 3 H), 3.38 (d, J=12.6 Hz, 1 H), 3.16 (td, J=12.8, 3.1 Hz, 1 H), 2.60 (m, 2 H), 2.45-2.05 (m, 3 H), 1.70 (m, 6 H), 1.50 (s, 9 H), 1.45 (m, 2 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 0.90 (t, J=7.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.1, 168.2, 167.6, 158.5, 153.6, 141.7, 137.0, 130.1, 120.9, 120.2, 114.6, 113.7, 105.7, 82.7, 66.2, 61.2, 56.5, 51.7, 47.1, 44.6, 38.2, 32.9, 32.4, 28.4, 26.8, 25.3, 23.9, 23.5, 21.6, 9.1.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonarnide (61.2 mg) in acetonitrile (10 mL) were added sodium iodide (49.3 mg) and chloro(trimethyl)silane (0.166 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (53.4 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[C:27]2=[O:34])[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:31]([CH:28]1[CH2:29][CH2:30][N:26]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([F:25])([F:23])[F:24])=[C:16]([F:15])[CH:17]=2)[C:27]1=[O:34])=[O:32]
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Yield: 19.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxylic acid (0.130 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.0389 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][OH:44])=[O:19].[C:45](O)(=[O:63])[CH2:46]CCCCCCCCCCCCCCCC>C1(C)C=CC=CC=1>[CH2:17]([C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:46][CH2:45][OH:63])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reaction time: 8 h

Procedure:
PEG400MS (polyethylene glycol 400 monostearate)—100 g (0.25 mol) of CARBOWAX™ 400 diol (commercially available from Union Carbide Corp., Danbury, Conn.) was combined with 71 g (0.25 mol) of stearic acid in 400 g of toluene in a 3-necked flask equipped with stirrer, heating mantle, thermometer and condenser. The contents were heated, azeotroped dry using a Dean Stark trap, and were allowed to cool. Next, 1.0 g (0 5% by weight of solids) of p-toluene sulfonic acid was added, and the mixture was refluxed with stirring overnight with the continuous removal of water. Infrared analysis indicated no acid carbonyl remained. A solution of 0.5 g of NaHCO3 in deionized water was then added. The resulting two-phase system was stirred and the water and toluene were removed at 80° C. using a ROTO-VAC™ evaporator to produce the desired monoester, C17H35C(O)O(C2H4O)8C2H4OH. This monostearate and its constituent reactants are presented as the first entry in TABLE 1.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([S:23]([NH2:26])(=[O:24])=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (28.5 mg) in acetonitrile (5 mL) were added sodium iodide (22.9 mg) and chloro(trimethyl)silane (0.078 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (21.2 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:21]4[O:20][CH2:19][O:18][C:17]=4[CH:16]=3)[N:10]=[C:9]([S:24][CH2:25][C:26]#[N:27])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:13][C:11]3[CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([S:24][CH2:25][C:26](=[N:29][OH:30])[NH2:27])[N:10]=3)=[CH:16][C:17]=2[O:18][CH2:19]1
Reactant: NO
Reactant: N#CCSc1nc(NCc2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(CSc1nc(NCc2ccc3c(c2)OCO3)cc(-c2ccccc2)n1)=NO
Reaction time: 8 h

Procedure:
A mixture of 11.20 g. (0.03 mole) of [4-phenyl-6-(piperonylamino)-2-pyrimidinylthio]acetonitrile, 4.14 g. (0.06 mole) of hydroxylamine hydrochloride and 12.70 g. (0.12 mole) of sodium carbonate in 200 ml of N,N-dimethylformamide was heated on a steam bath for four hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and left at room temperature overnight. The precipitate which formed was collected and recrystallized from a mixture of ethyl acetate-petroleum ether to give 4.8 g. of product, mp. 160°-163°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16]CC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:20][NH2:21])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(C(C)(C)C)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Temperature: 95 °C
Yield: 83.9 %

Procedure:
To a room temperature solution of ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (1.0 g, 0.004 mol) in ethanol (10 mL) was added hydrazine hydrate (2 g, 0.04 mol) and the reaction mixture was then heated at 95° C. for 16 h. The mixture was then concentrated in vacuo and the solid that was obtained was washed with hexanes to afford 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (0.78 g, 82%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30](O)=[S:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:33][C:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:30]([N:10]1[CH2:9][CH2:8][N:7]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:6][C@@H:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[S:31])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)=S
Reactant: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=S)[C@@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
3(S)-n-Butyl-1-(2,3-dimethylbenzoyl)piperazine (0.240 g, 0.874 mmol) and 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropionic acid (0.405 g, 0.874 mmol) were dissolved in dimethylformamide. To this solution was added HOBT (0.114 g, 0.874 mmol), and EDC.HCl (0.184 g, 0.962 mmol). The reaction was stirred under nitrogen overnight. The dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with several portions of water, saturated sodium chloride solution, and dried over magnesium sulfate. Filtration and evaporation of solvent gave the crude product, which was chromatographed on silica gel with 50% ethyl acetate in hexane. The title compound as a white foam (0.620 g).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.II.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].Cl>O1CCCC1>[C:6]1([CH2:5][CH2:4][CH2:3][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 469.5 %

Procedure:
Into a four-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 4.8 g (0.2 mol) of magnesium flasks and 100 ml of anhydrous tetrahydrofuran were placed, followed by addition of a mixture of 4.0 g (20 mmol) of 1-bromo-3-phenylpropane and 10 ml of anhydrous tetrahydrofuran and a small quantity of iodine, heating of the flask contents to 60° C. and dropwise addition of a mixture of 35.8 g (0.18 mol) of 1-bromo-3-phenylpropane and 90 ml of anhydrous tetrahydrofuran at the same temperature. Thereafter, the mixture was stirred under reflux for 2 hours and then cooled to room temperature. The resulting mixture was added dropwise into a mixture consisting of 31.3 g (0.22 mol) of ethyl trifluoroacetate and 200 ml of anhydrous tetrahydrofuran. Thereafter, the mixture was stirred at -78° C. for 2 hours, then heated gradually to -50° C. and further stirred at the same temperature for 2 hours. Thereafter, 100 ml of 1N hydrochloric acid was added at -50° C., followed by heating to room temperature. The reaction mixture was extracted with 300 ml of ether and the formed organic layer was washed with water, a 5% sodium bicarbonate solution and brine successively in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: toluene/hexane (1/4)) to give 20.3 g of 5-phenyl-1,1,1-trifluoropentane-2-one (14-1) in a yield of 47%.
Reaction SMILES: CS(O[C:6]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:7]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)C(=O)O)c(OS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(C(C)C(=O)O)cc1

Procedure:
To a solution of 77.5 g. of 2-methane-sulphonyloxy-4-methyl-hydratropic acid in 600 ml. of methanol 84 ml. of triethyl amine and 6 g. of a 5% palladium on charcoal catalyst are obtained, and the mixture is hydrogenated at 25° C. until a calculated amount of hydrogen is used up. Catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the solution is acidified with a 20% aqueous hydrochloric acid solution. The separated 4-methyl-hydratropic acid is extracted with chloroform and the chloroform extract is dried over sodium sulphate. Evaporation of the solution affords 4-methylhydratropic acid.