Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(=O)=O.C(#N)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:38]1[CH2:41][CH2:40][CH2:39]1>ClCCl>[N:38]1([CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: C1CNC1
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(CN1CCC1)Oc1ccc(Cl)nc1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
2-(6-Chloropyridin-3-yloxy)-2-methylpropanal [prepared according to US2012/40949 A1] (28 g, 140 mmol, Eq: 1.00) was taken up in dry dichloromethane (252 ml) and cooled to −10° C. (dry ice/acetonitrile cooling bath) under nitrogen atmosphere. Acetic acid (10.4 ml, 182 mmol) and sodium triacetoxyborohydride (41.6 g, 196 mmol) were added. Azetidine (17 ml, 252 mmol) was next added via drop-wise addition over 6 minutes, with efficient stirring. After complete addition the mixture was stirred for 5 minutes and then the cooling bath was removed and the material warmed to ambient. After 1 hour a saturated solution of aqueous sodium bicarbonate (200 ml) was added as well as dichloromethane (80 ml). The biphasic material was transferred to a separatory funnel, agitated and the organic phase was collected. This was shaken with a 5% solution of sodium bicarbonate (200 ml) and then a 50% diluted solution of brine (200 ml). The organic phase was collected and the aqueous phases were back extracted with methylene chloride (2 100 ml). The organic phase was combined, dried with magnesium sulfate, filtered and stripped. The crude remainder was purified via column chromatography (silica gel, 40 g) eluting with a 4% solution of methanol in dichloromethane to provide the desired 5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-2-chloro-pyridin (29.66 g) as a golden brown mobile oil. LC/MS calc'd for C12H17ClN2O (m/e) 240.73, obs'd 241 (M+H, ES+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C@H:17]2[O:19][CH2:18]2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C@@H:17]([OH:19])[CH2:18][N:8]([CH2:9][CH2:10][OH:11])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Reactant: OCCNCc1ccccc1
Product: OCCN(Cc1ccccc1)C[C@H](O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-Benzylethanolamine (1.36 g, 1.5 equivalents) was added to (R)-4-chloro-styrene oxide (928 mg, 6.0 mmol), and the mixture was stirred at 70° C. for 3 hours. By cooling to room temperature, 2.56 g of the reaction mixture including the title compound was obtained (yield: 86%, chemical purity: 69.0 area %, N-benzyl ethanolamine: 9.2 area %, 10.4 area % of regioisomer was contaminated). The retention time in the chemical purity analysis method was 3.8 min.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:24]CC1.[OH2:28]>C(O)(C)(C)C.CCOCC.[Os](=O)(=O)(=O)=O>[OH:28][CH:2]([CH2:3][OH:24])[CH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: C=CCc1cnc2c(c1)CN(C(=O)OC(C)(C)C)C2
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2cc(CC(O)CO)cnc2C1
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 3-allyl-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (430 mg, 1.64 mmol) in tert-butanol (5 mL) and water (5 mL) was added N-methyl-morpholine N-oxide (422 mg, 3.6 mmol) followed by osmium tetroxide (20 μl, 4% aqueous solution). The resulting solution was stirred for 48 hr then diluted with ether, washed with 10% sodium thiosulphate solution and brine, dried over magnesium sulfate and concentrated to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate (125) (0.23 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration, light brown foam was obtained. Trituration with hexanes (containing 1% MeOH) afforded compound 126 as a white solid (0.175 g, 82%). mp 155-156° C. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.02 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 383 (M+H)+, m/z 381 (M−H)−. Anal. Calcd for C23H23ClO3.0.25H2O: C, 71.31; H, 6.11; Found: C, 71.26; H, 6.05.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH3:2].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[CH3:17])=[CH:11][CH:10]=1)[C:27](=[O:28])[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[CH3:2]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOCCCNCc1ccc(C(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
N-(3-ethoxypropyl)-N-(4-isopropylbenzyl)amine (0.62 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)-methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.0 gram of N-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-N-(4-isopropylbenzyl)propanamide (yield 75.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]#[N:14])([O-])=O.[Cl-].[NH4+].C1(C)C=CC=CC=1>CO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: N#CCCCc1ccccc1N

Procedure:
450 mg of 4-(2-nitrophenyl)butyronitrile, dissolved in 12.5 ml of methanol, are added dropwise to a mixture of 412 mg of iron powder (7.5 mmol) and 663 mg of ammonium chloride (12.5 mmol) in 12.5 ml of water at room temperature and under protective gas in a 100 ml glass round-bottomed flask. The mixture is heated for 5 hours with reflux. 25 ml of water are added to the cooled mixture and extraction is performed with toluene. The combined toluene phases are dried and the solvent distilled off under reduced pressure. The residue is purified by column chromatography on silica gel (eluent toluene/ethyl acetate 10:1 v/v). Yield: 276 mg (1.73 mmol, 72%).
Reaction SMILES: CCC1C=CC(C[CH2:10][O:11]C2C=CC(CC3SC(=O)NC3=O)=CC=2)=NC=1.Cl.C(O)[C@H]1O[C@H]([O:34][C@:35]2(CO)[O:39][C@H:38]([CH2:40][OH:41])[C@@H:37]([OH:42])[C@@H:36]2[OH:43])[C@H](O)[C@@H](O)[C@@H]1O>>[O:34]=[C:35]1[O:39][C@H:38]([C@H:40]([CH2:10][OH:11])[OH:41])[C:37]([OH:42])=[C:36]1[OH:43]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: Cl
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Compound A (24.8 g), sucrose (Osaka-Toka. Co., Ltd., 28.7 g), crystalline cellulose (Avicel PH-101, Asahi Kasei Corporation, 8.0 g) and L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd., 12.5 g) were thoroughly mixed to give a dusting powder. Ascorbic acid crystal (Wako Pure Chemical Industries, Ltd.) was sieved with a round sieve to give ascorbic acid crystal on 32 mesh (aperture 0.50 mm). The ascorbic acid crystal (150 g) was fed into a centrifugal fluidized-bed granulator (CF-mini, Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution (6 w/v %) of hydroxypropylcellulose (HPC-SL, NIPPON SODA CO., LTD.). The obtained spherical granules were dried under reduced pressure in a constant temperature vacuum drying oven (DP43, YAMATO SCIENTIFIC CO., LTD.) at 40° C. for 16 hr, and sieved with a round sieve to give granules at the range of 16-30 mesh (aperture 0.50-1.00 mm). The granules (450 mg) were filled in No. 0 gelatin capsules (Capsugel) to give capsules having the following composition per capsule.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([O:12][C:22]1[CH:21]=[CH:20][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8]
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 81 %

Procedure:
BocCys(Acm)ONp is prepared from BocCys(Acm)OH (Novabiochem, Laufelingen, CH) and p-nitrophenol by reaction with N,N'-dicyclohexylcarbodiimide (DCC) in etyl acetate and used without purification for the preparation of Boc-Cys(Acm)-Pro-OH (XII) by reacting it with H-Pro-OH in DMF/etyl acetate/H2O at 0° C. while keeping pH neutral by addition of Et3N. Yield 81%. Purity>95% (TLC).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:21][CH2:22][CH2:23][CH3:24])[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=1)(=O)=O.Cl.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[CH2:22]([O:21][C:7]1[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=[C:5]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:6]=1)[CH2:23][CH3:24]
Reactant: NC1CCOCC1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1nc(NC2CCOCC2)nc2oc(-c3cccc(C)c3)nc12
Yield: 20.7 %

Procedure:
A mixture of 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine, 40 mg of 4-aminotetrahydropyran hydrochloride and 39 μl of triethylamine in 3 ml of DMF was heated for 8 h to 50° C. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 22 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14](Cl)=[O:15]>ClCCl>[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14]([O:4][CH:2]([CH3:3])[CH3:1])=[O:15]
Reactant: O=C(Cl)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reactant: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reaction time: 1 h
Yield: 68.9 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.18 g of 2-propanol and 0.25 g of triethylamine, and a solution of 1.00 g of 2-chloro-3-(2-chloro-4-fluoro-5-phthalimidophenyl)propionyl chloride prepared by the process described in Example 4 in 15 ml of dichloromethane was slowly added thereto dropwise under stirring. After the dropwise addition, the stirring was continued at room temperature for 1 hour. The reaction mixture was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:8) to give 0.73 g of the title compound (No. 7 of Table 1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Product: CC(C)CNCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To an ice-cooled solution of benzyl bromoacetate (17.1 g, 74.6 mmol) in toluene (200 ml) was added isobutylamine (14.8 ml, 150 mmol) with stirring. The reaction mixture was allowed to warm to room temperature then heated at reflux for 1.5 h before leaving to cool to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (anhydrous MgSO4), filtered and evaporated to an oil which was purified further by column chromatography (silica gel, 25% ethyl acetate in hexane) to give the title compound as a yellow oil (8.96 g, 54%). 1H-NMR; δ(CDCl3), 7.35 (5H, m), 5.18 (2H, s), 3.45 (2H, s), 2.41 (2H, d, J=6.8 Hz), 1.74 (2H, m) and 0.92 (6H, d, J=6.8 Hz).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[C:11]([Br:14])[C:12]=1[SH:13].S(Cl)Cl.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])([CH3:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[C:11]([Br:14])[C:12]=1[S:13][C:30]1[CH:29]=[CH:28][C:27]([O:32][CH3:33])=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:31]=1
Reactant: COC(=O)Cc1cc(Br)c(S)c(Br)c1
Reactant: COc1ccccc1C(C)C
Agent: ClSCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(Sc2ccc(OC)c(C(C)C)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
Sulfuryl chloride (0.9 mL, 0.011 mol) in 5 mL of dichloromethane was added dropwise to a solution of methyl 3,5-dibromo-4-mercaptophenylacetate (3.4 g, 0.11 mol), from Preparation E, in 50 mL dichloromethane. The pale yellow solution was allowed to stand for 1 hour and transferred to an addition funnel. The resulting sulfenyl chloride was then added dropwise to an ice-cooled suspension of 2-isopropylanisole (1.8 g, 0.022 mol) and aluminum chloride (2.8 g, 0.02 mol) in methanol. The reaction mixture was allowed to warm to room temperature and stirred for an additional 15 min. The reaction mixture was then poured on to ice water and extracted twice with dichloromethane. The combined extract was washed with water and brine, dried (Na2SO4), and evaporated on a rotary evaporator. The residue was purified by flash chromatography (silica gel, 5:1 acetone:hexane) to obtain methyl 3,5-dibromo-4-(3-isopropyl-4-methoxyphenylthio)-phenylacetate (3.5 g, 0.007 mol, 70% yield), MP: 73°-76° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9].[O-2:19].[Ca+2]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]([O:1][CH2:2][CH:3]([O:4][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:5][O:6][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:19])=[O:9]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCC(=O)O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Product: CCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCC)OC(=O)CCCCCCCCC
Temperature: 25 °C

Procedure:
To a 250-mL flask containing glycerol (5.0 g, 54.3 mmol) and equipped with a condenser, were added capric acid (37.4 g, 217.2 mmol) and calcium oxide (45.4 mg, 0.8 mmol). The mixture was heated at 175° C. under partial vacuum (1 Torr, water pump vacuum) for 22 hours. The temperature of the water in the condenser was approximately 35° C. in order to maintain a gentle reflux of the capric acid and to accelerate removal of water under vacuum. The reaction was cooled to room temperature and the residue dissolved in hot ethanol (95%, 400 mL). This solution was treated with charcoal, filtered over fiberglass and cooled in an ice bath at 0-5° C. for 2 hours. Tricaprin was crystallized as a white solid which was filtered and washed with cold ethanol (95%, 40 mL). Yield of product: 27.5 g (91%); mp 29-31° C.; 1H NMR (400 MHz, CDCl3): δ 5.22-5.29 (m, 1H), 4.29 (dd, J=11.9, J=4.3, 2H), 4.14 (dd, J=11.9, J=6.1, 2H), 2.26-2.34 (m, 6H), 1.54-1.65 (m, 6H), 1.18-1.36 (m, 36H), 0.87 (t, J=7.0, 9H). 13C NMR (101 MHz, CDCl3): δ 73.54, 173.13, 69.07, 62.32, 34.44, 34.27, 32.09, 29.67, 29.65, 29.51, 29.50, 29.34, 29.30, 25.13, 25.08, 22.90, 14.33; MS (ES) m/z 578 (M+Na+); HPLC: 5.6 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OCCC(C)C)=O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Product: Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
During a 45 minute period 3-chloro-2-methylaniline (141.6 g, 1.0 mole) was added to a stirred solution of isoamyl nitrite (175.6 g, 1.5 moles) in benzene (842 g, 10.0 moles). The reaction mixture was stirred at room temperature for two hours, heated at reflux for one hour, then cooled to room temperature. Approximately 2 l of n-heptane was added to the reaction mixture. Most of the solvents were distilled from the mixture under reduced pressure, followed by distillation at atmospheric pressure (until a head temperature of 95° was reached). The pot residue was dissolved in 2 l of n-heptane and the solution filtered through 250 g of silica gel. The filtrate was subjected to column chromatography on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was rechromatographed on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was distilled in a Kugelrohr distillation apparatus (90°/0.05 mm) to give 3-chloro-2-methyl-[ 1,1'-biphenyl] (23.5 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[S:7].[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[S:7]
Reactant: FC(F)(F)c1cccc(C(=S)Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C=S)c1
Reaction time: 24 h
Yield: 73.9 %

Procedure:
A solution of 56.9 g (237 mmols) of 3-trifluoromethyl-thiobenzoic acid chloride in 285 ml of anhydrous toluene and 5.7g of 5 percent strength palladium on barium sulphate is introduced into a 1 liter three-necked flask equipped with a condenser, a mechanical stirrer and a gas bubbler tube. This mixture is heated, with stirring, for 12 hours at the reflux temperature, while a gentle stream of hydrogen is bubbled through it. The catalyst is filtered off and washed with diethyl ether. 125 ml of a solution of sodium bisulphite (d = 1.33) are added to the filtrate. This mixture is stirred vigorously for 24 hours and the bisulphite compound is filtered off, washed with diethyl ether and introduced into a three-necked flask. A solution of 80 g of potassium carbonate in 500 ml of water is added and the mixture is boiled, so as to steam distill the aldehyde as it is formed. The distillate is extracted twice in succession with diethyl ether. The combined ether phases are dried over sodium sulphate and filtered. The solvent is evaporated in vacuo on a water bath and the residue is rectified. 33.3g (67 % yield) of 3-trifluoromethylthio-benzaldehyde, as an oil, b.p. 108°-111° C./30-38 mm.Hg, are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH:28]([CH3:31])[CH2:29][OH:30].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC(N)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(CO)Nc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and 2-amino-1-propanol (200 mg) were added to pyridine (700 mg), and the mixture was stirred at 50° C. for 1.5 hours. Concentrated hydrochloric acid (200 mg) was added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure. Ethanol (3 ml) was added to the residue, and deposits were collected by filtration and washed with ethanol and disopropyl ether in that order to obtain the title compound (167 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>CCCCCCC>[C:10]([C:7]1[CH:6]=[C:4]([OH:5])[C:3]([OH:9])=[C:2]([CH3:1])[CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: Cc1cccc(O)c1O
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: Cc1cc(C(C)(C)C)cc(O)c1O
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A 1000 mL three neck flask equipped with stirrer, condenser and thermometer is charged with 3-methylcatechol (25.0 g, 0.20 mole), tert-butanol (38.0 mL, 0.40 mole) and 500 mL of heptane; followed by addition of sulfuric acid (98%, 20 g) slowly. The mixture is heated to 80° C. for 6 hrs until gas chromatography (GC) indicates the completion of the reaction. The solvent is removed in vacuo, and the residue is dissolved in CH2Cl2 and washed with water, NaHCO3 (aq.), brine and dried (Na2SO4). Filtration and concentration yield 5-tert-butyl-3-methylcatechol (36 g, 84%). 1H NMR: 6.79 (s, 1H), 6.75 (s, 1H), 5.01 (br, 1H), 2.29 (s, 3H), 1.29 (s, 9H).