Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S(NS(F)(=O)=O)(=O)=O)(F)(F)F.[Cl:13][C:14]([Cl:20])([Cl:19])[S:15]([NH2:18])(=[O:17])=[O:16].S(Cl)(Cl)=O.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[C:14]([S:15]([NH:18][S:26]([Cl:25])(=[O:28])=[O:27])(=[O:17])=[O:16])([Cl:20])([Cl:19])[Cl:13]
Reactant: NS(=O)(=O)C(Cl)(Cl)Cl
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)NS(=O)(=O)C(Cl)(Cl)Cl

Procedure:
This example illustrates synthesis of CF3SO2NHSO2F by the reaction of trichloromethane sulfonamide (CCl3SO2NH2), thionyl chloride (SOCl2), chlorosulfonic acid (ClSO3H) to produce CCl3SO2NHSO2Cl intermediate, and fluorinating the intermediate with anhydrous hydrogen fluoride (HF) to produce CF3SO2NHSO2F.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[F:15][C:16]1([F:20])[CH2:19][NH:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH3:10])[C:11]([N:18]1[CH2:19][C:16]([F:20])([F:15])[CH2:17]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: FC1(F)CNC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (400 mg, 2.11 mmol), 3,3-difluoroazetidine hydrochloride (383 mg, 2.96 mmol), HOBT (356 mg, 2.33 mmol) and EDC (446 mg, 2.33 mmol). DMF (9 ml) was added followed by N,N-diisopropylethylamine (1.0 ml, 5.73 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 509 mg (91%) of [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.14 (d, J=7.2 Hz, 1H), 4.59-4.80 (m, 1H), 4.17-4.55 (m, 4H), 1.45 (s, 9H), 1.32 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:7]>>[CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1
Temperature: 166 °C

Procedure:
The oxidation mixture at 166° C. exchanges heat with a decomposition liquid in a heat exchanger 3 through a pipeline I 2, so as to generate an oxidation mixture liquid at 114° C. The oxidation mixture liquid enters a dehydration and rectification column 5 or a first chamber of a decomposition reaction and distillation vessel 8 through a pipeline II for flash evaporation and dehydration. Chromic acid tert-butyl ester containing 3 wt % of chromium is added at a rate of 100 Kg·h as a catalyst into the first chamber of the decomposition reaction and distillation vessel 8 through a pipeline III 9. A tubular heater bundle in the decomposition reaction and distillation vessel 8 is inputted with steam which serves as a heating medium through a pipeline V 11, and resulting condensate water is discharged through a pipeline VI 12. Because of a strong exothermic property of a CHHP decomposition reaction and the heating by the tubular heater bundle, a large amount of the cyclohexane in the cyclohexane oxidation mixture liquid is evaporated in the decomposition reaction and distillation vessel 8, which intensely stirs up the reaction mixture and removes water which is generated by the CHHP decomposition via a azeotropic evaporation. A gas phase of the cyclohexane is rectified in the dehydration and rectification column 5, and condensed in a condenser 6 at a top of the dehydration and rectification column 5, so as to obtain 130,000 Kg/h of cyclohexane and water containing fewer than 0.04 wt % of cyclohexanol and cyclohexanone. Thereafter, the 130,000 Kg/h of cyclohexane and water are separated by a separator for separating cyclohexane and acidic water 7, wherein 30,000 Kg/h of the cyclohexane is refluxed at the column top; 98,764 Kg/h of the cyclohexane containing around 0.04 wt % of cyclohexanol and cyclohexanone returns to an oxidation reaction system through a pipeline XII 20; and 1236 Kg/h of the acidic water is discharged into a waste water processing device through a pipeline XI 19. A cyclohexane solution containing 10% of 1-hydroxy ethidene-1,1-diphosphonic acid (di)octyl ester is continuously added into a second chamber of the decomposition reaction and distillation vessel 8 through a pipeline IV 10 at a rate of 30 Kg/h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].C([O:19][CH2:20][CH3:21])(=O)C.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1>C1C=CC=CC=1>[CH3:22][C:23]1[CH:21]=[C:20]([OH:19])[C:7]2[C:2](=[C:3]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=3[Cl:15])[CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Reactant: Nc1ccncc1-c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: Cc1cc(O)c2cncc(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 1 h

Procedure:
A solution of B1 (2.41 g, 10.1 mmole), ethyl acetate (1.31 g, 10.1 mmole) and p-toluenesulfonic acid (70 mg) in benzene (50 ml) is heated at reflux for 2 h. during which 10 ml of solvent is removed by distillation. After evaporation, the residue is added to boiling diphenyl ether (10 ml) and heating is continued for 1 h; then the solution is cooled and poured into high boiling petroleum ether with vigorous stirring. The resulting solid formed is filtered off and washed with diethyl ether to give the product B2.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40]([O:28][C:26]3[CH:25]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:30])[CH3:29])[CH:27]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)=[O:15])=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 160 °C
Yield: 94.2 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide (103 mg, 0.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (66 mg, 0.29 mmol) in acetonitrile (2 mL), containing potassium carbonate (66 mg, 0.48 mmol), was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give the required product as a white foam (142 mg).
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OCCO[C:28]1[CH:40]=[CH:39][C:31]2[N:32]=[C:33]([S:35]([NH2:38])(=[O:37])=[O:36])[S:34][C:30]=2[CH:29]=1)(=O)C.N>C(OCC)C>[S:34]1[C:30]2[CH:29]=[CH:28][CH:40]=[CH:39][C:31]=2[N:32]=[C:33]1[S:35]([NH2:38])(=[O:37])=[O:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCOc2ccc3nc(S(N)(=O)=O)sc3c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CCOCC
Product: NS(=O)(=O)c1nc2ccccc2s1
Reaction time: 8 h

Procedure:
The unpurified 6-[2'-(2",3",4",6"-tetra-O-acetyl-β-glucopyranosyl)oxyethoxy]-2-benzothiazolesulfonamide (3.02 g.; 5.00 mmole) was dissolved in anhydrous diethyl ether (100 mL) and combined with cold (0° C.) saturated methanolic ammonia (100 mL) and stirred overnight with the temperature rising to room temperature over a six hour period. The solution was evaporated to dryness at reduced pressure and chromatographed on a silica gel column (150 g.) and eluted with chloroform/methanol (9.1). The product fractions (UV light and charring positive) were combined and evaporated to dryness at reduced pressure, and lyophilized to yield 6-[β-lucopyranosyl)oxyethoxy]-2-benzothiazolesulfonamide. The product conformed to accepted standards of purity and its structural assignment verified by standard spectroscopic methods (mass spec,13C and 1H nuclear magnetic resonance).
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[C:31]3[C:23](=[C:24]4[C:28](=[C:29]([OH:32])[CH:30]=3)[NH:27][C:26]([C:33]([F:36])([F:35])[F:34])=[C:25]4[C:37]([O:39][CH3:40])=[O:38])[C@H:22]([CH2:41][Cl:42])[CH2:21]1)=[O:19])=[CH:12]2)=O)(C)(C)C.Cl.[CH3:44][N:45]([CH3:50])[CH2:46]C(O)=O>>[Cl:42][CH2:41][C@H:22]1[C:23]2=[C:24]3[C:28](=[C:29]([OH:32])[CH:30]=[C:31]2[N:20]([C:18]([C:13]2[NH:14][C:15]4[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:6]([CH2:44][N:45]([CH3:50])[CH3:46])=[O:5])=[CH:17][CH:16]=4)=[O:19])[CH2:21]1)[NH:27][C:26]([C:33]([F:34])([F:36])[F:35])=[C:25]3[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)CN(C)C)ccc2[nH]1

Procedure:
Methyl (1S)-1-chloromethyl-3-[5 (dimethylaminomethylcarbonyl)amino-1H-indol-2-ylcarbonyl]-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate was prepared from 12.1 mg (20 μmol) of methyl (1S)-3-[5-(t-butoxycarbonyl)amino-1H-indol-2-ylcarbonyl]-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate and 2.8 mg (20 μmol) of N, N-dimethylglycine hydrochloride in the same manner as in Example 6 in a yield of 7.8 mg (66%).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([Br:15])[N:9]=1)([OH:7])[CH3:6])=[N+]=[N-].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(OCC)C>[Br:15][C:10]1[N:9]=[C:8]([C:5]2([CH3:6])[CH2:4][NH:1]2)[C:13]([F:14])=[CH:12][CH:11]=1.[CH:32]1[CH:33]=[CH:34][C:29]([P:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:7])=[CH:30][CH:31]=1
Reactant: CC(O)(CN=[N+]=[N-])c1nc(Br)ccc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(c2nc(Br)ccc2F)CN1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-azido-2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol (11.2 g, 40.7 mmol) in THF (60 ml) was added triphenylphosphine (10.68 g, 40.7 mmol) and the reaction mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue obtained was dissolved in diethylether and filtered through a cotton plug to remove triphenylphosphine oxide. The filtrate was washed with citric acid (9.6 g in 20 ml of water) and the organic phase was separated. The aqueous layer was made basic with 2N NaOH and extracted with diethylether. The organic layer was dried over sodium sulfate, filtered and evaporated to yield the title compound with some TPPO present: 8.1 g yellow oil (69% yield). TLC (cyclohexane/ethyl acetate 2:1) Rf=0.28; LCMS RtH6=0.46 (ES+ 231, 233); 1H-NMR (400 MHz, CDCl3): 7.34 (dd, 1H), 7.24 (dd, 1H), 1.99 (s, 1H), 1.89 (s, 1H), 1.65 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:11]([O-:29])=[CH:10][C:9]=2[N:18]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 99.9 %

Procedure:
[1-(2-Fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.59 g, 5.03 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (1.52 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 20 mL of 5% Na2CO3 solution and the layers were separated. The organic layer was washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.67 g of [1-(2-fluoro-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:12]([Cl:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(C)C)(C)C>[Cl-:19].[CH2:12]([N+:9]([CH2:8][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])([CH3:10])[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC(=O)OCCN(C)C
Reactant: ClCc1ccccc1
Solvent: CC(C)OC(C)C
Product: CCCC(=O)OCC[N+](C)(C)Cc1ccccc1
Product: [Cl-]
Reaction time: 96 h

Procedure:
In 20 ml of isopropyl ether were dissolved 4.47 g (30 millimoles) of 2-dimethylaminoethyl butyrate ##STR8## and 3.8 g (30 millimoles) of benzyl chloride, and the solution was left to stand at room temperature for 4 days. The solvent was then evaporated. The crystals that precipitated were separated by suction filtration, washed fully with isopropyl ether, and dried under reduced pressure to give N-benzyl-N-(2-butyryloxyethyl)-N,N-dimethylammonium chloride (compound No. 29 in Table 1 given hereinbelow) represented by the following formula. ##STR9##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\Br)/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Zn]CC)[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)\[CH2:25][CH3:26])[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccc(Cl)cc2)COC1(C)C
Reactant: CC[Zn]CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of (S)-4-[(Z)-2-bromo-2-(4-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.04 g) in THF (8 ml) were added bis(tri-tert-butylphosphine)dipalladium (0) (64 mg) and diethylzinc (4.99 ml, 1.1 M solution in toluene). The mixture was stirred at r.t. for 90 min then was diluted with ethyl acetate and washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (824 mg, 90%) as a colourless oil. MS (ISP): 368.5 ([{37Cl}M+H]+), 366.5 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NCc1ccccc1)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Into a 4 mL vial is added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (75 mg, 0.289 mmol), anhydrous pyridine (1 mL) and benzyl isocyanate (0.036 mL, 0.289 mmol). The reaction mixture was stirred at r.t. for 2 days. To the reaction mixture is added H2O to precipitate the product. The solid is filtered and purified by preparative TLC (MeOH/CHCl3 10:90) to give a colorless solid (84.3 mg, 75%). m.p. 163-164° C. (dec). 1H NMR (DMSO & CHCl3) 4.23 (d, 2H), 6.05 (t, 1H), 7.05 (m, 1H), 7.08 (m, 4H), 7.25 (t, 3H), 7.42 (d, 2H), 8.02 (s, 1H); ESIMS: m/z 393 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]([N:35]2[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]2)[N:7]=1
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(Cl)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.3 %

Procedure:
A mixture of methyl 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylate (502.6 mg, 1.610 mmol), N-ethyldiisopropylamine (0.3 mL, 1.718 mmol) and N-ethylpiperazine (0.21 mL, 1.653 mmol) in THF (8 mL) was stirred at RT for 12 h. Saturated aq NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound (152.6 mg, 24%). 1H NMR (500 MHz, CDCl3) δ ppm 1.12 (t, J=6.5 Hz, 3H), 2.35 (s, 3H), 2.48 (br s, 6H), 3.82-3.97 (m, 7H), 6.92-6.93 (m, 1H), 7.21-7.22 (m, 1H), 7.37-7.42 (m, 2H), 10.45 (s, 1H). [M+H] calc'd for C19H25ClN5O2, 390; found, 390.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (2RS,3SR)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (7.0 g), methyl 3-mercaptopropionate (30.8 ml) and 28% sodium methylate-methanol solution (19.6 ml) in methanol (210 ml) was refluxed for 2 hours. 28% Sodium methylate methanolic solution (9.8 ml) was added to the resultant solution and refluxed for 1 hour. Thereafter, methyl 3-mercaptopropionate (4 ml) was added to the resultant solution and refluxed for 2 hours. After ice-cooling, the reaction mixture was diluted with water (100 ml) and neutralized with 5% aqueous phosphate solution, and extracted with methylene chloride (200 ml×2). The extract was dried over anhydrous sodium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (4×50cm), eluting with ethyl acetate-hexane (3:1). The collected fractions of the object compound were concentrated and ethyl ether was added to the residue to obtain (2RS,3 RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2butanol (5.5 g) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([O:10][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
1.1 3, 5-Dihydroxy-benzoic acid methyl ester (149 mmol), potassium carbonate (1 eq.) and 18-crown-6 (0.1 eq.) are dissolved in acetone (750 ml) and stirred for 1 hour at RT. Benzylbromide (0.8 eq.) is added and the reaction solution is heated to reflux for 8 hours. The solvent is removed in vacuo and 3-benzyloxy-5-hydroxy-benzoic acid methyl ester is isolated after column chromatography in a yield of 26%. The isolated compound is dissolved in acetone (180 ml), potassium carbonate (1.2 eq.) and isopropyl iodide (2. eq.) is added and the reaction solution is heated under reflux for 24 hours. The reaction is quenched with water and extracted with ethyl acetate. The combined organic layer is dried over Na2SO4 and the solvent removed in vacuo. 3-Benzyloxy-5-isopropoxy-benzoic acid methyl ester is obtained after column chromatography in a yield of 67%. The isolated compound is dissolved in methanol/TNF/water (90 ml, 1:1:1) and LiOH (4 eq.) is added. The reaction is stirred for 2 hours at RT and quenched with citric acid solution and the pH was adjusted to 7. The solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-benzoic acid is isolated as a brown powder in a yield of 93%; HPLC (Method 8): 3.43 min; LC-MS (Method B): 2.391 min, 287.15 (M+H+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1)[NH2:6].Br[CH:20]([CH2:25][CH2:26][CH2:27]Br)[CH2:21][C:22]([O-:24])=[O:23].C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]2[CH2:27][CH2:26][CH2:25][CH:20]2[CH2:21][C:22]([OH:24])=[O:23])[CH:7]=[C:8]([C:10]([CH3:17])([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1
Reactant: CCCCCCC(C)(C)c1cc(N)cc(OC)c1
Reactant: O=C([O-])CC(Br)CCCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(OC)cc(N2CCCC2CC(=O)O)c1
Reaction time: 1 h

Procedure:
A mixture of 24.9 g. (0.10 mole) 3-methoxy-5-(1,1-dimethylheptyl)aniline, 34.5 g. (0.12 mole) methyl dl-3,6-dibromocaproate, 15 g. triethylamine and 100 ml. ethyl ether is stirred under nitrogen at room temperature for 20 hours. The ether is evaporated and the residue heated at 90°-120° C. for three hours. Additional methyl dl-3,6-dibromocaproate (5 g.) and triethylamine (5 g.) is added and heating continued at 90° C. for 2 hours and finally at 120° C. for one hour. The reaction mixture is worked up as described in Example 16 to provide the methyl ester of the desired product which is hydrolyzed in methanolic sodium hydroxide by the method of Example 17 to provide the title acid.