Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:33][C:13]([CH3:12])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl 2,2-dimethylpropanoate (631 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 47 (23 mg, 3% yield) as an off-white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.81-0.94 (br. m, 8H), 1.12 (s, 9H), 1.17-1.38 (m, 3H), 1.64-1.72 (br. m, 2H), 1.82-2.00 (br. m, 3H), 2.09 (tt, J=12.4, 3.2 Hz, 1H), 2.72-2.89 (br. m, 2H), 6.40 (d, J=4.8 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:8]([NH:33][C@@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:35][OH:36])=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)=[N:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:36][CH2:35][C@@H:34]([NH:33][C:8]1[C:7]([F:6])=[CH:12][N:11]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[CH:14]=2)[CH:9]=1)[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CO)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1.83 mL, 23.67 mmol) was added to a cold (0° C.) solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol, 54a, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) in dichloromethane (118 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 10.5 g of the desired product as a pale yellow foam: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 580.41 (M+H) RT=2.00 minutes.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6][C:5]1=O.S(Br)([Br:17])=O.[CH3:19][OH:20]>>[CH3:19][O:20][C:5](=[O:6])/[C:4](/[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:7][Br:17])=[N:3]/[O:2][CH3:1]
Reactant: CON=C1C(=O)OCc2ccccc21
Reactant: O=S(Br)Br
Reactant: CO
Product: CO/N=C(/C(=O)OC)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of isochroman-3,4-dione 4-(O-methyl-oxime) (5.6 g, 0.028 mol) in methanol (27 g) was added dropwise at 10-20° C. thionyl bromide (45.4 g, 0.22 mol) over a period of 1 h and the resulting mixture was stirred at ambient temperature overnight. The reaction was monitored by HPLC. Concentration of the mixture in vacuo led to a crude residue (14.2 g). A small amount of the residue (3.2 g) was purified by silica column chromatography to yield (2-bromomethyl-phenyl)-[(E)-methoxyimino]-acetic acid methyl ester as a colorless solid (0.8 g).
Reaction SMILES: [Br-:1].[Li+].[C:3](=[O:11])([O:7][CH:8](Cl)[CH3:9])[O:4][CH2:5][CH3:6]>CN(C)C=O>[C:3](=[O:11])([O:7][CH:8]([Br:1])[CH3:9])[O:4][CH2:5][CH3:6]
Reactant: [Br-]
Reactant: CCOC(=O)OC(C)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Lithium bromide (17.4 g, 0.2 m) was dissolved in dimethyl formamide (150 ml) and the mixture cooled to ambient temperature. Ethyl alphachloroethyl carbonate (30.5 g, 0.2 m) was added and the mixture stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate vacuum distilled to afford after careful re-fractionation, ethyl alpha-bromoethyl carbonate in 76% yield based upon recovered ethyl alphachloroethyl carbonate.
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:17][N:16]=[C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]([O:23]CC3C=CC(OC)=CC=3)=[O:22])[N:14]=2)=[C:6]([CH2:36][CH2:37][CH3:38])[C:5]=1[OH:39])(=[O:3])[CH3:2].O>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:17][N:16]=[C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]([OH:23])=[O:22])[N:14]=2)=[C:6]([CH2:36][CH2:37][CH3:38])[C:5]=1[OH:39])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nc(NC(=O)CC(=O)OCc3ccc(OC)cc3)n[nH]2)ccc(C(C)=O)c1O
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(OCCCSc2nc(NC(=O)CC(=O)O)n[nH]2)ccc(C(C)=O)c1O
Yield: 63.8 %

Procedure:
In a mixture of 1.5 ml of trifluoroacetic acid and 0.1 ml of anisole was dissolved 100 mg of p-methoxybenzyl 3-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1H-1,2,4-triazol-3-yl]amino]-3-oxopropionate obtained in Example 31 at 10° to 20° C. and after stirring the solution thus obtained for 30 minutes, trifluoroacetic acid was distilled off under reduced pressure. The residue thus formed was mixed with 20 ml of water and extracted with 20 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to provide a solid product. The solid product was washed with methylene chloride and dried to provide 50 mg of 3-[[5-[[-3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1H-1,2,4-triazol-3-yl]amino]-3-oxopropionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (2.17 g) in toluene (40 mL) was added p-anisidine (900 mg) and molecular sieves 4A (6.0 g). The mixture was refluxed overnight, then filtered and the filtrate was evaporated. The residual oil was dissolved in ethanol (40 mL) and sodium borohydride (276 mg) was added. The mixture was stirred at room temperature for 2 hours before concentration in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to silica gel column chromatography using chloroform-methanol (50:1) to give the title compound as yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:33][CH2:34][CH2:35][N:36]([CH3:44])[C:37](=[O:43])OC(C)(C)C.[CH:45](N(C(C)C)CC)(C)[CH3:46].C(=O)C1C=CC=CC=1>CN(C)C=O.CN1CCCC1=O>[C:37]([N:36]([CH3:44])[CH2:35][CH2:34][NH:33][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9])(=[O:43])[CH:45]=[CH2:46]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: O=Cc1ccccc1
Product: C=CC(=O)N(C)CCNc1nc(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)c(C(N)=O)nc1CC
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (21 mg), tert-butyl (2-aminoethyl)methylcarbamate (31 mg), diisopropylethylamine (16 μL), and N-methylpyrrolidone (0.3 mL) was stirred at 140° C. for 2 hours and a half. To the reaction mixture was added PS-benzaldehyde (Biotage, 150 mg) at room temperature, N,N-dimethylformamide (1 mL) was added thereto, followed by stirring for 2 hours, and the insoluble matter was filtered. The filtrate was evaporated under reduced pressure and the obtained residue were added methanol (0.5 mL) and a 4 M hydrogen chloride-dioxane solution (0.45 mL), followed by stirring at room temperature for 8 hours. The solvent was evaporated under reduced pressure, and to the obtained residue were added tetrahydrofuran (0.9 mL) and a saturated aqueous sodium hydrogen carbonate solution (1 mL), followed by stirring at room temperature. Acryloyl chloride (8 μL) and tetrahydrofuran (0.1 mL) were added thereto at room temperature, followed by stirring for 4 hours. The reaction mixture was extracted with chloroform. The solvent of the organic phase was evaporated under reduced pressure and the obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 5-({2-[acryloyl (methyl)amino]ethyl}amino)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([NH2:18])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:20])([CH3:19])[O:8][C:5]2=[CH:6][CH:7]=1.O.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:13]3([CH2:17][O:16][C:15]([NH2:18])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:20])([CH3:19])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2ccc(Br)cc2C2(COC(N)=N2)C12CC2
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CO
Product: CC1(C)Oc2ccc(Br)cc2[C@@]2(COC(N)=N2)C12CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
To a solution of 6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (3.7 g, 11 mmol) in methanol (50 ml) was added (+)-dibenzoyl-D-tartaric acid monohydrate (4.1 g, 11 mmol). The mixture was stirred at room temperature for 5 minutes and concentrated in vacuo. To the residue was added dioxane (25 ml). The mixture was heated under reflux for 5 minutes, cooled to room temperature and stirred at room temperature overnight. The resulting precipitate was collected, washed with dioxane, and dried in vacuo. The resulting powder was dissolved in saturated aqueous sodium hydrogen carbonate and chloroform. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (4′R)-6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (1.5 g). The mother liquor was concentrated in vacuo and purified by NH-silica gel column chromatography (CHCl3/MeOH=20:1). The purified material was treated with (−)-dibenzoyl-L-tartaric acid monohydrate (2.0 g, 5.4 mmol) in the same manner as described above which lead to isolation of (4′S)-6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (1.2 g).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:30])[NH:21][CH2:22][CH:23]([CH3:29])[CH2:24][C:25]([F:28])([F:27])[F:26])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:31][CH3:32])[CH:5]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH3:32][O:31][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:30])[NH:21][CH2:22][CH:23]([CH3:29])[CH2:24][C:25]([F:26])([F:27])[F:28])[CH:18]=2)[NH:13][CH:12]=1)[C:3]([OH:33])=[O:2]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
To a solution of 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester (1.80 grams, 3.90 mmol) in 2:2:1 methanol:tetrahydrofuran:water (30 mL) was added lithium hydroxide monohydrate (0.82 grams, 19.50 mmol). The resulting solution was stirred, at room temperature, for 48 hours then concentrated in vacuo. The resulting crude product was treated with 1 M hydrochloric acid (aq), and the resulting precipitate was collected via filtration to vie 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid (1.74 grams, 99% yield).
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].[CH:18]1([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(OCC)(=O)C>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])=[O:2].[CH:25]1([NH2+:24][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=Cc1c(O)cccc1OCCCCC(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCOC(C)=O
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: O=Cc1c(O)cccc1OCCCCC(=O)[O-]
Temperature: 0 °C

Procedure:
5-(2-Formyl-3-hydroxyphenoxy)pentanoic acid (119 mg, 0.5 mM) was dissolved in ethyl acetate (5 ml) and cooled to 0° C. under nitrogen with stirring. Dicyclohexylamine (0.11 ml, 100 mg, 0.55 mM) was then added and the mixture stirred at 0° C. (1/2 hr) under nitrogen. The precipitated solid was then filtered off and washed with ethyl acetate to give dicyclohexylammonium 5-(2-formyl-3-hydroxyphenoxy)pentanoate, 0.25 hydrate, m.p. 114°-115° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:6]=[C:7]([CH:11]=[C:12](Br)[C:13]=1[NH2:14])[C:8]([OH:10])=[O:9].CN(C)[CH:18]=[O:19]>[Cu-]=O.CO>[NH2:14][C:13]1[C:12]([O:2][CH3:1])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:19][CH3:18]
Reactant: CN(C)C=O
Reactant: C[O-]
Reactant: Nc1c(Br)cc(C(=O)O)cc1Br
Agent: O=[Cu-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)O)cc(OC)c1N
Temperature: 5 °C
Yield: 88 %

Procedure:
258 g of copper(I) oxide and 1670 ml of sodium methylate solution (30% in methanol) were boiled at reflux (88°-93° C.) for 15 minutes while stirring and gassing with argon. At this temperature, there was added dropwise with simultaneous distillation a solution consisting of 531 g of 3,5-dibromo-4-aminobenzoic acid, 1670 ml of sodium methylate solution (30% in methanol) and 2700 ml of dimethylformamide (dried over molecular sieve). The solvent was subsequently further distilled. 2200 ml were distilled off in total. The resulting red suspension was stirred at 113°-114° C. for an additional 45 minutes. Thereafter, 1300 ml of dimethylformamide were distilled off in a water-jet vacuum. 7500 ml of 4N sodium hydroxide solution were added to the resulting red residue and the suspension was stirred at about 100° C. for 30 minutes. Thereby 800 ml were again distilled off. The hot suspension was suction filtered over an internal glass suction filter. The residue was suspended three times in 1800 ml of hot water and filtered off each time. The solution, cooled to 5° C., was adjusted to PH 5 with 2000 ml of acetic acid while stirring. The resulting brown suspension was suction filtered and the residue was washed with 1000 ml of ice-water. The residue was dried at 60° C. in a water-jet vacuum. The thus-obtained crude product was boiled up with 3200 ml of methanol. The brown suspension was suction filtered and the filtrate was evaporated to dryness. There were obtained 313 g (88%) of 4-amino-3,5-dimethoxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([NH2:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:12][N:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Nc1nsc(-c2ccc(Cl)cc2)n1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nsc(-c3ccc(Cl)cc3)n2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1,2,4-thiadiazol-3-amine (423 mg, 2.0 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. EtOH was used in the second extraction to assist solublizing the sulfonamide. After drying over Na2SO4, solvent was removed in vacuo. The crude crystalline product weighed 0.45 g. The crude product was taken up in 13 mL of hot HOAc, diluted with 7 mL of H2O and seeded to give white needles (384 mg) after collection by filtration, washing with H2O, and drying in vacuo. The product had mp 220-221° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:31][O:32][CH2:33]Cl.C(N(CC)C(C)C)(C)C>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([CH:8]([CH:14]([O:25][CH2:31][O:32][CH3:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCl
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(O)c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(=O)OC(C)(C)C)C(OCOC)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(tert-butoxycarbonyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propanoate (9.25 g, 24.5 mmol) in DMF (3.78 mL, 49.0 mmol) and 1,2-dichloroethane (20 mL) was added tetra-n-butylammonium iodide (9.51 g, 25.7 mmol), chloromethyl methyl ether (5.59 mL, 73.5 mmol) and N,N-diisopropylethylamine (12.8 mL, 73.5 mmol). The mixture was gradually heated to 45° C. and stirred overnight. The crude product was concentrated in vacuo, diluted with CH2Cl2 and washed three times with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography: 16%-20%-25% EtOAc-Hexane. The product was obtained as a white solid. LCMS (API-ES) m/z (%): 322 (M+1-100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[O:1][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 35.3 g of methyl 3-hydroxybenzoate and 50.0 g of methyl 2-chloro-5-nitrobenzoate, dissolved in 400 ml of N,N-dimethylformamide, was added 48.1 g of anhydrous potassium carbonate. The mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by recrystallization from methanol to yield 75.4 g of methyl 2-(3-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 97-99° C.) (Reaction Scheme (27) described below).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1)([O-:7])=[O:6]>C1COCC1.O>[CH2:1]([S:3][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of sodium ethanethiolate (15.9 g; 0.189 mol) in 250 mL of THF and 100 mL of water at 0° C.-5° C. was added 5-nitro-2-chloropyridine (25.0 g; 0.158 mol). After 2 hours, the mixture was poured into 1200 mL of ice water, stirred for 15 minutes, and filtered. The solid was washed with water and dried in vacuo to provide 2-ethylsulfanyl-5-nitropyridine which was used without additional purification (28.1 g; 96%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=1[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[C:28]1([CH2:34]CO)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S([O-])(O)(=O)=O.[K+].CO>C1(C)C=CC=CC=1>[C:4]1([CH2:3][CH2:27][O:26][CH:3]([O:2][CH2:1][CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=2[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1OC(=O)OC(C)(C)C
Reactant: OCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1cccc(C(OCCc2ccccc2)OCCc2ccccc2)c1OC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
An amount of 1.43 g (3.73 mmol) of 2,3-bis-tert.-butoxycarbonyloxy-benzaldehyde dimethylacetal was dissolved in 40 ml of dried toluene. After the addition of 0.91 g (7.46 mmol) of 2-phenylethanol and 18 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 1 hour under reflux. The methanol formed was then distilled off slowly, while more toluene was added to the mixture. After complete removal of the methanol, the mixture was cooled down and the potassium hydrogensulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil which was dried in an oil pump vacuum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).