Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([CH2:31][C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][CH:33]=3)([CH3:30])[C:19](=[O:29])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C>[NH2:17][C:18]([CH3:30])([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[C:19]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:29]
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(N)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-9H-Fluoren-9-ylmethyl[1-(1H-indol-3-yl-methyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (10 g, 18.4 mmol) was dissolved in a 20% piperidine in DMF solution (50 mL) and stirred for 12 hours at room temperature. The solvent was removed in vacuo and chromatographed over silica gel using CH2Cl2 then 5% MeOH:95% CH2Cl2 as eluants. The title compound was crystallized from ethyl acetate (4.73 g, 80%), mp 106°-110° C. (EtOAc); IR (film) 1646 cm-1 ; NMR (CDCl3) δ1.39 (3H, s), 2.56-2.74 (2H, m), 2.82 (1H, d, J 14 Hz), 3.28-3.40 (1H, m), 3.48 (1H, d, J 14 Hz), 3.44-3.53 (1H, m), 7.1-7.7 (11H, m), 8.3 (1H, s); Anal. (C20H23N3O) C, H, N.
Reaction SMILES: I.[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][CH3:28])SC)[N:18]=1)[C:11]([NH2:13])=[NH:12].C(=O)([O-])[O-:30].[K+].[K+]>O>[OH2:6].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:27][CH3:28])=[O:30])[N:18]=1)[C:11]([NH2:13])=[NH:12].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:27][CH3:28])=[O:6])[N:18]=1)[C:11]([NH2:13])=[NH:12].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CN=C(NCCSCc1csc(NC(=N)N)n1)SC
Agent: I
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: O
Product: CNC(=O)NCCSCc1csc(NC(=N)N)n1
Reaction time: 16 h

Procedure:
A solution of 2-guanidino-4-[2-(2,3-dimethylisothioureido)ethylthiomethyl]thiazole hydrogen maleate hydriodide (0.8 g.) in water (10 ml.) was treated with an aqueous solution of potassium carbonate (0.3 g. in 5 ml. water) and the solution heated on the steam bath for 4 hours. After cooling and allowing to stand for 16 hours the aqueous layer was decanted from the brown gum and the gum taken up into ethanol and filtered. The filtrate was evaporated to dryness and the residue converted to the hydrogen maleate salt which was recrystallized from ethanol to give 2-guanidino-4-[2-(3-methylureido)ethylthiomethyl]thiazole hydrogen maleate hemihydrate, m.p. 167°-170° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCc2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (134 mg, 0.57 mmol), HBTU (327 mg, 0.86 mmol), and diisopropylethylamine (150 μL, 0.86 mmol) was stirred in methylene chloride (3.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (Example SP-272) (234 mg, 0.57 mmol) and diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (3.0 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroquinoline-7-carboxamide (130 mg): ESI MS m/z 550 [M+H]+
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[NH:11](CCO)[CH2:12][CH2:13][OH:14]>C(O)CCC>[OH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: OCCNCCO
Solvent: CCCCO
Product: O=C1OCCN(CCO)C1=O
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A 4(2-hydroxyethyl)morpholine-2,3-dione was prepared by charging 125 g diethyl oxalate and 80 g n-butanol into a suitable reaction vessel and heated to 22° C. under nitrogen blanket. A mixture of 89.9 g diethanolamine and 72 g n-butanol was slowly charged into the reaction vessel while maintaining the reaction mixture below 50° C. After stirring for 30 minutes, the reaction mixture was refluxed for one hour and then allowed to stand at room temperature for 16 hours. The product was collected by filtration and the solid was washed twice with diethyl ether and dried under nitrogen to give 100 g (73.4% yield) of white crystals with 83.3° C.-84.4° C. melting point. IR (Nujol mull) 1759 (ester carbonyl), 1684 (amide carbonyl) cm−1. 1H NMR (500 MHz, acetone-d6) δ 4.592 (approx. triplet, 2H, J=5.0 Hz, ring CH2O), 3.903 (approx. triplet, 2H, J=5.0 Hz, ring CH2N), 3.767 (t, 2H, J=5.5 Hz, CH2OH), 3.597 (t, 2H, J=5.5 Hz, chain CH2N). 13C NMR (500 MHz, D2O) δ158.514 (ester C═O), 155.338 (amide C═O), 67.036 (ring CH2O), 60.399 (CH2OH), 51.034 (ring CH2N), 47.600 (chain CH2N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[CH2:31]([NH2:34])[CH2:32][NH2:33]>C1COCC1>[NH2:33][CH2:32][CH2:31][NH:34][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:10]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:11]=2[N:12]=1
Reactant: NCCN
Reactant: CS(=O)(=O)c1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Solvent: C1CCOC1
Product: NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Yield: 97.2 %

Procedure:
To a solution of 4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (30 mg, 0.070 mmol) in dry THF (1 mL) was added ethylenediamine (23 uL, 0.35 mmol). The white precipitate initially formed redissolved on stirring. The mixture was stirred for about 15 min at about 20° C. LC/MS showed no starting material. The solvent was evaporated and the residue redissolved in DCM (1 mL) and water (1 mL). The layers were separated and the aqueous phase was basified with 2M sodium hydroxide (1 mL). The aqueous phase was extracted with DCM (2×1 mL) and the combined organic layers were evaporated to give 28 mg (100%) of the title compound. LC-MS m/z 412 (M+H)+, 2.19 min (ret time).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C1(C)C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>C(OCC)(=O)C>[F:33][CH2:32][CH2:31][O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Sodium hydride (55% oiliness, 140 mg, 3.2 mmols) was added to DMF (5 mL) solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil Sil FLASH 25+M, ethyl acetate:hexane=1:10→2:8) to provide the title compound (253 mg, 41%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[CH2:13][CH:12]1[CH2:11][CH2:10][CH:9]([C:14](OC)=[O:15])[CH2:8]2>C(OCC)C>[CH:7]12[CH2:13][CH:12]1[CH2:11][CH2:10][CH:9]([CH2:14][OH:15])[CH2:8]2
Reactant: COC(=O)C1CCC2CC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCC2CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a mixture of lithium aluminum hydride (0.74 g, 19.50 mmol) in anhydrous diethyl ether (11 mL) was added a solution of methyl bicyclo[4.1.0]heptane-3-carboxylate (1.00 g, 6.50 mmol) in anhydrous diethyl ether (4.6 mL) at 0° C. The resulting mixture stirred at 0° C. for 0.5 hour. The mixture was slowly quenched with water (1 mL) at 0° C. and warmed to ambient temperature. The mixture was filtered through diatomaceous earth and washed with diethyl ether. The filtrate was concentrated in vacuo to afford the title compound as colorless oil (0.70 g, 85%): MS (ES+) m/z 127.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][N:5]2[C:6](=[O:14])[NH:7][C:8](=[O:13])[C:9]([CH:10]3[CH2:12][CH2:11]3)=[C:4]2[C:3]=1[CH3:18].O1CCCC1.[H-].[Na+].[N+:26](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O>[NH2:26][N:7]1[C:8](=[O:13])[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:4]2[C:3]([CH3:18])=[C:2]([Cl:1])[C:16]([F:17])=[CH:15][N:5]2[C:6]1=[O:14]
Reactant: Cc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a 5° C. solution of 6-chloro-4-cyclopropyl-7-fluoro-5-methyl-pyrido[1,2-c]pyrimidine-1,3-dione (0.76 g, 2.8 mmol (Example 2)) in a mixture of dry tetrahydrofuran (20 mL) and dry dimethylformamide (10 mL) was added sodium hydride (0.12 g, 3.0 mmol, 60% mineral dispersion) portionwise. After stirring at room temperature for 30 minutes, 2,4-dinitrophenylhydroxylamine (0.65 g, 3.00 mmol) was added. The mixture was then heated at 80° C. for 45 minutes, cooled to ambient temperature, poured into ice water, and extracted with dichloromethane. The combined extracts were washed with brine, dried with sodium sulfate and concentrated. The residue was purified by column chromatography (9:1 ethyl acetate/hexanes) to afford the title compound (0.635 g). MSCI: m/z=284 (MH+).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[C:16]=1[CH3:17]>>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[C:16]([CH3:17])[C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1C)CCCC2
Product: [Li]C1CCCc2c1ncc(C)c2C

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 25 ml, 0.034 mol), and 3,4-dimethyl-5,6,7,8-tetrahydroquinoline-(5.65 g, 0.034 mol) the title compound is prepared and converted to methyl 3,4-dimethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate which is then converted to the corresponding 8-thioamide by the procedure of U.S. Ser. No. 460,265.
Reaction SMILES: NC1C=C(C=C(S(=O)(=O)N)C=1CC1C=CC=CC=1)C(OC)=O.[NH2:23][C:24]1[C:25]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:26]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[C:28]([CH:33]=1)[C:29](OC)=[O:30]>>[NH2:23][C:24]1[C:25]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:26]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[C:28]([CH:33]=1)[CH2:29][OH:30]
Reactant: CCCCOc1cc(C(=O)OC)cc(N)c1Cc1ccccc1
Agent: COC(=O)c1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Product: CCCCOc1cc(CO)cc(N)c1Cc1ccccc1

Procedure:
By replacing in Example 4 methyl 3-amino-4-benzyl-5-sulfamylbenzoate with an equimolar amount of methyl 5-amino-4-benzyl-3-n-butoxybenzoate (mp 82°-83° C.) and following the procedure described, 5-amino-4-benzyl-3-n-butoxybenzyl alcohol is obtained with a melting point of 105°-107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 67.6 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using epoxide compound (450 mg, 1.6 mmol) obtained in step 1 of example 2 and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (332 mg, 1.6 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (528 mg, yield: 69%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:43]=[CH:44][C:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:46][CH:47]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:39][CH2:40][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:43]=[CH:44][C:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:46][CH:47]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:36][CH2:37]1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (218 mg, 0.771 mmol) in 3 mL of THF at rt was added n-BuLi (482 μL, 0.771 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 61a (263 mg, 0.642 mmol) in 5 mL of THF. The resulting mixture was stirred at rt for 1 h then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, and the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc-DCM) to afford compound 61b as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 9.07 (d, J=2.0 Hz, 1H), 8.25-8.31 (m, 1H), 8.17-8.25 (m, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.77 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.29-7.37 (m, 1H), 7.23-7.29 (m, 1H), 6.13 (d, J=5.9 Hz, 1H), 4.02-4.11 (m, 4H), 3.91-4.02 (m, 4H), 2.88-2.98 (m, 2H), 2.69-2.83 (m, 2H), 1.86-1.96 (m, 2H), 1.77-1.86 (m, 2H), 1.68 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H34N6O3, 539.3 (M+H). found 539.5.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH2:12]([O:11][C:9]([C:8]1[S:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:14]([OH:20])[C:15]=1[OH:16])=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CSCC(=O)OCC
Product: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O

Procedure:
The diethyl thioglycolate and diethyl oxalate are mixed, and then added to a first solution containing a first electron donor in the microwave reactor. The microwave reactor is heated by the 2.45 GHz microwave at a power of 100-500 W to perform a condensation reaction for 20-60 minutes to obtain 2,5-diethoxycarbonyl-3,4-dihydroxythiophene. The reaction is shown in the chemical formula (B).
Reaction SMILES: CC[C:3]1[C:7](=[O:8])[N:6]([C:9]([NH:11]CCC2C=CC(S(NC(N[C@@H]3CC[C@@H](C)CC3)=O)(=O)=O)=CC=2)=[O:10])[CH2:5][C:4]=1C>C1(C)C=CC=CC=1>[O:8]=[C:7]1[CH2:3][CH:4]=[CH:5][N:6]1[C:9]([NH2:11])=[O:10]
Reactant: CCC1=C(C)CN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)N[C@H]3CC[C@H](C)CC3)cc2)C1=O
Solvent: Cc1ccccc1
Product: NC(=O)N1C=CCC1=O
Reaction time: 2 h

Procedure:
To a solution of glimepiride in dry toluene was added dropwise polytetrafluoroethyleneoxide-co-difluoromethyleneoxide-α,ω-diisocyanate (Mw ˜2,000, 0.2 equivalents) at ambient temperature. The reaction mixture was stirred for 2 hours, concentrated and then added to acetone. The resulting white solid was washed with ether and dried, yielding perfluoropolymer-labeled 3-ethyl-2,5-dihydro-4-methyl-N-[2{4-[[[(trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.Cl.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:20]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1cnc(C2CCNC2)cn1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3cnccn3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (15.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.0 mg). Calcd for C19H18N4O2: 334.1430, found 334.1426.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.10 min.; [M+H]+: 410.4 g/mol.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])#[C:8][CH3:9].Cl>CS(C)=O>[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:18])=[O:19])=[C:8]=[CH2:9]
Reactant: CC#COc1ccccc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: C=C=COc1ccccc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.8 %

Procedure:
4.4 g of potassium tert-butylate are added in portions to a solution of 6.33 g of 2-propynyloxyphenylsulfonamide and 40 ml of dimethyl sulfoxide such that the temperature does not exceed 28° C. The reaction mixture is stirred for 4 hours at 20°-25° C. and, after addition of ice-water, adjusted to pH 7 by the dropwise addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed through a column of silica gel to give 1 g of 2-allenyloxyphenylsulfonamide of m.p. 94°-95° C.
Reaction SMILES: COC.[NH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[C:15]2/[C:16]([CH3:30])=[C:17]([CH2:26][CH2:27][O:28][CH3:29])[C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[NH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[C:15]2\[C:16]([CH3:30])=[C:17]([CH2:26][CH2:27][O:28][CH3:29])[C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: COCCC1=C(C)/C(=C/c2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Agent: COC
Agent: O=C(c1ccccc1)c1ccccc1
Product: COCCC1=C(C)/C(=C\c2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Yield: 12.9 %

Procedure:
A solution of the Z methyl ether, E 1-(4-aminosulfonylphenyl)-methylene-5-methoxy-2-methyl-1H-3-indenyl-(2-methoxy)ethane (17a) (700 mg) and benzophenone (3.5 g) was irradiated with a medium pressure Hanovia lamp (450 watt) through a quartz well for 75 minutes under nitrogen. Following the work up procedure of Method A, there was obtained E 1-(4-aminosulfonylphenyl)methylene-5-methoxy-2-methyl-1H-3-indenyl-(2-methoxy)ethane (18a) (90 mg, 13% yield): m.p. 139.5°-140.0° C.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]=[CH2:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([CH:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)[C:8]([O:10][CH2:21][CH:20]=[CH2:19])=[O:9])=[CH:16][CH:15]=1
Reactant: C=CCO
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
A mixture of 2,2-bis(p-tolyl)acetic acid (8.52 g), allyl alcohol (6.6 ml) and p-toluenesulfonic acid monohydrate (0.34 g) in toluene (25 ml) was refluxed for 20 hours with continuous removal of water with Dean-Stark apparatus. After being cooled, the mixture was poured into 1N Sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide aqueous solution, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give allyl 2,2-bis(p-tolyl)acetate (8.09 g).