Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32][N:11]1[C:12](=[O:31])[C:13]([C:14]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=3[S:16](=[O:29])(=[O:30])[N:15]=2)=[C:4]([OH:3])[C@@H:6]2[C@H:7]1[CH2:8][CH2:9][CH2:10]2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@H]2CCC[C@H]21
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a solution of cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester (125.8 mg, 0.226 mmol) in absolute ethanol (10 mL) was added a 21% w/w solution of sodium ethoxide in ethanol (0.84 mL, 2.25 mmol). After stirring at 60° C. for 4 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-100% ethyl acetate in hexanes) to afford the desired product, cis-N-{3-[2-(3,3-dimethylbutyl)-5-hydroxy-3-oxo-2-aza-bicyclo[4.3.0]non-4-en-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (52.7 mg, 0.103 mmol, 46%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (9H, s), 1.56-1.57 (5H, m), 2.08-2.15 (3H, m), 3.05 (3H, s), 3.17 (1H, bs), 3.34 (1H, bs), 3.64-3.72 (1H, m), 3.90 (1H, bs), 7.48-7.60 (3H, m), 10.17 (1H, bs). LC-MS (ESI) calcd for C22H30N4O6S2 510.16, found 511.4 [M+H+]. Anal. calcd for C22H30N4O6S2 0.3H2O: C, 51.20; H, 5.98; N, 10.86; S, 12.43, found C, 51.39; H, 5.81; N, 10.65; S, 12.26.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[K+]>[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:2])=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
50.5 g of 19.66 percent poly(4-vinylpyridine) methanol solution from Ex. 2 (˜10.0 g of polymer) was placed in a 500 ml single neck flask and stripped of solvent on a rotary evaporator. To the dried polymer was then added 110 g of RO water and 10.0 g of con. hydrochloric acid. The mixture was stirred until a uniform pale yellow aqueous solution was obtained. This solution was then charged into a 500 ml three-necked round bottom flask equipped with a mechanical paddle stirrer, a nitrogen inlet, a pot thermometer, heating mantle and condenser. 0.43 g of potassium persulfate was then added followed by 30.0 g (˜0.288 moles) of styrene. The biphasic stirred mixture was then rapidly heated to 65° C. under nitrogen. After only 2 hrs., the latex solids were determined to be 27 percent (theory 27.1 percent) or ˜100 percent conversion. A small portion of the final latex was coagulated in dilute potassium hydroxide solution for analysis. NMR indicated a composition of 24.8 percent poly(4-VP) and 75.2 percent polystyrene (theory 25 percent poly(4-VP) and 75 percent PS). Latex particle size was 150 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2OCC1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2OCC1
Reaction time: 42 h
Yield: 93.5 %

Procedure:
To a solution of ethyl 7—(4-chlorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (400 mg) in tetrahydrofuran-ethanol (10-10 ml) was added 1N sodium hydroxide (2.0 ml) at room temperature, and the mixture was stirred for 42 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7—(4-chlorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (342 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:21]([C:5]1([CH2:4][C:3]([OH:23])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])[CH3:22]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
1,8-Diethyl-1,3,4,9-tetrahydro-4-oxopyrano[3,4-b]indole-1-acetic acid methyl ester 17 (1.5 g, 4.8 mmol) was suspended in 30 mL of MeOH and a solution of K2CO3 (3.5 g) in 30 mL of H2O was added. The mixture was heated to reflux, upon which the solution became homogeneous. After refluxing for 2 hours, the solution was cooled to room temperature, and the MeOH removed in vacuo. The aqueous solution was made acidic with 6N HCl, and the resulting cloudy solution was extracted with ether (2×50 mL). The ether layer was washed with 25 mL of saturated NaCl solution, then dried over MgSO4. The MgSO4 was removed and the ether was evaporated. Hexane was gradually added until a slight turbidity was observed. The solution was left at 0° C. overnight and the resultant solid was collected by filtration and dried to provide analytically pure product (1.31 g, 93%), m.p. 200°-202° C.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][CH2:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 104 °C
Yield: 72 %

Procedure:
4-(Diphenylmethoxy)-1-(methyl)piperidine (prepared by neutralization of the commercial HCl salt; 4 g, 14.2 mmol, 1 equiv.) in anhydrous toluene (20 mL) was stirred at room temperature under nitrogen. Ethyl chloroformate (4.66 g, 43 mmol, 4.1 mL, 3 equiv.) was added dropwise over 5 minutes, whereupon significant effervescence was noted. The mixture was heated over the course of 1 h to reflux with an oil bath (bath temperature 104° C.). The mixture was then cooled to room temperature, whereupon more ethyl chloroformate (4 mL) was added. The mixture was heated at reflux (bath T=104° C.) for 7 h and again cooled to room temperature. The cooled mixture was concentrated and the residue purified by dry column chromatography (4×8.5 cm silica bed; 2:1 heptane:ethyl acetate) to yield 3.49 g (72%) of 4a as a slightly yellow oil. 1H NMR was consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][O:20][C:19]=2[CH3:23])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][O:20][C:19]=3[CH3:23])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1occc1COc1ccc(I)cc1
Product: Cc1occc1COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A mixture of (4-fluoro-phenyl)-boronic acid (300 mg, 2.1 mmoles), 3-(4-iodophenoxymethyl)-2-methyl-furan (123). (500 mg, 1.6 mmoles) and potassium acetate (0.6 g) in N,N-dimethylformamide (70 mL) was degassed, treated with [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90 mg) and the mixture was agitated at 95° C. for 12 hours under an argon atmosphere. The mixture was concentrated in vacuo, partitioned between water (100 ml) and diethyl ether (200 ml). The aqueous phase was re-extracted with diethyl ether, and the combined ethereal phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124 (200 mg) as a solid. This material was used directly.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[F:22][CH:23]([F:31])[N:24]1[CH:28]=[C:27]([NH2:29])[C:26]([CH3:30])=[N:25]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:29][C:27]2[C:26]([CH3:30])=[N:25][N:24]([CH:23]([F:31])[F:22])[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C(F)F)cc1N
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Product: Cc1nn(C(F)F)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1

Procedure:
This compound was prepared from 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one and 1-(difluoromethyl)-3-methyl-pyrazol-4-amine. Column chromatography (SiO2, 50 equiv.; 50:50; EtOAc:MeOH) followed by re-crystallisation from warm MeOH (1-2 mL) furnished 64 mg of the desired product.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.Cl[CH2:17][CH2:18][CH2:19][C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:20]([CH2:19][CH2:18][CH2:17][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)#[N:21]
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCCOc1c2ccoc2cc2oc(=O)ccc12
Reaction time: 0.29 h

Procedure:
800 mg (3.956 mmol) of 5-hydroxypsoralen and 0.7 ml (655.5 mg, 6.33 mmol) of 4-chlorobutyronitrile were refluxed in 50 ml of 2-butanone in the presence of an excess (2.6 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 48 hours. The progress of the reaction was monitored by thin layer chromatography. After 48 hours the reaction mixture was concentrated under reduced pressure. The residual oily layer was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and then filtered. The solids were washed with water to neutral pH, dried by suction and then further washed with petroleum ether. The dried solids were dissolved in refluxing methanol, treated with charcoal and recrystallized from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:25](=[O:27])[CH3:26])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (300 mg) was dissolved in 1.5 ml of dry pyridine. Acetic anhydride (1.5 ml) was added thereto. The resulting mixture was stirred at room temperature for 5 hours, diluted with water, extracted with ether, washed successively with brine, dilute hydrochloric acid, brine, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-acetoxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:22][C:11]3=[N:12][C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([I:16])[CH:15]=[C:10]3[C:9]=2[C:23]([NH:25][CH3:26])=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].CN(C=O)C>O>[CH3:26][NH:25][C:23]([C:9]1[C:10]2[C:11](=[N:12][C:13]([N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])=[C:14]([I:16])[CH:15]=2)[O:22][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:24]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (440 mg), Cs2CO3 (322 mg, 1.1 eq.), 5-bromopent-1-ene (402 mg, 3 eq.) and dry DMF (4.5 ml) was stirred in a microwave reactor at 150° C. for 15 min and cooled to rt. Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with 2× water. Silica gel flash chromatography using 0-11% ether-methylene chloride yielded the title compound (250 mg, 55%). MS (ESI) m/z 558.1 (M+1). Retention time=1.33 min (Method A).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=3F)=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH-](CC)CC)C.[Li+].[Li]>O1CCOCC1.C1COCC1>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[O:18][C:35]4[C:30](=[CH:31][C:32]([F:37])=[CH:33][C:34]=4[F:36])[C:20]4[C:19]3=[C:28]3[C:23](=[CH:22][CH:21]=4)[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27]3)=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Agent: [Li]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1OC3c1ccc(OCCN2CCCCCC2)cc1
Reaction time: 1 h

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-methanone (2.63 g, 5.1 mmol) in 60 mL dioxane and add 10 mL of a 1.0 M solution of lithium triethylborohydride in THF. At the end of one hour, add another 10 mL of the lithium reagent mixture is added and gently warm the reaction. After a further one hour, add an additional 25 ml of lithium triethylborohydride and heat the reaction to reflux and hold for 8 hours. Cool the reaction and quench with water. Extract the water with methylene chloride, dry the organic layer with molecular sieves and concentrate. Purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][CH2:14][CH3:15])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]2[NH:21][C:22](=[O:24])[S:23][C:19]=2[CH:18]=1>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:16][C:17]3[C:26]([O:27][CH3:28])=[CH:25][C:20]4[NH:21][C:22](=[O:24])[S:23][C:19]=4[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]=1[CH2:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCCc1[nH]c2ncnc(Cl)c2c1CC
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCCc1[nH]c2ncnc(Nc3cc4sc(=O)[nH]c4cc3OC)c2c1CC

Procedure:
100 mg (447 μmol) 4-chloro-5-ethyl-6-propyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 22a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 3.2 mg (2%) of the title compound.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[C:3]2[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Prepared from δ-oxobenzenepentanoic acid and (4-fluorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 40% δ-oxobenzenepentanoic acid) δ8.04 (1H, s), 7.56-7.39 (5H, m), 7.30-7.25 (2H, m), 6.98-6.93 (1H, m), 3.23-3.18 (2H, m), and 2.71-2.67 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:34][C:33]2[C:35]([CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=[CH:38][C:32]=2[CH:29]([CH3:31])[CH3:30])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: CC(C)c1cccc(C(C)C)c1N=C(c1ccccc1)c1cccc(Br)c1
Temperature: 170 °C
Reaction time: 50 h
Yield: 84 %

Procedure:
In 25 mL Claisens flask in an argon atmosphere, a mixture of 5.22 g (20.0 mmol) of 16, 5.00 g (24.0 mmol) of Si(OEt)4, and 3.90 g (22.0 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.13 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 50 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×70 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.). This procedure gave 7.06 g (84%) of the title product 17.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[C:20](O)=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:27].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[CH2:20][Cl:27])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)[nH]c1=O
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)ccc1CCl

Procedure:
From 5.0 g. of 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 2.0 ml. of triethylamine, 1.75 ml. of trimethylsilyl chloride and 2.0 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:31][O:30][C:26]([CH2:27][CH3:28])=[O:29])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCOC(=O)CC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
In a similar manner to Example 12, bumetanide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in dimethylformamide (DMF) to yield ethylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](O)=[O:19])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:22]1([NH:21][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:17]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Yield: 70 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (30 mg, 0.11 mmol) synthesized in Preparation Example 4, aniline (21 μl, 0.23 mmol), triethylamine (0.20 ml, 1.4 mmol), propanephosphonic acid anhydride (0.3 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (0.25 ml), a similar procedure to a) in Example 29 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 7:3) to obtain N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol) having the following physical properties:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].C(CN)O.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Solvent: NCCO
Product: Cc1ccc(C(=O)NCCO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 63 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-(1-[(methylamino)carbonyl]methyl)benzamide using ethanolamine (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (551.7 mg, 63%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.68 (t, 2H), 3.48 (t, 2H), 2.19 (s, 3H); ES-HRMS m/z 494.0518 (M+H C21H19BrF2N3O4 requires 494.0522).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.O=[CH:10][C:11](=[CH2:13])[CH3:12]>>[CH3:13][C:11]1[CH:10]=[N:1][C:2]2[C:7]([CH:12]=1)=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2
Reactant: Cc1ccc(N)cc1
Reactant: C=C(C)C=O
Product: Cc1ccc2ncc(C)cc2c1
Yield: 70 %

Procedure:
The procedure described in Example 1 was followed, except that 107 g/hour of 4-toluidine and 84 g/hour of methacrolein were employed. The product was distilled off under 5 mbar until the bottom temperature reached 250° C., and 110 g (70% of theory) of 3,6-dimethylquinoline of melting point 50° C. were obtained by crystallization with xylene.