Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid (669, 2.0 g, 0.0076 mol) in methanol (20.0 mL) was added sulfuric acid (0.90 mL, 0.017 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified with silica gel column chromatograph eluting with 20% ethyl acetate in hexane to give a white solid (670, 1.27 g, 62%). MS (ESI) [M−H+]−=274.1.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[Cl:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>>[C:4]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:24](=[O:25])[CH:23]([Cl:22])[CH3:27])=[CH:12][CH:11]=2)[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Product: CC(Cl)C(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
By treating [3-(phthalimido)propoxy]benzene and 2-chloropropionyl chloride in the same manner as in Example 79-(1), 4-[3-(phthalimido)propoxy]-1-(2-chloropropionyl)benzene was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=1>>[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])[CH:20]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Nc1cc(C(=O)O)ncn1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncn1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (195 mg, clear colorless oil) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (167 mg, 0.58 mmol, Amine-5, single enantiomer) and 6-aminopyrimidine-4-carboxylic acid (80 mg, 0.58 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>[N+]([O-])([O-])=O.[Ag+]>[OH:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCCNCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: N#Cc1cc([N+](=O)[O-])ccc1N(CCO)CCO
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25.5 g) and silver nitrate (28.5 g) were added to diethanolamine (102 g) and the mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give 2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (21.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C1N2CCN(CC2)C1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CN(C)C(=S)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A DMF (100 mL) solution of 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (15.2 g, 67.7 mmol) and DABCO (15.2 g, 135.5 mmol) was charged dropwise with N,N-dimethylthiocarbamoyl chloride (16.7 g, 135.5 mmol) in 20 mL DMF over 15 min. The reaction was stirred at rt for 18 h and then quenched with water. The reaction was partitioned between water (1L) and EtOAc (500 mL) and the organic layer washed with 1N HCl (500 mL). After drying (MgSO4) and concentration, the crude product was obtained as a tan oil. Purification by flash chromatography (15% EtOAc/hexane) provided the product (15.8 g, 75%) as a pale yellow oil: 1H NMR (CDCl3) δ 1.32 (t, 3H), 1.65 (s, 6H), 3.37 (s, 3H), 3.50 (s, 3H), 4.30 (q, 2H), 6.93 (dd, 4H); MS (m/e) 312.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].Br[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:20][CH:19]([N:8]1[C:9]2[C:5]3[C:4](=[CH:15][CH:14]=[CH:13][C:6]=3[C:7]1=[O:12])[C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH3:21]
Reactant: CC(C)Br
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c3c(cccc13)C(=O)N2C(C)C

Procedure:
A mixture of 2.0 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 2), 0.48 g of 60% sodium hydride and 2.33 ml of 2-bromopropane in 100 ml of N,N-dimethylformamide is reacted for 23 hours using the conditions of Example 4 to yield 1.15 g of the desired product as a bright yellow solid, m.p. 70°-71° C.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]([NH:28]/[N:29]=[C:9]2\[C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16]3[C:11]\2=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NNC(=O)CC1CCCCC1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC2CCCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-cyclohexylacetohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.01-1.07 (m, 2H), 1.18 to 1.39 (m, 7H), 1.60-1.72 (m, 5H), 1.81 (d, 2H), 1.92-1.94 (m, 1H), 2.27 (d, 1H), 2.69 (d, 1H), 3.70 (t, 2H), 3.87 (s, 3H), 6.42 (s, 1H), 6.62 (d, 1H), 7.52 and 7.74 (d for isomers, 1H), 12.39 and 13.99 (br s for isomers, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([O:21]CC)=O)[N:8]=2)=[N:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.C1COCC1>CC(N(C)C)=O>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:21])[N:8]=2)=[N:2]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(OC)cc2n1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3cc[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Reaction time: 2 h
Yield: 60 %

Procedure:
To ethyl 4-(1H-pyrazol-3-ylamino)-7-methoxyquinazoline-2-carboxylate (30 mg, 0.10 mmol) in dry DMA (2.5 mL) cooled in a −20° C. cooling bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (0.306 mL, 0.306 mmol). After 2 h additional 1 N 4-fluorophenyl magnesium bromide (0.050 mL) was added. After 2 h, the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and purified by preparative thin layer chromatography on silica gel eluting with 10% MeOH/DCM to give a solid (21 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 6.73 (br. s., 1H) 7.29 (m., 2H) 7.38 (m, 2H) 7.63 (br. s., 1H) 8.08 (m, 2H) 8.64 (m., 1H) 10.63 (br. s., 1H) 12.47 (br. s., 1H) LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl[CH2:21][O:22][CH3:23]>CCN(C(C)C)C(C)C>[CH3:21][O:22][CH2:23][O:1][C:2]1[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (Intermediate 13, 2.6 g, 10 mmol)) in i-Pr2NEt (28 mL) was added chloromethylmethyl ether (4.8 mL, 63 mmol). The mixture was stirred at ambient temperature for overnight, was quenched with 1M HCl, and extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to give the title compound as a white solid (2.79 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([CH:31]=O)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][C:24](=[O:26])[CH3:25])[O:10][C:9]1([CH3:34])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][C:24](=[O:26])[CH:25]=[CH:31]2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(CC(C)=O)C(C=O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(=O)C=CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of 4-benzyl-5-(2-formyl-3-methoxycarbonyl-5-oxo-hexyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (13.5 g, 27 mmol) and para-toluenesulfonic acid monohydrate (660 mg, 2.7 mmol) in dry toluene (250 ml), was refluxed for 24 hours using a Dean-Stark apparatus to remove water formed during the reaction. The mixture was then cooled to room temperature and treated with and saturated aqueous sodium hydrogen carbonate solution (20 ml). After dilution with ethyl acetate and brine, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel provided 4-benzyl-5-(6-methoxycarbonyl-4-oxo-cyclohex-2-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (5.64 g, 43%). Mass spectrum 458 [M+H]+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g) was dissolved in 20 ml toluene. Water (5 ml) and 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-furoylchloride (0.68 g). After stirring for 7 hours at room temperature, 0.3 g 2-furoylchloride was added and the mixture stirred for a further 6 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2-furoyl)hydrazine, was removed by filtration and washed with water. m.p. 155°-175° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:28]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]1[CH2:37][CH2:36][N:35]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])=[CH:17][CH:18]=3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N3CCOCC3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)c2)CC1
Yield: 72 %

Procedure:
The title compound was prepared from 1-(3-cyanophenyl)-3-(4-(morpholinosulfonyl)phenyl)urea following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].O.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:37])([F:36])[C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:29]([C:28]([F:32])([F:33])[C:27]([F:34])([F:35])[C:26]([F:37])([F:36])[F:25])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 21 %

Procedure:
A solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in heptafluorobutanoic acid (2 ml) was stirred overnight at 90° C. The mixture was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (solution) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a pink solid (34.1 mg, 21%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]([OH:18])[C:13](=[NH:17])[O:14]CC)[CH3:3].[O:19]1CCC[CH2:20]1>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]1[O:18][C:20](=[O:19])[NH:14][C:13]1=[O:17])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(F)cccc1OCC
Agent: Cl
Product: CCOc1cccc(F)c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 66, using a reaction time of 3 hours at room temperature, ethyl 1-(2-ethoxy-6-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (0.56 g., 2 mmoles) in 55 ml. of tetrahydrofuran was converted to crude product. Recrystallization from toluene afforded purified 5-(2-ethoxy-6-fluorophenyl)oxazolidine-2,4-dione. (147 mg., m.p. 127-128° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
Then, 0.15 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) was dissolved in 0.88 ml of pyridine, to which 52 μl of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with 2N hydrochloric acid, water, saturated sodium hydrogen-carbonate solution, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 45 mg (yield, 25%) of 3-(2,4-dichloro-5-methanesulfonylaminophenyl)1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-343; m.p., 189.2° C.).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 52.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-octadecanol (36 grams, 210 mmol), pyridine (20 milliliters), and dichloromethane (500 milliliters) was heated to reflux. The alcohol dissolved and the solution was allowed to cool 5° C. 4-Nitrobenzoyl chloride (39.0 grams, 210 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with 250 milliliters of water. The aqueous layer was washed with 250 milliliters of dichloromethane. The organic layers were combined and concentrated under reduced pressure to a light tan solid. Added 500 milliliters of hexane and heated to reflux. A white precipitate formed as the solution was cooled to room temperature. Filtered off the white precipitate and concentrated the filtrate to a light tan solid. The solid was recrystallized from ethanol (500 milliliters) to obtain 46 grams of octadecyl 4-nitrobenzoate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[C:4](NC(=O)C)[CH:3]=1.Cl.[NH:18]([C:20]1[CH:31]=[CH:30][C:23]([CH2:24][S:25]([NH:28][CH3:29])(=[O:27])=[O:26])=[CH:22][CH:21]=1)[NH2:19]>>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:19][NH:18][C:20]3[CH:31]=[CH:30][C:23]([CH2:24][S:25](=[O:27])(=[O:26])[NH:28][CH3:29])=[CH:22][CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[NH:8][C:7](=[O:11])[CH3:6]
Reactant: CC(=O)Nc1cc(O)cc2c1C(=O)C(=O)N2
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NN=C2C(=O)Nc3cc(O)c(NC(C)=O)cc32)cc1
Yield: 4 %

Procedure:
Condensation of N-(6-hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide and 4-hydrazino-N-methyl-benzylsulfonamide hydrochloride according to Procedure G gave the title compound in 4% yield: 1H NMR (DMSO-d6): δ2.04 (s, 3H), 2.51 (d, J=4.8 Hz, 3H), 4.24 (s, 2H), 6.45 (s,1H), 6.84 (t, J=4.8 Hz, 1H), 7.30 (s, 4H), 7.82 (s, 1H), 9.12 (s, 1H), 10.20 (s, 1H), 10.77 (s, 1H), 12.50 (s, 1H); APCI−MS m/z416 (M−H)−.
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1([OH:19])[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=2)[N:14]([S:39]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)(=[O:40])=[O:41])[C:13]1=[O:18])[CH3:28]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(C#N)cc21
Reaction time: 1 h
Yield: 68.3 %

Procedure:
2.3 g (10.6 mMol) of potassium tert-butanolate are added to 5.5 g (18.7 mMol) of the intermediate 1b in 40 ml of DMF at 0° C. The reaction mixture was stirred for 1 h. Then 4.25 g (18.7 mMol) of 8-quinolinesulfonyl chloride were added at 0° C. The reaction solution was stirred at 0° C. for three hours and then at room temperature for 16 h. This reaction solution was poured into aqueous K2CO3 solution, resulting in a precipitate which was isolated. This solid was dissolved in methylene chloride, dried and concentrated in vacuo. The resulting residue was recrystallized from ethanol. 6.2 g of the product were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CNOC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the quinoline-3-carboxylic acid (480 mg, 2.77 mmol) and N,O-dimethyhydroxylamine hydrochloride (405 mg, 4.15 mmol), in dichloromethane (10 mL) was added triethyl amine (1.93 mL, 13.8 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (1.55 g, 3.32 mmol). After stirring the reaction mixture at room temperature for 1 hour, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM. The organic layer dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 75% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 8.25 (d, J=1.8 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 3.61 (s, 3H), 3.48 (s, 3H). LC-MS: 1.24 min; (M+H)=217.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][OH:23])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][OH:23])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCO
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO

Procedure:
4-Benzyl-1-tert-butoxycarbonyl-2(S)-(2-hydroxyethyl)piperazine (7.0 g, 21.8 mmol) was hydrogenated at 60 psi in methanol (80 mL) in the presence of 10% Pd/C (1.56 g) according to the procedure described in Example 2, Step C. The title compound was obtained as an oil (4.43 g). NMR (CD3OD, 300 MHz) δ 4.17 (1H, m), 3.80 (1H, d, J=4 Hz), 3.54 (2H, t, J=7Hz), 2.75-3.05 (4H, m), 2.58 (1H, dt, J=4, 13 Hz), 2.0 (1H, m), 1.8 (1H, m), 1.45 (9H, s).