Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:6]
Reactant: NOCCO
Reactant: CS(=O)(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CS(=O)(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 52 %

Procedure:
The title compound was prepared from reaction of the product of Example 28, Step A, 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid purified by dry flash column chromatography on silica (5% isopropanol/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (52%); m.p. (Et2O) 85-88° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.78 (br s, 1 H), 8.88 (br s, 1 H), 7.72 (dd, J=11.1, 2.1 Hz, 1 H), 7.55 (ddd, J=8.8, 2.1, 0.6 Hz, 1 H), 7.48-7.35 (m, 2 H), 6.87 (td, J=8.8, 4.0 Hz, 1 H), 4.68 (br s, 1 H), 3.81 (t, J=4.6 Hz, 2 H), 3.54 (td, J=4.9, 4.2 Hz, 2 H), 3.18 (s, 3 H). Anal. Calcd for C16H15F3N2O5S: C, 47.5; H, 3.6; N, 6.9. Found: C, 47.3; H, 3.8; N, 6.6.
Reaction SMILES: C1(N(C2C=CC=CC=2)[C:8]([NH:10][S:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])C=CC=CC=1.[NH:28]1[CH2:38][CH2:37][CH:31]([C:32]([O:34]CC)=[O:33])[CH2:30][CH2:29]1.CN(C)C=O>CCOCC.O1CCCC1>[C:32]([CH:31]1[CH2:30][CH2:29][N:28]([C:8]([NH:10][S:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])[CH2:38][CH2:37]1)([OH:34])=[O:33]
Reactant: O=C(NS(=O)(=O)C=Cc1ccccc1)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)C1CCN(C(=O)NS(=O)(=O)C=Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 g. of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide and 10.3 g. of ethyl isonipecotate in 20 ml. of N,N-dimethylformamide is maintained at ca. 90° C. for 40 minutes. The mixture is cooled to ambient temperature, diluted with ether, and then it is extracted with water. The water extract is acidified using concentrated hydrochloric acid, and then it is extracted with methylene chloride. The dried methylene chloride is evaporated to dryness in vacuo leaving a viscous oil. The oil is redissolved in a small volume of tetrahydrofuran, absorbed onto a column of silica gel, and then eluted from the column with an excess of the same solvent. The solvent is evaporated in vacuo, and the residue is dissolved in 50 ml. of 0.5N sodium hydroxide solution. After 1 hour it is re-precipitated by acidification, and recovered by vacuum filtration in the form of white crystals. It is then dissolved in a mixture of 100 ml. of acetone and 100 ml. of tetrahydrofuran, and the solution is concentrated slowly to effect precipitation of the product. The solid is filtered off, and then triturated with acetone to give pure N-([4-carboxypiperidino]carbonyl)-2-phenylethenesulfonamide, m.p. 179°-181° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[O-][CH2:23][CH3:24].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:17]2[CH2:16][CH:15]([CH3:14])[CH2:20][C:19](=[CH:8][C:7]3[CH:10]=[CH:11][C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:18]2=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC1CCC(=O)CC1
Reactant: CC[O-]
Reactant: CCN(CC)c1ccc(C=O)cc1
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)c1ccc(C=C2CC(C)CC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1

Procedure:
In 50 ml of anhydrous ethanol were dissolved 35.4 g of p-diethylaminobenzaldehyde and 11.2 g of 4-methylcyclohexanone, and 20 ml of 10% ethanolic solution of sodium ethoxide was added dropwise to the resulting solution and the resulting mixture was subjected to reaction under reflux for 5 hours. The reaction mixture was cooled, and the crystals thus precipitated were collected by filtration, and then recrystallized from toluene, to obtain 30.2 g of 2,6-bis(4'-diethylaminobenzal)-4-methylcyclohexanone (m.p. 169° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1I
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccccc1I
Yield: 90.1 %

Procedure:
To 10 g (0.038 mole) of o-iodophenylacetic acid was added 50 ml of a solution of 5.7 g (0.048 mole) of thionyl chloride in anhydrous benzene, and the mixture was refluxed for 2 hours under agitation. Then, the solvent and unreacted thionyl chloride were removed by distillation under reduced pressure below 40° C. and the residue was subjected to distillation under reduced pressure to obtain 9.6 g of o-iodophenylacetyl chloride as a light yellow oily product having a boiling point of 153° to 156° C. under 8 mmHg in a yield of 90%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[CH2:29]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) (785 mg, 2.7 mmol) was dissolved in acetonitrile (50 mL). Triethylamine (1 g, 10 mmol) and benzyl bromide (510 mg, 3 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The mixture was then concentrated on the rotovap, dissolved in methanol (5 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O: 25 minute gradient). The pure fractions were pooled and concentrated and the product was recrystallized form ethanol to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-1,2,4-triazolidine-3,5-dione (210 mg, 20%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 3.09 (s, 3H), 4.81 (s, 2H), 5.18 (s, 2H), 7.30-7.35 (m, 5H), 7.76 (s, 1H), 8.18 (s, 1H). MS M+H calculated 381.1; found 381.1. Melting point: 124-126° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:43]([O:42][C:41]([NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]1[NH:33][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(Cl)nc1Nc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of ethyl 2-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (96.3 mg, 0.214 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (58.14 mg, 0.271 mmol) and Et3N (0.030 mL, 0.214 mmol) in DMA (2 mL) was stirred at 80° C. for 3 h. Saturated aq NaHCO3 was added to the mixture, which was extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=3/1) to give the title compound as a yellow oil (123.8 mg, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.71 (m, 20H), 2.33 (s, 3H), 3.39-3.57 (m, 1H), 3.84-3.99 (m, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.55-4.79 (m, 1H), 5.16 (s, 2H), 5.41 (br s, 1H), 6.87-6.89 (m, 1H), 7.16-7.49 (m, 3H), 7.74-7.75 (m, 2H), 7.90-7.91 (m, 2H), 10.68-10.81 (m, 1H). [M+H] calc'd for C34H41N6O6, 629. found, 629.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, is charged with 50 mL of DMF, 3.50 g (10 mmol) of (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 6.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture is stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicates complete reaction. The mixture is transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture is then added hexanes, 50 mL. The formed white solid is collected by filtration to afford the title compound of Formula 203 (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers are separated and the organic is concentrated to dryness. The residue is chromatographed to afford an additional yield of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20]=O)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]4)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=CCN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCN(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A mixture of (1R,2S) and (1S,2R)-2-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde (0.1 mmol), (1-Isopropyl)piperazine (0.15 mmol) and acetic acid (catalytic amount) in DCM (2 ml) was stirred for 20 minutes at room temperature. The mixture was cooled to 0° C. and NaBH(OAc)3 (2 mmol) was added carefully. The mixture was warmed to room temperature and stirred for 14 hours at room temperature. The mixture was concentrated under reduced pressure and dissolved in DMF. Purification by preparative HPLC gave the title product as colorless oil (35 mg). LC/MS m/e calcd. for C25H30ClN3O: 423, observed (M+H)+: 424.1 1HNMR (400 MHz, MeOD-d4) δppm 1.37 (d, J=6.57 Hz, 6 H) 2.18 (dd, J=8.46, 5.94 Hz, 2 H) 2.46-2.64 (m, 1H) 2.85 (d, J=3.54 Hz, 2 H) 3.22 (s, 2 H) 3.50 (d, J=6.57 Hz, 2 H) 3.90-4.27 (m, 2 H) 6.09 (d, J=7.58 Hz, 1H) 6.76 (s, 1 H) 7.10 (d, J=7.83 Hz, 1 H) 7.16-7.25 (m, 3 H) 7.33 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=[O:7].C(O)(=O)C.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH:20]1([NH:12][C:4]2[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:22][CH2:21]1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cc(F)c(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 4,5-difluoroanthranilic acid (1.13 g, 6.53 mmol) in anhydrous methanol (40 mL) is added molecular sieves (3 Å), acetic acid (3.70 mL, 65.3 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.25 mL, 26.11 mmol). After 30 minutes, sodium cyanoborohydride (2.08 g, 32.64 mmol) is added, and the reaction mixture is heated to reflux. After 16 hours, the reaction is cooled to room temperature, filtered, washed with methanol, and the combined filtrate concentrated under vacuum to afford a viscous oil. The resulting oil is dissolved in ethyl acetate and washed with 1.0 M hydrochloric acid, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated under vacuum to afford as a beige solid (1.32 g). MS CI: m/z 212 (M+).
Reaction SMILES: [CH2:1]1[C:7]([OH:12])([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:6])[O:4][C:2]1=[O:3].[OH2:13]>>[C:2]([OH:13])(=[O:3])[CH2:1][C:7]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:4])=[O:6])[OH:12]
Reactant: O=C(O)CC1(O)CC(=O)OC1=O
Reactant: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Following a procedure resembling that of Example 11, a beverage is prepared by first preparing a mixture of about 43 grams of citric anhydride and 957 grams of water to prepare 100 grams of water to provide 1000 grams of 0.25 molar solution of citric acid. Using power mixing, about 90 grams of Corn Starch Solids marketed as C-STAR-DRY GLO 1920 from Cerestar, Cargill Foods, Cedar Rapids, Iowa, 52406-1467. Such dispersion was aged for 15 minutes, and then a mixture consisting of orange flavor, an artificial sweetener, and sodium citrate bugger were added. Using power mixing. A glass electrode pH meter is employed during the terminal stages of adding mixing. A glass electrode pH meter was employed during the terminal stages of adding about 3,000 g. of tap water to prepared about 4000 g of beverage having a pH between 3.2 and 3.5 of liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([NH:11][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1NC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
0.055 mL of triethylamine and 0.036 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.014 mL of triethylamine and 0.012 mL of 4-fluorobenzoyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate=4:1] to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: [Na+:1].C(NC([N:12]1[CH2:18][CH2:17][C@@H:16]2[C@H:13]1[C:14](=O)[N:15]2[S:19]([O-:22])(=[O:21])=[O:20])=O)C1C=CC=CC=1.C(N(CC)CC)C.[C:31](Cl)(=[O:40])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Na+:1].[C:34]1(/[CH:33]=[CH:32]/[C:31]([C@:13]23[CH2:14][N:15]([S:19]([O-:22])(=[O:20])=[O:21])[C@@H:16]2[CH2:17][CH2:18][NH:12]3)=[O:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(NCc1ccccc1)N1CC[C@@H]2[C@H]1C(=O)N2S(=O)(=O)[O-]
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)[C@]12CN(S(=O)(=O)[O-])[C@@H]1CCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1S,5R)-2,6-Diazabicyclo[3.2.0]heptan-7-one (Example 2) (500 mg, 4.5 mmol) were suspended in 50 ml of dichloromethane. 0.75 ml (5.4 mmol) of triethylamine and subsequently 890 mg (5.4 mmol) of cinnamoyl chloride were added dropwise thereto while cooling with ice and the mixture was left to stir for 30 minutes while cooling and for 3.5 hours at room temperature. Thereafter, it was extracted once each time with saturated aqueous sodium carbonate solution, 2% aqueous citric acid solution, water and saturated aqueous sodium chloride solution. The combined organic phases were dried over magnesium sulphate and concentrated. Purification was effected by flash chromatography over silica gel with ethyl acetate. Yield: 560 mg (52%).
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:4]1[CH3:28].C([O-])(=O)C.[NH4+:33]>C(O)C>[NH2:33][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:4]1[CH3:28]
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CN)C2=O

Procedure:
A mixture of 5.0 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, benzyl ester and 5.0 g. of ammonium acetate in 200 ml. of ethanol is heated to reflux for 35 min. The reaction mixture is concentrated to dryness and the residue taken up in 200 ml. of chloroform. The chloroform solution is then washed successively with water (1 × 100 ml.), 1N aqueous sodium hydroxide (2 × 100 ml.) and brine (1 × 100 ml.), dried over magnesium sulfate and concentrated to dryness. The residual oil is crystallized from ethyl acetate, 3.34 g., m.p. 143°-149.5°C. and 1.3 g. recrystallized from the same solvent, 660 mg., m.p. 144°-146.5°C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[C:4]([CH3:17])=[N:3]1.[Cl:18][CH2:19][CH2:20][OH:21]>C(OCC)(=O)C>[Cl-:18].[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][N+:11]([CH2:19][CH2:20][OH:21])([CH3:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c(NCCCN(C)C)c1[N+](=O)[O-]
Reactant: OCCCl
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(NCCC[N+](C)(C)CCO)c1[N+](=O)[O-]
Product: [Cl-]
Temperature: 25 °C
Yield: 82.5 %

Procedure:
0.5 g of N-(2,5-dimethyl-4-nitro-2H-pyrazol-3-yl)-N′,N′-dimethylpropane-1,3-diamine and 2.2 g of 2-chloroethanol were introduced into a 10 ml three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was maintained at reflux for 2 hours. The medium was cooled to room temperature and diluted with 50 ml of ethyl acetate. The precipitate was filtered off. 0.55 g of [3-(2,5-dimethyl-4-nitro-2H-pyrazol-3-yl-amino)propyl](2-hydroxyethyl)dimethylammonium chloride was obtained in the form of yellow crystals, in a yield of 82%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([C:29]([OH:31])=O)[CH2:28][CH2:27]1.CC[N:34]=C=NCCCN(C)C>>[CH:26]1([C:29]([NH:34][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[O:31])[CH2:28][CH2:27]1
Reactant: O=C(O)C1CC1
Reactant: CCN=C=NCCCN(C)C
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Product: NC(=O)c1ccc2[nH]nc(-c3ccccc3NC(=O)C3CC3)c2c1
Yield: 24.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (600 mg, 1.79 mmol) with cyclopropanecarboxylic acid (0.43 mL, 0.46 g, 5.4 mmol) and EDCI (1.06 g, 5.4 mmol) furnished 140 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.35 (s, 1H), 1.9-1.68 (m, 1H), 0.8 (m, 4H); ES-MS (m/z) 321 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][NH:14][CH3:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC#N>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:14]([CH3:15])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC#N
Product: CC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.2 %

Procedure:
A mixture of 4-acetylbenzoic acid (10.0 g, 60.9 mmol), 40% aqueous solution of dimethylamine (8.24 g, 73.1 mmol), EDC (14.0 g, 73.1 mmol), HOBT (11.2 g, 73.1 mmol) and DIEA (21.3 mL, 122 mmol) in CH3CN (150 mL) was stirred at room temperature for 15 h and concentrated. The residue was dissolved in ethyl acetate (600 mL), washed with water (2×80 mL), brine (80 mL), dried (MgSO4) and concentrated to provide 4-acetyl-N,N-dimethylbenzamide (9.80 g, 84%). MS (E+) m/z: 191 (M+H); HPLC retention time: 0.88 min (Analytical HPLC Method F).