Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C[O:18][C:19](=O)[N:20]=[C:21](SC)[C:22]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([O:46][CH3:47])[CH:45]=1)[O:42][CH2:41][CH2:40][CH2:39]2)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([N:8]2[C:19](=[O:18])[NH:20][C:21]([CH:22]([C:36]3[CH:37]=[C:38]4[C:43](=[C:44]([O:46][CH3:47])[CH:45]=3)[O:42][CH2:41][CH2:40][CH2:39]4)[NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:26][CH:25]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCCC2
Reactant: NNc1ncccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3F)c(=O)[nH]2)cc2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
After adding 25 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 100 mg of {2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (24a)) in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoro-pyridin-2-yl)-5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([OH:20])=O)[CH3:15])=[CH:10][CH:9]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N.[N-]1C=CN=C1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([NH2:23])=[O:20])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(SCC(=O)O)c1ccc(-c2ccccc2Cl)cc1
Agent: N
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CC(SCC(N)=O)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
63.0 gm (0.205 mol) of [1-(2'-chloro-4-biphenylyl)-ethylthio]-acetic acid were dissolved in 630 ml of dry tetrahydrofuran, and 33.3 gm (0.246 mol) of carbonyldiimidazole were added. After stirring the mixture for 1/2 hour, dry ammonia was introduced into 300 ml of the obtained solution of the imidazolide (corresponding to 0.0683 mol), while cooling slightly, until the mixture was saturated. Subsequently, the mixture was stirred for 2.5 hours more and then evaporated in vacuo. The residue was distributed between water and ethyl acetate, and washed several times with dilute hydrochloric acid. The organic layer was dried and evaporated. Yield: 100% of theory; oil, Rf -value: 0.2 on carrier 1 with cyclohexane/ethyl acetate = 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH2:28]([O:31][C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1)[CH:29]=[CH2:30].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH2:28]([O:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:36][CH:37]=1)[CH:29]=[CH2:30]
Reactant: C=CCOc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 80.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 510 mg, 1.54 mmol) in methylene chloride (15 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (0.27 mL, 3.09 mmol). After stirring for 5 min, the cooling bath was removed, and the stirring continued at 25° C. for 10 min. The solvents were concentrated in vacuo, the residue was dissolved in benzene (25 mL), and the solvent was concentrated in vacuo again. The resulting acid chloride was dissolved in methylene chloride (10 mL), cooled to 5° C. and then treated with a solution of 5-allyloxy-pyrazin-2-ylamine (238 mg, 1.57 mmol) and pyridine (0.32 mL, 3.96 mmol) in methylene chloride (15 mL). The mixture was further stirred at 25° C. for 16 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL). Each aqueous layer was back-extracted with another portion of methylene chloride (25 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, eluted with increasing concentrations of ethyl acetate/hexanes) afforded N-(5-allyloxy-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide as a white foam (574 mg, 80%).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]1)[C:4](=[O:10])[CH2:3][C:2]2=[O:11].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:39][CH3:40])=[C:36]([Pb+3])[CH:37]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:39][CH3:40])=[C:34]([CH:3]2[C:2](=[O:11])[CH:1]3[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]3)[C:4]2=[O:10])[CH:33]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: O=C1CC(=O)C2C=CC1CC2
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2C=CC(CC2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A solution of bicyclo[3.2.2]non-6-ene-2,4-dione (0.835 g, 5.58 mmol), prepared by the method of R. Beaudegnies et al., WO2005/123667, in dry chloroform (30 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is added 4-dimethylaminopyridine (3.41 g, 28 mmol) and anhydrous toluene (5 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (4.75 g, 8.36 mmol) is added portionwise over 20 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (40 ml) is added, and the suspension is vigorously stirred for 30 minutes then filtered through diatomaceous earth (washing with additional dichloromethane, 40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (40 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown oil. The crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione (0.400 g, 22%) as a yellow gum.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([F:15])[C:10]([C:16]#[N:17])=[C:9]([F:18])[C:8]=1[F:19].[OH2:20]>>[F:6][C:7]1[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([F:15])[C:10]([C:16]([NH2:17])=[O:2])=[C:9]([F:18])[C:8]=1[F:19]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Product: NC(=O)c1c(F)c(F)c(F)c(C(N)=O)c1F
Temperature: 30 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
In a three neck flask having an inner volume of 1 liter, 63.08 g of purified water and 1048.74 g of 98% sulfuric acid were placed and stirred to prepare a 92% sulfuric acid solution. The resultant solution was heated to 80° C. and then kept cooled to keep the inner temperature of the flask in the range of 90 to 100° C. and 350.13 g (1.75 mols) of tetrafluoroisopthalonitrile was added piece meal to the cooled solution. After completion of this addition, the reaction solution in the flask was stirred for one hour while the inner temperature of the flask was kept at 90 to 100° C. and then the reaction solution was cooled to 30° C. Then, 1400 g of ice was placed in a beaker having an inner volume of 3 liters and the reaction solution was gently added dropwise to the ice so as to keep the inner temperature of the beaker from exceeding 60° C. After the completion of the dropwise addition, the mixture was cooled to 20° C. and then kept at 20° C. for one hour. A white solid which was precipitated was separated by filtration, washed with 1000 g of water, and then dried to obtain 407.95 g (1.73 mols) of tetrafluoroisophthalamide as a white solid (yield 98.8%).
Reaction SMILES: C(O[C:4](OCC)([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:5](=[O:7])[CH3:6])C.Cl.C1C[O:30]CC1>>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:4][C:5](=[O:7])[CH:6]=[O:30])[CH:12]=[C:13]([O:21][CH3:22])[C:14]=1[O:19][CH3:20]
Reactant: CCOC(CCCc1cc(OC)c(OC)c(OC)c1)(OCC)C(C)=O
Reactant: C1CCOC1
Agent: Cl
Product: COc1cc(CCCCC(=O)C=O)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution 1.8 g of 6-(3,4,5-trimethoxyphenyl)-2-keto-3-hexanal-diethylacetal in 15 ml of THF was added sufficient 6N HCl so that the pH<1. this mixture was refluxed for 18 hours. the mixture was cooled to room temperature and the solvent evaporated. the residue was triturated with 50 ml of ethyl acetate, the ethyl acetate solution dried with sodium sulfate (Na2SO4) and evaporated. the residue was chromatographed on 30 g of silica using CHCl3 as the elutant. Appropriate fractions were combined and evaporated to yield 0.8 g of 6-(3,4,5-trimethoxyphenyl)-2-keto-hexanal as an oil. 1H NMR: (CDCl3) δ 9.15 (s, 1 H), 6.40 (s, 2 H), 3.80 (s, 6 H), 3.76 (s, 3 H), 2.50 (m, 4 H), 1.60 (m, 4 H).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[C:30]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([O:23][CH3:30])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: Cc1c(Cc2cc3ccccc3s2)cc(C2OC(CO)CC(O)C2O)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C2OC(CO)CC(O)C2O)cc(Cc2cc3ccccc3s2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A 20 ml vial was charged with 22 (38.2 mg, 0.09 mmol) and Cs2CO3 (45 mg, 0.14 mmol) and to which was added 1 ml of dry acetone, followed by methyl iodide (12 μL, 0.18 mmol). The resulting mixture was stirred at room temperature for 16 h and the solid was filtered of, washed with acetone. The solvent was evaporated and the crude residue was purified by flash column chromatography on silica gel (4 g column, EtOAc/heptane: 0>>>100%) to afford 28.4 mg (71.8%) of 23 as a white solid. 1H NMR (CD3OD) δ 7.71 (d, J=7.58 Hz, 1H), 7.60 (d, J=7.58 Hz, 1H), 7.14-7.28 (3H), 6.87 (s, 1H), 4.52 (d, J=9.60 Hz, 1H), 4.22 (s, 2H), 3.76 (s, 3H), 3.65-3.75 (m, 2H), 3.49-3.59 (m, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.02 (m, 1H), 1.50 (q, J=11.62 Hz, 1H). MS (ES) 451.1 (M+Na+).
Reaction SMILES: [F: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>>[F: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=C(O)Cc1ccccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1F

Procedure:
2-(2-Fluorophenyl)acetic acid, (1.7 mmol) was dissolved in thionyl chloride (0.372 ml, 5.10 mmol) and heated to reflux for 1 h. The reaction was cooled and the excess thionyl chloride was evaporated. The residue was instantly dissolved in dry THF and refridgerated until used. No purity analysis or weighing were performed.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[BH4-].[Na+]>C(O)C.O.C(O)(=O)C>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: OCC1OC2CC(O)CC(C2)O1
Reaction time: 2 h

Procedure:
A solution of 340 mg of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one of the formula Ia in 10 ml of absolute ethanol is treated at room temperature with 150 mg of sodium borohydride and the mixture is stirred for 2 hours. The reaction mixture is diluted with 10 ml of water, the pH adjusted to 8 with a few drops of glacial acetic acid and the resulting solution is concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with altogether 100 ml of methylene chloride, the combined extracts are dried with sodium sulphate and the solvent is distilled off to give 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa, which melts at 146°-149°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.NC1C=CC(C)=NC=1.N(OCCCC)=[O:18].CCOCC>C(O)C.F[B-](F)(F)F.[H+]>[F:1][C:2]1[CH:7]=[N+:6]([O-:18])[C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: CCCCON=O
Reactant: Cc1ccc(F)cn1
Agent: Cc1ccc(N)cn1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(F)c[n+]1[O-]
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Preparation of 5-fluoro-2-picoline was based on E. J. Blanz, F. A. French, J. R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124–1130. 5-Amino-2-picoline (12.5 g) in ethanol (105 ml) and 50% fluoroboric acid (44.5 ml) was stirred at −5° C. and treated dropwise over 45 mins. with n-butyl nitrite (31.25 ml). The solution was maintained at this temp. for 3 hours, treated with ether (100 ml, precooled to −20° C.) and the solid filtered off, quickly transferred to a flask and covered with hexane (precooled to −20° C.). After allowing to warm to approx. 20° C. and standing for 3 days the hexane was decanted and 2M NaOH solution added until basic (pH10). The mixture was filtered and the filtrate extracted with dichloromethane (10×200 ml). The organic solution was dried, evaporated to 200 ml and treated with m-chloroperbenzoic acid (26.5 g). After stirring 16 hours the solution was washed with excess aqueous sodium bicarbonate and the aqueous re-extracted with dichloromethane (10×200 ml). The organic fraction was dried and evaporated and the residue chromatographed (15% EtOH/EtOAc) to give the product (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15]CC)=O)=[CH:7]2.[NH3:18].CO>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([NH2:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vessel containing NH3/MeOH (10 mL) was added ethyl 8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (500 mg, 1.99 mmol). The vessel was sealed and the resulting solution was stirred at RT for 1 hour. The reaction mixture was subsequently concentrated in vacuo to give the title compound, which was used without further purification (0.5 g, 98%). ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:22].O>C(#N)C>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
The suspension of the title A compound, 4,5-dimethyl-2-(4-trifluoromethylphenyl)-oxazole 3-oxide hydrochloride (500 g, 1.70 mol) in 4.06 L of acetonitrile is stirred for 15 minutes at room temperature, then cooled to 10° C. 491 g (3.17 mol) of POCl3 are added at 15° C. over a period of 30 minutes. The suspension is stirred at room temperature for 16 hours, and the mixture is cooled to 10° C., and 6 L of water are added into the reaction mixture slowly (first 400 mL of water addition is very exothermic). The suspension is then stirred at room temperature for 6 hours further, and the solids are collected by filtration, washed with 2 L of water and dried to a constant weight at 50° C. (20 mbar) to afford 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole as a white solid (400 g, 85% yield): m.p. 97–98° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[CH:40][C:39]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Add methanesulfonyl chloride (8 μl, 0.103 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.050 g, 0.094 mmol) and pyridine (8 μl, 0.103 mmol) in dichloromethane (2 mL) at 0° C. under atmosphere of nitrogen. Stir the suspension for 30 min, then remove the cooling bath and warm to room temperature while stirring overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N hydrochloric acid, water, and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (10:1 to 1:2), to provide the title compound as a white solid (0.037 g, 65%): ESI MS 610 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
A suspension of Example 113C (0.35 g, 0.831 mmol) in methanol (9.2 mL) was treated with 2 N aqueous sodium hydroxide solution (2.08 mL, 4.15 mmol), and the reaction was heated to 70° C. for 10 minutes. The reaction was cooled to ambient temperature, and the pH was adjusted to pH ˜7 with 10% aqueous HCl solution. The neutralized mixture was treated with water (12 mL), and the resulting suspension was cooled to 0° C. and filtered. The solid was collected, washed with water, and dried in a vacuum oven at 60° C. to provide the title compound. MS ESI(+) m/z 267.6 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].F[C:14]1C=[C:18]2C(O[C:22](=[O:24])[NH:23][C:17]2=[CH:16][CH:15]=1)=O.FC1C=C2[NH:35]C(=O)OC(=O)C2=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]1[C:5](=[O:12])[C:16]3[C:17]([N:23]1[C:22]2=[O:24])=[CH:18][N:35]=[CH:14][CH:15]=3
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Product: O=C1c2ccncc2-n2c1nc1ccc(F)cc1c2=O

Procedure:
Using the procedure in Example 36 and substituting 6-azaisatin (Example 9, J. Parrick et al., Tetrahedron Lett. 25:3099, 1984) for 5-fluoroisatin and 5-fluoroisatoic anhydride for 4-fluoroisatoic anhydride gives the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
To a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv) in DMF (10 mL) was added 1-phenylpiperazine (50 mg, 0.31 mmol, 2.00 equiv) and DIEA (100 mg, 0.78 mmol, 5.3 equiv). The resulting solution was placed in a 20-mL sealed tube, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) yielded 70 mg (crude) of methyl 2-phenyl-3-(4-phenylpiperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20]C(C=O)=CC=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:22]([O:24][CH:25]([O:44][CH2:45][CH3:46])[C:26]1[CH:43]=[CH:42][C:29](/[CH:30]=[N:31]/[C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][O:35][C:36]3=[O:41])=[CH:28][CH:27]=1)[CH3:23].[CH3:47][O-:48].[Na+].CO>C(OCC)(=O)CC>[CH2:22]([O:24][CH:25]([O:44][CH2:45][CH3:46])[C:26]1[CH:27]=[CH:28][C:29]([CH:30]2[CH:20]([C:21]3[CH:14]=[CH:12][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:11][CH2:10]4)=[O:13])=[CH:21][CH:20]=3)[C:47](=[O:48])[C:33]3[C:37]([C:36]([O:35][CH3:34])=[O:41])=[CH:38][CH:39]=[CH:40][C:32]=3[NH:31]2)=[CH:42][CH:43]=1)[CH3:23]
Reactant: C[O-]
Reactant: CC(C)C(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CCOC(OCC)c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccc(C(=O)N3CCN(C(=O)C(C)C)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A mixture of 4-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (950 mg, 3.3 mmol) and (E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (1.018 g, 3 mmol) in ethyl propionate (40 mL) was cooled to 0° C. Then a solution of sodium methoxide in methanol [sodium (345 mg, 12 mmol) in methanol (8 mL)] was added dropwise. After the addition, the mixture was stirred at room temperature for 24 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give methyl 2-(4-(diethoxymethyl)phenyl)-3-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (491 mg, yield 25%).