Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH:5]1[CH:11]=[CH:10][N:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[S:6]1.[C:26]1([CH3:35])[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH:11]=[CH:10][N:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:32](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH3:35])=[CH:15][CH:14]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[S:6]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN(C)CCC1C=CN(C(=O)c2ccc(N)cc2)c2ccccc2S1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2C=CC(CCN(C)C)Sc3ccccc32)cc1

Procedure:
Compound 12 as prepared in Example 7 (0.118 mg, 0.37 mM) was treated following the procedure of Example 8, with 2-toluoyl chloride (0.04 ml, 0.33 mM) substituted for 2-phenylbenzoyl chloride, to give a white solid product. m/z (MH+) 474.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21](=[O:22])[N:23]([CH3:25])[CH3:24])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: CN(C)C(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCC(=O)N(C)C)c12
Reaction time: 8 h
Yield: 90 %

Procedure:
To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), α-bromo-N,N-dimethylacetamide (1.1 eq.) potassium carbonate (5 equiv.), and 10 ml of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 ml) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 ml), washed with brine (20 ml), dried over MgSO4. Filtration and evaporation of the solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 90% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14]1>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCCC1CO1
Solvent: CO
Product: CCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 34.1 %

Procedure:
A solution (50 ml) of 4-methanesulfonylbenzylamine (5.0 g) and 1,2-epoxypentane (2.8 g) in methanol was stirred at room temperature for 96 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (2.5 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:20][CH:19]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)(=O)C.O>[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[S:20][C:19]=2[Cl:1])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1csc(C2CCOCC2)c1)N1CCCCCC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(C2CCOCC2)sc1Cl)N1CCCCCC1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
N-Chlorosuccinimide (0.024 g, 0.18 mmol) was added to a solution of azepan-1-yl-[5-(tetrahydro-pyran-4-yl)-thiophen-3-yl]-methanone (53 mg) in acetic acid (2 mL). The reaction mixture was heated to 100° C. for 3 minutes using microwave irradiation, then diluted with water and purified by HPLC, eluting with 20%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (38 mg). LCMS m/z 328.17 [M+H]+ RT=10.59 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 6.6 (s, 1H), 4.05 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.4 (m, 2H), 2.9 (m, 1H), 1.9-1.5 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]([O:18]CC)=O.C([O-])(=O)C.[NH4+:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:26][C:16](=[O:18])[C:12]2[N:11]([CH:15]=[CH:14][N:13]=2)[CH:10]=1
Reactant: CCOC(=O)c1nccn1CC(=O)c1ccc(Cl)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 0 °C

Procedure:
920 mg (2.8 mmol) of ethyl 1-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1H-imidazol-2-carboxylate (Example 3A) were dissolved in 45 ml of glacial acetic acid, and 2.17 g (28 mmol) of ammonium acetate were added. The mixture was stirred under reflux for 12 h. The reaction mixture was added to ice-water and neutralized and with sodium carbonate. The precipitate was filtered off and dried under high vacuum. This gave 650 mg (82% of theory) of the product as a solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COCc1ccccc1B(O)O
Reactant: O=C(O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
To a suspension of 4-iodobenzoic acid (0.82 g, 3.31 mmol) and 2-methoxymethylphenylboronic acid (0.55 g, 3.31 mmol) in dry acetonitrile (30 mL) was added a 0.4 M aqueous sodium carbonate solution (30 mL) and the reaction mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) was then added and the reaction mixture heated to 90° C. for 19 hours. The hot reaction mixture was filtered through celite, concentrated in vacuo to remove acetonitrile and the resulting aqueous suspension washed with ethyl acetate (2×30 mL). The aqueous phase was acidified to pH 1 by the addition of concentrated hydrochloric acid, the resulting white suspension cooled to 4° C. for 1 hour and the solid product filtered. Recrystallization from dichloroethane gave the title compound (0.469 g, 59%) as a white solid, m.p. 164.5-165.5° C.
Reaction SMILES: Cl[C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[H][H]>[Ni]>[C:3]([CH:2]([C:7]([F:10])([F:9])[F:8])[F:11])([F:6])([F:5])[F:4]
Reactant: [H][H]
Reactant: FC(F)(F)C(F)(Cl)C(F)(F)F
Agent: [Ni]
Product: FC(C(F)(F)F)C(F)(F)F

Procedure:
2-Chloroheptafluoropropane (1.38 g/hr) and hydrogen (22 cc/min) were fed into the 1/4" Inconel® nickel alloy reactor filled with Inconel® nickel alloy chips (10 g). Operation at 500° C. and 250 psig for 33.3 hours gave an average of 91.3% conversion with 99.4% selectivity to CF3CHFCF3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O>C(#N)C.C(Cl)(Cl)Cl>[Br:12][C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]cnc1C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1[nH]c(Br)nc1C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
To a stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (2.00 g, 13.0 mmol) in acetonitrile (25 mL) and chloroform (25 mL) was added N-bromosuccinimide (2.31 g, 13.0 mmol). The reaction mixture was stirred under nitrogen atmosphere for 20 h, then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate as a light yellow solid (1.88 g, 62%): 1H NMR (300 MHz, CDCl3) δ 4.35 (q, J=7.1 Hz, 2H), 2.51 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); MS (ES+) m/z 233.1 (M+1), 235.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[OH:23][C:17]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:18]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cccs1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccs3)C2)c1

Procedure:
The compound of Example 14 was prepared according to the general preparation protocol A from thiophene-2-carbonyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:10](=[O:12])[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:13][S:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To acetonitrile solution (120 ml) of 2-(4-methoxyphenyl)-3-(3-methoxyphenylthio)propionic acid (4) (12.8 g, 40.3 mmol) obtained above was added potassium carbonate (1.59 g, 11.5 mmol) and phosphorus oxychloride (18.7 ml, 200 mmol) at 0° C. and then stirred for 18 hours at 60° C. The reaction solution was quenched with ice-water and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The obtained crude product was washed with ether to obtain 6.8 g of the first crop of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (5). Further, the filtrate was concentrated and the residue was then purified with silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 1.0 g of the second crop of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (5) (total yield: 7.8 g, 65%). NMR data of the compound (5) was identical to that described in Example 25.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:27]=2[C:36]([OH:38])=[O:37])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:40]>C1C=CC=CC=1.CO>[CH3:40][O:37][C:36]([C:27]1[C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=2[CH:34]=[CH:35][C:26]=1[NH:25][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:24])=[O:23])=[O:38]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 396 (2.69 g, 5.0 mmol) in benzene (40 mL) and methanol (10 mL) was treated with TMSCHN2 (3.0 mL, 6.0 mmol, 2.0M solution in hexanes). The reaction was stirred at room temperature for 1 hour, then quenched with acetic acid, and diluted with ethyl acetate. The organic layer was washed with aqueous NaHCO3, dried (MgSO4), filtered, concentrated, and purified by column chromatography (25% ethyl acetate/hexanes) to provide the desired product. MS (ESI(+)) m/e 528 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49])(=[O:5])=[O:4]
Reactant: COC(=O)C1=C(O)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Yield: 58.4 %

Procedure:
Trifluoromethanesulfonic anhydride (5.32 g, 18.9 mmol) was added dropwise to a solution of 6-hydroxy-5-methoxycarbonyl-3-phenyl-3-(4-pyrrolidinophenyl)-2H-naphtho-[1,2-b]pyran (4.8 g, 10 mmol) and pyridine (1.7 g, 21.6 mmol) in DCM (100 mL) at 0° C. under N2 with stirring. After 1 h the resulting solution was washed with HCl (100 mL, 2 M), water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM as eluent. The solvent was removed under reduced pressure to give the title compound (3.57 g, 58%) as a blue powder.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)(=O)C.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=1
Reactant: CC(C)CN
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)OC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(O)cc2C1=O
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
4-Hydroxy-N-isobutylphthalimide is prepared as described in Example 2, starting with 7.26 g of 4-acetoxyphthalic anhydride, 7.35 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 75 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 4 hours and then cooled to a temperature in the region of 40° C. and concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in 175 cm3 of ethyl acetate and 150 cm3 of saturated sodium hydrogen carbonate solution. The aqueous phase is separated out after settling has taken place and then extracted twice with 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 200 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up and stirred in 100 cm3 of cyclohexane at a temperature in the region of 20° C. for 1.5 hours and then filtered. The solid is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 4.0 g of 4-hydroxy-N-isobutylphthalimide are thus obtained in the form of a white solid. (Rf=0.25, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:31]([O:33][C:34](=[O:39])[C:35]([NH:37]O)=[NH:36])[CH3:32]>CN(C=O)C.O>[CH2:31]([O:33][C:34]([C:35]1[N:37]=[C:12]([C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[O:14][N:36]=1)=[O:39])[CH3:32]
Reactant: CCOC(=O)C(=N)NO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid (1000 mg, 2.79 mmol, 1.00 eq), and Di-imidazol-1-yl-methanone ((543 mg, 3.35 mmol, 1.20 eq) in DMF was stirred for 4 hrs at RT under argon. Then hydroxyamino-imino-acetic acid ethyl ester (612 mg, 4.19 mmol, 1.5 eq.) was added and the reaction mixture was stirred overnight, and then diluted with water. A yellow precipitate was formed that was filtered to afford the product (785 mg). [5.46 min; 455 (M+1)]
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)=[O:40].[ClH:1]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL, 0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (94) as an HCl salt (29 mg). MS found for C28H38N8O4 as (M+H)+ 551.3, (M−H)− 549.3. UV: λ=274, 281, 313, 344, 369 nm.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:26](C4CCCCO4)[N:25]=[CH:24][C:13]=3[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16]=2[CH:17]=1.[O-][N+]1C=CC=CC=1C1C=CC2C3NN(C4CCCCO4)CC=3C(=O)N(CC(F)(F)F)C=2C=1.[ClH:65].O>O1CCOCC1>[ClH:65].[O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[NH:26][N:25]=[CH:24][C:13]=3[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]=2[CH:17]=1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccc[n+]3[O-])cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccc[n+]4[O-])cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Solvent: C1COCCO1
Solvent: O
Product: O=c1c2cn[nH]c2c2ccc(-c3cccc[n+]3[O-])cc2n1CC(F)(F)F
Yield: 99 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. by treating 7-(1-oxidopyrid-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(1-oxidopyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with 4M HCl in dioxane, in the form of a white powder (hydrochloride, 1 H2O; yield 99%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCCCCC>C(OCC)(=O)C>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Nc2ccc(C)cc2)cc1
Yield: 98.2 %

Procedure:
Following the general procedure, 4-chloroacetanilide (85 mg, 0.5 mmol) was coupled with p-toluidine (80 mg, 0.75 mmol) with the reaction temperature of 90° C. and the reaction time of 14 h. Chromatography on silica gel column with 2:1 hexane:ethyl acetate gave 118 mg (98%) of the title compound as a pink solid.
Reaction SMILES: [CH2:1](Br)[CH3:2].C([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:18]([O:20]CC)=[O:19])[CH:14]=[N:15]2)=[CH:10][C:9]=1[F:24])(=O)C>O.C(O)C.[OH-].[Na+]>[F:24][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[NH2:7])[N:15]([CH2:1][CH3:2])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[C:12]2=[O:23]
Reactant: CCBr
Reactant: CCOC(=O)c1cnc2cc(NC(C)=O)c(F)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)cc21

Procedure:
1.5 ml of ethyl bromide is added to a solution of 1 gram of ethyl 7-acetamido-4-hydroxy-6-fluoro-3-quinolinecarboxylate in 25 ml of water, 60 ml of ethanol and 2.5 ml of 10% sodium hydroxide solution, and the mixture is maintained under reflux for 4 hours. The mixture is then concentrated to half its volume, 5 ml of 10% sodium hydroxide solution are added and refluxing is maintained for 1 hour. The mixture is allowed to cool and is acidified with hydrochloric acid, and the precipitate formed is filtered off. The precipitate is washed with water, dried, and recrystallized in a dimethylformamide/water (10:1) mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][S:25]4(=[O:32])=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 48.9 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (196 mg) described in Preparation Example 114 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (109 mg) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].[NH2:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([NH:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccco2)CCCCC1

Procedure:
2.00 g (7.48 mmol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was used instead of 2-benzothiophenecarboxylic acid, and 772 mg (7.48 mmol) of L-valinol was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference Example 197 to obtain 2.67 g (quantitative) of the title compound and 2.64 g (quantitative) of the title compound.