Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])/[C:5](/[NH2:12])=[CH:6]/[C:7]([O:9]CC)=O.[CH2:15]([N:17]([CH2:31][CH3:32])[C:18](=[O:30])[C:19]1[CH:24]=[C:23]([N:25]=[C:26]=[O:27])[C:22]([F:28])=[CH:21][C:20]=1[Cl:29])[CH3:16].O>CN(C)C=O.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:31]([N:17]([CH2:15][CH3:16])[C:18](=[O:30])[C:19]1[CH:24]=[C:23]([N:25]2[C:7](=[O:9])[CH:6]=[C:5]([C:4]([F:3])([F:13])[F:14])[NH:12][C:26]2=[O:27])[C:22]([F:28])=[CH:21][C:20]=1[Cl:29])[CH3:32]
Reactant: CCN(CC)C(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
An 80% suspension of 1.75 g of sodium hydride in refined oil is placed in 20 ml of dimethylformamide and 2.5 ml of toluene. 10.2 g of ethyl 4,4,4-trifluoro-3-aminocrotonate in 50 ml of dimethylformamide are added dropwise to the mixture at 5° to 15° C. and the thus-obtained reaction solution is stirred for 1 hour and subsequently cooled to -50° to -60° C. 12.6 g of N,N-diethyl-2-chloro-4-fluoro-5-isocyanatobenzamide in 25 ml of toluene are then added dropwise thereto and the mixture is stirred at this low temperature for a further 2 hours. Thereafter, the reaction solution is left to stand for about 16 hours, whereby it warms to room temperature. The solution is poured into 1 l of water and the aqueous solution is adjusted to a pH value of 5 with the addition of glacial acetic acid. Subsequently, the solution is extracted twice with 1 l of acetic acid, washed once with 1 l of water and once with 500 ml of saturated sodium chloride solution. The organic phases are combined, dried with anhydrous magnesium sulphate and concentrated. The residue obtained is recrystallized from ethyl acetate. In this manner there is obtained N,N-diethyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, m.p. 253°-254° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49](Cl)(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46](=[O:48])[NH2:47])(=[O:35])[NH2:34]>C(#N)C>[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46]([NH2:47])=[O:48])(=[O:35])[NH2:34]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(N)=O)c(OCC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (369.3 mg) was suspended in acetonitrile (10 ml)-triethylamine (2 ml) and 3,4-bis(carbamoylmethoxy)benzenesulfonyl chloride (340 mg) was added. The reaction mixture was stirred at room temperature overnight. Solids were filtered and washed with acetonitrile (10 ml) followed with acetone (5 ml). The solids were again resuspended in methanol (3 ml), filtered and dried in vacuo to give 2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetamide (527 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]1=[O:25].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[CH:19][C:18](=[O:25])[N:17]([CH3:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(=O)n(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:15][C:14](=[O:16])[C@@H:13]2[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
15.0 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and 13.5 ml of triethylamine were dissolved in 150 ml of dried dimethylformamide, and 12.66 ml of p-methoxybenzyl chloride was added dropwise to the solution under a nitroben stream, followed by stirring at 70° C. for 10 hours. The reaction mixture was diluted with 500 ml of ethyl acetate, washed with water, dried over sodium sulfate and distilled off to remove the solvent. Recrystallization of the residue from diethyl ether gave trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:36]>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (1.03 g×3, 5.95 mmol) and ammonium hydroxide (15 mL), the title compound was obtained as a white solid (1.86 g, 61% yield). MS (ESI): 502 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)([O-:16])=[O:15]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1

Procedure:
In 20 volume parts of ethanol is dissolved 2.16 parts of o-nitrobenzyl chloride, followed by the addition of 1.02 parts of N-methyl piperazine and 1.3 parts of potassium carbonate. The mixture is reacted under reflux for 1 hour. The reaction mixture is then filtered and the solvent is removed from the filtrate by distillation under reduced pressure. The residue is extracted with water-ether (1:1). The ethereal layer is taken and dried over anhydrous sodium sulfate and the solvent is then distilled off. This procedure gives N1 -methyl-N4 -(2-nitrobenzyl)piperazine as a brown colored oily substance. Infrared absorption spectrum (liquid film)cm-1 : 1610, 1538.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)[CH2:14][CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(CCCc2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(CCCC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 1.17 h
Yield: 51.1 %

Procedure:
A mixture of 2-(4-[3-phenylpropyl]-1,2,3,6-tetrahydropyridin-1-ylmethyl)benzimidazole (1.01 g, 3.05 mmol) and platinum (IV) oxide hydrate (56 mg) in ethyl acetate (75 ml) was hydrogenated on a Parr apparatus (30 psi maximum) for 70 minutes. Fresh catalyst was added (40 mg) and the mixture hydrogenated for a further 2.5 h. The mixture was filtered and evaporated to dryness. Flash chromatography eluting with 7.5% methanol in dichloromethane followed by recrystallisation from ethyl acetate/petrol (60°-80° C.) gave the title compound (0.52 g, 52%) as a white solid, m.p. 140°-141° C.; (Found: C, 79.25; H, 8.07; N, 12.39. C22H27N3 requires C, 79.24; H, 8.16; N, 12.60%); δH (DMSO-d6) 1.19 (SH, m, 2×CH2 +piperidinyl CH), 1.57 (4H, m, 2×CH2), 2.02 (2H, m, CH2), 2.55 (2H, m, piperidinyl CH2), 2.81 (2H, m, piperidinyl CH2), 3.66 (2H, s, CH2N), 7.15 (SH, m, ArH), 7.26 (2H, m, ArH), 7.43 (1H, br d, ArH), 7.51 (1H, br d, ArH), and 12.16 (1H, br s, N3H); m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([Cl:15])[CH:6]=1.[NH4+:17].[OH-]>>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([NH2:17])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COC(=O)Cc1cc(Cl)nc2ccccc12
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-chloro-quinolin-4-yl)-acetic acid methyl ester (100 mg, 0.42 mmol) is suspended in 28% NH4OH (2.0 mL). The mixture is stirred at RT overnight. The solvent is evaporated to afford 2-(2-chloro-quinolin-4-yl)-acetamide as a solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH3:23])[S:21][CH:22]=1.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:17][C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)O)cs1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (0.5 g, 12.5 mmoles) in anhydrous dimethylformamide (20 ml) under nitrogen was treated with methyl 4-amino-5-chloro-2-hydroxybenzoate (2.02 g, 10 mmoles), stirred for 30 minutes, then treated with 4-chloromethyl-2-methylthiazole (1.85 g, 12.5 mmoles). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (150 ml). The aqueous mixture was extracted with ether (2×100 ml), and the combined ethereal solution was dried (MgSO4), concentrated in vacuo, and taken up in 95% ethanol (20 ml). Water (10 ml) and 50% sodium hydroxide (10 ml) were added, and the mixture was refluxed for one hour, cooled in on ice, and concentrated in vacuo to remove most of the ethanol. Water was added to a total volume of 100 ml, and the aqueous solution was extracted with ether (2×50 ml), cooled in an ice bath, and adjusted to pH 4 with concentrated hydrochloric acid (16 ml). A resultant precipitate was filtered, washed with water, air dried, and recrystallized from 95% ethanol to yield 1.96 g (64%) of tan crystals, mp 188°-189° C.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][C:32](=[O:37])[CH:33]=[CH:34][CH2:35]Br)[CH3:30].[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[CH2:29]([O:31][C:32](=[O:37])[CH:33]=[CH:34][CH2:35][N:6]1[C:5]([C:12](=[O:13])[C:14]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:16]([C:17]#[N:18])[CH:15]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH3:30]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCOC(=O)C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (412 mg, 1.386 mmol, 1.0 eq.) was dissolved in 8 mL DMF. Potassium carbonate (191 mg, 1 eq.) was added and the reaction mixture was stirred at room temperature for 10 minutes. 4-Bromo-but-2-enoic acid ethyl ester (0.24 mL, 1 eq.) and lithium iodide (186 mg, 1 eq.) were added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give a light yellow foam (384 mg, 68%). LC-MS shows 410.4 (M+1).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].O1CCOCC1.Cl.[C:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)(=[NH:30])[NH2:29]>C(=O)(O)[O-].[Na+]>[C:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:36])=[CH:33][CH:32]=1)(=[NH:29])[NH2:30]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: N=C(N)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N=C(N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (313 mg) in sodium bicarbonate solution (20 ml)-dioxane (20 ml) was added 4-amidinobenzoyl chloride hydrochloride (219 mg) and the solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated, to which were added dichloromethane and water. The organic layer was separated and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give a colorless solid of the title compound (223 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].FC(F)(F)S(O)(=O)=O.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[Br:20][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.3 %

Procedure:
25 g (165 mmol) of 4-ethylnitrobenzene are placed in 200 ml of dichloromethane in a round-bottomed flask and under a stream of nitrogen. 20 ml (230 mmol) of trifluoromethanesulfonic acid and 33 g (115 mmol) of 1,3-dibromo-5,5-dimethylhydantoin are added and the reaction medium is stirred for 2 hours at room temperature. Saturated aqueous sodium hydrosulfite solution is then added. The phases are separated and the organic phase is neutralized with aqueous 2M sodium carbonate solution and then washed with water. It is then dried over magnesium sulfate, filtered and evaporated. 35 g (92%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: ClCCC(O[CH2:7][CH2:8][N:9]=C=O)=O.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:18]=[CH:7][CH:8]=1
Reactant: Cc1ccccc1
Reactant: O=C=NCCOC(=O)CCCl
Product: c1ccc2ncccc2c1

Procedure:
A three-necked flask was charged with 250 ml of toluene, 60 g (0.34 mol) of (2-isocyanatoethyl) 3-chloropropionate obtained in Synthesis Example 2, and 63 g (0.49 mol) of quinoline (boiling point: 237.7° C.), followed by heating at 50° C. for 6 hours with stirring. No acryloyloxyethyl isocyanate was confirmed by gas chromatography analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cccc(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[CH3:20][C:21]1[C:22]([C:27]2[CH:35]=[CH:34][C:30](C(O)=O)=[CH:29][CH:28]=2)=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9](=[O:11])[C:30]2[CH:34]=[CH:35][C:27]([C:22]3[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:28][CH:29]=2)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccnc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ncccc3C)cc2)C1
Yield: 50 %

Procedure:
Following the general method as outlined in Example 4 (Method B), starting from 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4-(3-methyl-2-pyridinyl)benzoic acid, the title compound was obtained, after flash-chromatography (eluent cyclohexane/ethyl acetate 8:2), as a mixture of two isomers in 50% yield (100% purity by HPLC).
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[CH:10][C:9]([C:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=1)=[C:8]([O:35][CH3:36])[CH:7]=2)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:35][CH3:36])=[C:9]([C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Yield: 63 %

Procedure:
A solution of tert-butyl 4-(3-cyano-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Method 85, 600 mg, 1.23 mmol) in CH2Cl2 (4.9 mL) and trifluoroacetic acid (4.9 mL, 63.6 mmol) was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with chloroform to remove trifluoroacetic acid, and the residue purified with reverse phase HPLC (MeCN/water) to give 302 mg (63%) product. m/z 390.
Reaction SMILES: Cl.CC([CH:6]1[CH2:11][N:10]([C:12]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([CH3:23])=[N:17]3)[CH2:9][CH2:8][N:7]1C([O-])=O)(C)C>O1CCOCC1>[F:22][C:21]1[C:12]([N:10]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:11]2)=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:23])[CH:15]=[CH:14]2
Reactant: Cc1ccc2c(N3CCN(C(=O)[O-])C(C(C)(C)C)C3)c(F)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(N3CCNCC3)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 156.2 %

Procedure:
A solution of hydrogen chloride in dioxane (4M, 4 mL) was added to a solution of 1,1-dimethylethyl-4-(6-fluoro-2-methyl-5-quinolinyl)-1-piperazinecarboxylate (0.178 g) in dioxane (4 mL) at 0° C. The resulting mixture was warmed to room temperature and stirred for 15 h. The mixture was concentrated in vacuo and partitioned between aqueous sodium hydroxide solution and DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford the title compound (198 mg, 100% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:6]=2[N:5]=[CH:4]O1.C([O-])(=O)C.[NH4+:19]>[NH4+].[OH-].CO>[O:1]=[C:2]1[C:7]2[C:6](=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][NH:19]1
Reactant: O=C(O)c1cccc2c(=O)ocnc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2c(=O)[nH]cnc12
Temperature: 80 °C
Yield: 17529.5 %

Procedure:
4-oxo-4H-3,1-benzoxazine-8-carboxylic acid derivative (51.5 g; 251.26 mmol) was dissolved in NH4OH (360.0 ml; 6.98 V; 28% solution). Ammonium acetate (77.5 g; 1.005 mmol) was added, and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with MeOH (40 mL) then heated for 72 h at 80° C. in a pressure bottle. The reaction mixture was concentrated on the rotary evaporator then cooled on ice and filtered. The solid was dried under vacuum to provide the desired product (33.5 g, 65% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>CO.O1CCCC1.[OH-].[Na+]>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Using pyrrolidin-2-one (432 mg) and methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1.54 g) described in Preparation Example 13 and by the reaction and treatment in the same manner as in Example 1, methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was obtained. The obtained methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was dissolved in a solution of methanol (5 mL) and tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated from the reaction mixture, and the mixture was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (720 mg). A mixture of the obtained 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (250 mg), 1-(2,4-dimethylphenyl)piperazine (154 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (242 mg) was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (330 mg).