Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].FC(F)(F)C(O)=O>C1COCC1.C(OCC)(=O)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:9](=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH:3]([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: COC(CC=CC=CC(=O)O)c1ccc(N(C)C)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(CC=CC=CC(=O)Nc1ccccc1N)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of carboxylic acid 16 (207 mg, 0.753 mmol) in anhydrous THF (10 mL) was added 1,1′-carbonyldiimidazole (128 mg, 0.790 mmol) at rt, and the mixture was stirred overnight. To the resulting solution was added 1,2-phenylenediamine (570 mg, 5.27 mmol), followed by trifluoroacetic acid (52 μl ), and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated NaHCO3 solution (5 mL) and then water (10 mL), dried (MgSO4), and concentrated. Purification by flash silica gel chromatography (50% ethyl acetate in toluene) afforded the title compound 20 (115 mg, 42% yield): 1H NMR (300 MHz, CDCl3) δ 7.44 (br. s, 1H), 7.01-7.29 (m, 5H), 6.70-6.78 (m, 4H), 6.09 (m, 2H), 5.90 (d, J=15.0 Hz, 1H), 4.10 (br. t, J=6.6 Hz, 1H), 3.89 (br. s, 2H), 3.18 (s, 3H), 2.95 (s, 3H), 2.66 (m, 1H), 2.50 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 40.5, 41.6, 82.8, 112.3, 118.1, 119.4, 121.7, 124.4, 125.1, 127.0, 127.6, 128.6, 130.0, 140.0, 140.8, 142.5, 150.2, 164.7.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A suspension of 4-methyl-1H-imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (2 g, 9.56 mmol) in DMF (15 mL). Cs2CO3 (6.23 g, 19.13 mmol) was added and the mixture was stirred at 80° C. for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg, 2.95 mmol, 30.8% yield): 1H NMR (400 MHz, CD3OD) δ 8.61-8.78 (m, 1H), 8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:23][CH:20]3[CH2:22][CH2:21]3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NC1CC1
Product: Clc1nc(SCc2ccccc2)nc2nc(NC3CC3)sc12

Procedure:
Prepared by the method of Example 220, using the product of Example 219 and cyclopropanamine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:12][CH2:13][S:14][CH2:15][C:16]([OH:18])=O)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][S:14][CH2:13][CH2:12][C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCNCC
Reactant: CCc1cc2c(cc1CCSCC(=O)O)OCO2
Product: CCc1cc2c(cc1CCSCC(=O)N(CC)CC)OCO2
Yield: 87.1 %

Procedure:
2.1 g of the title compound was prepared from 2.0 g of [{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]-acetic acid by using 2.7 g of diethylamine as a pale yellow oil according to the same procedure as that described in Example 32.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:13][CH:14]=1
Reactant: COC(=O)Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
The crude 4-(tetrahydropyranyloxy)methyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl (250 mg) dissolved in 4 mL of methanol was treated with 1 mL of 10% methanolic p-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 1 hour. The s reaction mixture was made basic by the addition of saturated aqueous sodium bicarbonate, then diluted with ethyl acetate. The organic layer was washed with water (2×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride-methanol (100:3) to give 137 mg of the product. 1H NMR (200 MHz, CDCl3): δ3.51 (s, 3H), 4.75 (s, 2H), 6.62 (br s, 1H), 7.14 (dd, 2H), 7.34 (dd, 1H), 7.4 (dd, 4H). FAB-MS (Li+ spike): calculated for C15H15NO3 (257); found 264 (M+Li).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41]C2CCCCO2)=[CH:33][CH:32]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:17][CH2:18][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=1
Reactant: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCOC4CCCCO4)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
0.6 g of the compound obtained in stage 16H) and 2 ml of 2N etheral hydrochloric acid are added to 15 ml of methanol. After 2 hours at AT, the expected compound is filtered off. 0.385 g of the expected compound is obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)([O-:16])=[O:15]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccccc3[N+](=O)[O-])CC2)nc[nH]1

Procedure:
6-[4-(2-Nitro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-nitrobenzaldehyde. Mass spectrum (ES) MH+=316.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][CH:26]=[C:27]([C:29](=[O:31])[NH2:30])[N:28]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:29]([C:27]1[N:28]=[C:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([OH:18])[CH2:20]2)[S:25][CH:26]=1)(=[O:31])[NH2:30]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2nc(C(N)=O)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(N2CC[C@@H](O)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (3R)-3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (950 mg, 2.10 mmol) (obtained as described in Reference Example 18(5)) in anhydrous tetrahydrofuran (20 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.52 ml, 2.52 mmol) in an ice bath. The mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→10% methanol in ethyl acetate as the eluant to afford (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (428 mg, yield 96%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.C(N(CC)CC)C.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl.C(Cl)(Cl)Cl>[OH:9][CH2:8][CH:3]([NH:2][C:36]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)N1CCCCC1
Reactant: COC(=O)C(N)CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.43 mmol) of methyl 2-amino-3-hydroxypropionate hydrochloride and 960 mg (14.1 mmol) of imidazole were dissolved in 10 ml of dichloromethane. 10 ml of a solution of 1.07 g (7.07 mmol) of t-butyldimethylchlorosilane in dichloromethane was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 1 hour. After concentrating under reduced pressure, ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous ammonium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 1.35 ml (9.65 mmol) of triethylamine and 0.97 ml (7.72 mmol) of 1-piperidinecarbonyl chloride were added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. 20 ml of chloroform was added to the reaction mixture, and they were stirred at 50° C. for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 15 ml of methanol. 10 ml of 2 N hydrochloric acid was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. After the concentration under reduced pressure, ethyl acetate was added to the residue. The product was washed with 1 N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=1:0 to 9:1) to obtain the title compound.
Reaction SMILES: C[Mg]Cl.[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14].[Cl-].[NH4+].[C:17](OCC)(=O)C>C1COCC1>[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:17])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: COc1cc(C=O)ccc1F
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)ccc1F
Reaction time: 2 h

Procedure:
Methyl magnesium chloride (3 M tetrahydrofuran solution, 7.8 mL) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (3 g) in THF (200 mL) while cooling with ice, and the reaction solution was stirred for 2 hours while cooling with ice. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain 2.65 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13](O)=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH2:22][CH2:23]3)[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: O=C(O)C1CCN(c2ccc(Cl)cc2)C1=O
Agent: C=O
Solvent: CO
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
3.0 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone and 2.32 g of 4-(2-methoxyethyl)piperazine were mixed with 6 ml of methanol. Thereto was added 0.465 g of 80% paraformaldehyde. The mixture was subjected to a reaction for 10.5 hours under refluxing and then cooled to room temperature. Thereto was added 10 ml of methanol, and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was mixed with 15 ml of water. The resulting crystals were collected by filtration and washed with 3 ml of 95% aqueous methanol twice to obtain 3.42 g of 1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][N:12]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[NH2:45]>C1COCC1.CN(C=O)C>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][N:12]=2)/[C:8]([NH:45][C:41]2[S:40][CH:44]=[CH:43][N:42]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)nc1

Procedure:
A solution of (E)-3-cyclopentyl-2-(5-methylsulfanylpyridin-2-yl)acrylic acid (Preparation 5, 1.00 g, 3.8 mmol), EDCI (0.95 g, 4.9 mmol), HOBt (0.67 g, 4.9 mmol) and thiazol-2-ylamine (1.52 g, 15.2 mmol) in anhydrous THF (62 mL) and DMF (50 mL) was stirred at 20° C. for 4 d. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 and saturated aqueous Na2CO3. The organic layer was washed with H2O and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (7:31H-EtOAc) provided the title compound: RTA=3.96 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[OH:33][C@@:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C#C[C@@](C)(O)c1ccccn1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@](C)(O)c3ccccn3)cc1-2
Yield: 6.1 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (2R)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure G to afford 3.4 mg (6.1%) of 10-[(3S)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=432.0
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[NH:5][CH:4]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:3]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]1[O:44][CH:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=1>CN(C)C=O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:4]2[N:5]([CH2:42][C:43]3[O:44][CH:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=3)[C:6](=[O:18])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)[C:2]([CH3:1])=[C:3]2[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:28])=[CH:20][CH:21]=1)#[N:24]
Reactant: CC1=C(C(=O)c2cccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3cccnc3)C2c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of 4-{6-methyl-2-oxo-5-(pyridin-3-ylcarbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 21A) (100 mg, 0.22 mmol and potassium carbonate (60 mg, 0.43 mmol) in dimethylformamide (3 ml) is added methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (57 mg, 0.32 mmol). The reaction mixture is stirred for 72 hours at room temperature. The crude product is quenched with water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:17][NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[CH3:16])[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:17][NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)[CH3:16])[C:11]([C:31]([F:33])([F:32])[F:34])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(NNC(=O)c1ccc(C(=O)O)cc1)=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C(F)(F)F
Temperature: 0 °C
Yield: 88.9 %

Procedure:
4-Methoxycarbonylbenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide (0.107 mmol, 50.7 mg) was dissolved in methanol (2 ml) and stirred with 1M aqueous sodium hydroxide (0.534 mmol, 0.534 ml) at room temperature for 2 hours and at 60° C. for 1.5 hours. Then, the reaction vessel was cooled to 0° C., and 1M hydrochloric acid (0.534 mmol, 0.534 ml) and water were added. The precipitated solid was collected by filtration with water and dried to obtain 4-carboxybenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide as a yellow solid (43.8 mg, 89%).
Reaction SMILES: [S:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=O)([OH:4])(=[O:3])=[O:2].[OH-].[Na+:14].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[Na+:14].[O:8]=[C:6]1[CH:5]([S:1]([O-:4])(=[O:3])=[O:2])[CH2:9][C:10](=[O:11])[O:12]1
Reactant: O=C(O)CC(C(=O)O)S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(S(=O)(=O)[O-])C(=O)O1

Procedure:
Tetrahydro-2,5-dioxo-3-furansulfonic acid sodium salt was prepared by stirring 1.71 moles of sulfosuccinic acid with 1.87 moles of sodium hydroxide at 50° C. until a milky suspension formed and then adding 1 kg acetic anhydride over 6 hours. After cooling, 1 L of ethyl acetate was added and the mixture was filtered. The filter cake was washed with 500 mL ethyl acetate. On drying 344.32 g of white crystalline product was obtained. 13C-NMR (d6-DMSO) 171.3, 167.2, 60.4, 34.0 ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:52])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:51]=[CH:50][C:38]([C:39]([NH:41][NH:42]C(OC(C)(C)C)=O)=[O:40])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:42][NH:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:52])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:51][CH:50]=1)=[O:40]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 206 mg of the title compound (87%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](O)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:14])([F:15])[F:16])=[C:10]([CH2:17][OH:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-carboxylic acid (0.30 g) in tetrahydrofuran (10 ml) stirred under a nitrogen atmosphere at 0° C. was treated with a 1M solution of borane in tetrahydrofuran (10.33 ml) and the reaction stirred at room temperature for 2 hours. The reaction was cooled to 0° C.; treated with methanol (4 ml) and after 15 minutes the reaction mixture was evaporated. The residue was purified by SPE (Si cartridge) sequentially using dichloromethane, chloroform and chloroform:ether (9:1) as eluents to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)=[O:3].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]1[C:17]2[C:12](=[CH:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:2]([NH2:1])=[O:3])=[CH:19][CH:18]=2)[CH2:13][CH2:14][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3cccc(C(N)=O)c3)ccc2C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2ccc3c(c2)CCNC3)c1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 6-[3-(aminocarbonyl)phenyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.725 g; 2.20 mmol; I-VII-9) and Et3SiH (0.88 mL; 5.5 mmol) in CH2Cl2 (25 mL) at room temperature was added TFA (10 mL) in one portion. The mixture was aged 3 h and concentrated in vacuo (2×PhMe chase). The residue was partitioned between satd Na2CO3/CHCl3 (Note 1), layers were separated and the aqueous layer was extracted with CHCl3 (×4). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo, affording the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (t, J=5.7 Hz, 2H), 2.96 (t, J=5.8 Hz, 2H), 3.87 (s, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.40-7.48 (m, 3H), 7.51 (t, J=7.8 Hz, 1H), 7.78 (ddd, J=7.7, 1.8, 1.1 Hz, 1H), 7.82 (ddd, J=7.8, 1.4, 1.3 Hz, 1H), 8.10 (s, 1H), 8.12 (t, J=1.6 Hz, 1H).