Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:38][CH3:39])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:38][CH3:39])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Reaction time: 6 h
Yield: 55.5 %

Procedure:
To a solution of 0.15 g (0.27 mMol) of 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml THF 50 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 6 h, then filtered and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate) to yield 0.083 g (55%) 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam. ES-MS m/e (%): 554 ([M+H]+, 100).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([F:2])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]1[C:31]([O:32][CH3:33])=[O:34]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)c(F)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Methyl 2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylate hydrochloride (3.957 g, 12.22 mmol) and DIPEA (4.68 mL, 26.89 mmol) were dissolved in DCM (20 mL) and methyl carbonochloridate (1.059 mL, 13.45 mmol) was added. The reaction was stirred at room temperature for 18 h, diluted with DCM (200 mL), washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried through a phase separator and evaporated in vacuo to yield dimethyl 2-(3,4,5-trifluorobenzyl)piperidine-1,4-dicarboxylate (4.01 g, 95%) as a brown oil. MS m/z 346 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23][CH2:24][NH2:25])[CH2:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N([CH2:38][CH3:39])CC)C.[C:40]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[C:40]1([CH2:46][C:47]([NH:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23][CH2:24][NH:25][C:47]([CH2:46][C:39]2[CH:38]=[CH:42][CH:41]=[CH:40][CH:45]=2)=[O:48])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCCCN(CCCCCCCCN(CCCN)Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NCCCN(CCCCCCCCN(CCCNC(=O)Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Chill a solution of 5,14-bis[(phenyl)methyl]-1,5,14,18-tetraazaoctadecane (2.2 g, 5 mmole) and triethylamine (2 g, 20 mmole) in chloroform (100 ml) in an ice bath. Add a solution of phenylacetyl chloride (2.3 g, 15 mmole) in chloroform (10 ml) dropwise. Remove the ice bath and stir the mixture at ambient temperature for 18 hours. Extract the reaction mixture with aqueous sodium bicarbonate, dry the organic layer and evaporate. Chromatograph the residue on a flash silica gel column (ethyl acetate) to give 3 g of the desired product as a thick oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1.[N:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1.C(OC(=O)C)(=[O:21])C>C1COCC1>[N:1]1([CH2:15][CH2:14][NH:13][C:18](=[O:21])[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH2:3][CH2:2]1
Reactant: c1cc2ccc3c(c2[nH]1)CCO3
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCN1CCc2ccc3c(c21)CCO3

Procedure:
To a stirred solution of Intermediate 7 (77 mg) in dry THF (5 ml) containing pyridine (0.09 ml) was added acetic anhydride (0.06 ml). After 18 h at 20° C. the mixture was partitioned between 2N Na2CO3 (30 ml) and EtOAc (2×30 ml). The dried extracts were evaporated and the residue chromatographed on silica gel (20 g). Elution with System A (200:8:1) gave the title compound as a colourless crystalline solid (56 mg), m.p. 126°-7° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+]>[Pd].O1CCOCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C1CCNC1
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(N3CCCC3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 g (0.18 mmol) of 1-(1-allyl-6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol, 28.0 mg (0.4 mmol) of pyrrolidine, 5.0 mg of Pd catalyst (prepared according to a procedure described in Org. Lett. 2003 14 2413-2415), and 35.0 mg (0.36 mmol) of sodium tert-butoxide in 10 mL of dioxane was warmed at 90° C. After 2 hours, the mixture was cooled to room temperature, filtered through CELITE® filter aid, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate in hexanes (30-80% gradient). The major fractions were combined and concentrated in vacuo to afford 21.0 mg 21.4%) of the title compound. MS m/z 534.5 (MH+).
Reaction SMILES: CC(C)[C@H]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])C(OC)=O.BrC[C:30]1[CH:35]=[CH:34][C:33](C2C=CC([N+]([O-])=O)=CC=2)=[CH:32][C:31]=1[C:45]([O:47][CH3:48])=[O:46].Cl.NC1CCCC(C(OC)=O)C1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([CH:35]4[CH2:34][CH2:33][CH2:32][CH:31]([C:45]([O:47][CH3:48])=[O:46])[CH2:30]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Agent: COC(=O)C1CCCC(N)C1
Agent: Cl
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)C1
Yield: 59 %

Procedure:
The compound of example 542 was prepared analogous to compound of example 5 by reaction of compound of example 4 with methyl 3-aminocyclohexanecarboxylate hydrochloride.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[CH:17][C:16]=1Cl.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Fc1ccc2ncc(Cl)c(Br)c2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccnc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 113.3 %

Procedure:
To a suspension of NaH (60% in oil dispersion, 2.2 g, 54 mmol) in 1,4-dioxane (26 mL) was added diethyl malonate (9 mL, 59 mmol). The reaction mixture was stirred at rt for 5 min and heated at 80° C. for 1 h. After cooling to rt, CuBr (1.0 g) and 4-bromo-3-chloro-6-fluoro-quinoline (5 g, 19.4 mmol) in dioxane (8 mL) were successively added. The mixture was stirred at 100° C. overnight. After cooling, 10% aq. NaHSO4 (100 mL) was added. The mixture was stirred 30 min. The two layers were decanted and the aq. layer was extracted three times with EA (3×150 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated in DCM to yield the title compound as a yellow solid (6.71 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:12])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)NCc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 0.98 mmol) and 1,1'-carbonyldiimidazole (206 mg, 1.27 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.64 mL, 5.88 mmol) is added and stirring is continued at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:2) provides 5-chloro-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=80°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (49 μl) was added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to quantitatively give the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])C)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7].Cl.C(N([CH2:43][CH3:44])CC)C.[Cl-].[Na+].[OH2:47]>C(Cl)Cl>[OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C@H:33]1[CH2:36][CH2:44][CH2:43][O:47][CH2:35]1)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2(S)-hydroxy-3(S)-(t-butyloxycarbonyl)amino-1-(4-nitrobenzenesulfonyl)-1-isobutylamino-4-phenylbutane (93 mg, 0.19 mmol) in 1 mL of dry CH2Cl2 was passed anhydrous HCl gas for 0.5 h. After removal of HCl gas bubbler, the mixture was stirred for 1 h. The solvent was removed in vaccuo and the residue was dissolved in 1 mL of dry CH2Cl2. To the mixture were added triethylamine (30 μl, 0.23 mmol) and N-succinimidyl (S)-(+)-3-hydroxytetrahydrofuran carbonate (44 mg, 0.19 mmol) at room temperature. The mixture was stirred for 4 h until no starting material remained by TLC and it was poured into brine (2 mL) and extracted with EtOAc (10 mL). The organic extract was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude compound was recrystallized in ethyl acetate to give 86 mg of 2(S)-hydroxy-3(S)-[3(S)-tetrahydropyranyloxycarbonyl]amino-1-(4-nitrobenzenesulfonyl)-1-isobutylamino-4-phenylbutane.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH:5](=[O:9])[CH:6]([CH3:8])[CH3:7].N1CCC[C@H]1C(O)=[O:13]>CN(C)C=O.C(OCC)C>[OH:9][C@@H:5]([CH:2]([CH3:3])[CH3:1])[C@H:6]([CH3:8])[CH:7]=[O:13]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)C=O
Reactant: CCC=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[C@H](O)[C@H](C)C=O
Reaction time: 30 h
Yield: 82 %

Procedure:
A solution of freshly distilled propionaldehyde (1.81 mL, 25.0 mmol) in 12.5 mL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 20 h to a stirring suspension of isobutyraldehyde (4.54 mL, 50 mmol), L-proline (288 mg, 2.5 mmol) and 12.5 mL dimethylformamide at 4° C. After 30 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 82% yield (2.65 g, 20.6 mmol), >99% ee and 96:4 anti:syn. Analytical data for this compound are identical in every respect to the previously reported values (Mahrwald, supra), with the exception of optical rotation which has not been reported. [α]D=−17.9 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=31.8 min, (2R, 3R) anti isomer tr=33.9 min, (2R, 3S) and (2S, 3R) syn isomers tr=29.4, 29.8 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:7]([CH3:8])[C:20](=[O:23])[CH2:21][CH3:22])[CH:9]=1
Reactant: CCC(=O)Cl
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(C)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
5-chloro-N-methyl-2-nitroaniline (500 mg) was dissolved in methylene chloride anhydrous (9 mL), added with triethylamine (3 mL) and propionyl chloride (1 mL) and refluxed. Then, saturated sodium bicarbonate was added thereto and extracted with ethyl acetate. The extracted organic layer was washed with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated under reduced pressure. The concentrated filtrate was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain a target compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[OH:12]O>C(O)=O>[C:6]12[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:1][C:2](=[O:12])[O:3][C:4]2=[O:5]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OO
Solvent: O=CO
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.7 parts of isatin are suspended in 80 parts of formic acid. 20 parts of 30 percent strength hydrogen peroxide solution are added dropwise, with slight cooling. The mixture is then stirred for 60 minutes at 25° C., after which it is worked up in a conventional manner. 13.2 parts of isatoic anhydride are obtained; melting point 252°-253° C., with decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]([CH2:16][CH2:17][CH2:18][N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)[CH3:15])=[O:13])=[O:8])[CH:2]=1.[CH3:34][I:35]>[N+](C)([O-])=O>[I-:35].[CH:30]1[C:21]2[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:19]([CH2:18][CH2:17][CH2:16][N:14]([C:12]([O:11][CH2:10][O:9][C:7]([C:3]3[CH:2]=[N+:1]([CH3:34])[CH:6]=[CH:5][CH:4]=3)=[O:8])=[O:13])[CH3:15])[C:20]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CI
Reactant: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)OCOC(=O)c1cccnc1
Solvent: C[N+](=O)[O-]
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)OCOC(=O)c1ccc[n+](C)c1
Product: [I-]
Yield: 83 %

Procedure:
Eight-tenths gram (0.0018 mol) of the product of Example 52 in 30 mL of nitromethane was methylated with 0.8 methyl iodide at 25°-30° C. for 48 hours. The solvent was removed in vacuo and the residue was slurried with ethyl ether, filtered and dried over P2O5. The quaternary salt was obtained in 83% yield (0.88 g) as a light yellow solid melting at 172°-175° C. (dec.) and having the structural formula: ##STR96##
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][C:6]1[C:11](C)=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=O)[C:14](C)([O:19][SiH3])C(C)(C)C.O.O1CCOCC1>CO>[CH3:2][O:3][N:4]=[C:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])[CH2:14][OH:19]
Reactant: CON
Reactant: Cc1cccc(C(=O)C(C)(O[SiH3])C(C)(C)C)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CON=C(CO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1.78 g of O-methylhydroxylamine hydrochloride were added to a solution of the 3.05 g of 2'-chloro-2-t-butyldimethyl silyloxyacetophenone prepared above in a mixture of methanol, water and 1,4-dioxane. The resulting mixture was stirred at room temperature for 14 hours, and the reaction mixture was then poured into water and extracted three times with 50 ml portions of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography through silica gel, eluted with a stepwise gradient of ethyl acetate (10-40%) in hexane, to give 691 mg (32.4% yield) of the less polar isomer of 2'-chloro-2-hydroxyacetophenone O-methyloxime compound and 370 mg (17.3% yield) of the more polar isomer of the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=1.[Cl:17][C:18]1[CH:23]=[C:22](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:20][N:19]=1.Cl.C(OCC)C>C1COCC1.CO>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:7]3[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Cl)c1)c1cccc(F)c1C#N
Reactant: Cc1cc(Br)cc(C(F)F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C2(c3ccnc(Cl)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-Butyllithium (1.174 mL, 2.94 mmol) was added to 4-bromo-2-(difluoromethyl)-6-methylpyridine (543 mg, 2.45 mmol) in THF (15 mL) at −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min before (E)-N-((2-chloropyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (890 mg, 2.45 mmol) in THF (5 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. MeOH (15 mL) was added followed by hydrochloric acid in diethylether (7.34 mL, 7.34 mmol) and the reaction was stirred for 1 hour. NaHCO3(sat) was added and the mixture was extracted with EtOAc (×2). The combined organic phases were dried and concentrated to give 0.5 g (51%) of the title compound, which was used without further purification. MS (ES+) m/z 403 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.ClC1C=CC2C(=O)OC(=O)[NH:29]C=2C=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[C:2]([NH:1][CH2:18][C:17]2[NH:29][CH2:19][CH2:20][N:16]=2)[CH:7]=1
Reactant: C1CCNC1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reactant: Nc1cc(Cl)ccc1C(=O)N1CCCC1
Product: O=C(c1ccc(Cl)cc1NCC1=NCCN1)N1CCCC1

Procedure:
(2-Amino-4-chlorophenyl)(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give (4-chloro-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]phenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>C1COCC1.CC(O)C.O>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18]([C:17]1[CH:25]=[CH:26][C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)=[CH:15][CH:16]=1)=[O:19])[CH3:24]
Reactant: CCN(CC)C(=O)c1ccc(N)cc1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Yield: 87.1 %

Procedure:
To a room temperature solution of 0.943 g (5 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 25 mL THF is added a solution of 2.11 g (11 mmol) of 4-amino-N,N-diethylbenzamide in 100 mL of 2-propanol, and the resulting mixture is heated and stirred at reflux for 1 hour. The mixture is then diluted with water, the solid precipitate is collected, washed with water, and dried, to give 1.50 g (87%) of the title compound: mp (EtOH) 213–215° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: CCOC=C1C(=O)Nc2ncc(Br)cc21

Procedure:
This compound was synthesized from 5-bromo-1H-pyrrolo[2,3-b]pyridin-2-one and and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 11.02 (s, 1H); 8.07 (s, 1H); 7.88 (s, 1H); 7.71 (s, 1H); 4.40 (m, 2H); 1.34 (m, 3H).