Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>O1CCCC1>[CH3:11][NH:12][C:13]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:14]
Reactant: CC(C)(C)C1=CCNCC1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 60 ml. of ml.of anhydrous tetrahydrofuran, there is dissolved 12.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine. Stirring is initiated and there is added 7.3 grams of methylisothiocyanate in 25 ml. of anhydrous tetrahydrofuran. After stirring the reaction mixture for 18 hours at room temperature, the tetrahydrofuran is evaporated in vacuo at 50°C/20 mmHg. The resulting oil is crystallized from methylene chloride/pentane 1:1 to give N-methyl-4-t-butyl-1,2,3,6-tetrahydro-1-pyridinethiocarboxamide; m.p. 76° to 78°C.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([C:27]3[S:31][C:30]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[N:29][C:28]=3[CH3:42])[CH2:19][CH2:20][CH:21]3[O:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[O:26]1[CH2:25][CH2:24][CH2:23][O:22][CH:21]1[CH2:20][CH2:19][CH:18]([C:27]1[S:31][C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=2)=[N:29][C:28]=1[CH3:42])[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:43])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCC1OCCCO1)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCC1OCCCO1)Oc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], [rac]-(6-{3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain [rac]-(6-{3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33]>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2ccc(Cl)cc2Cl)n1
Yield: 81 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2,4-dichlorophenol in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 81% yield.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:18]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][N:11]=2)[CH2:18][NH:3]1
Reactant: C=O
Reactant: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C3CCCCC3)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:3][CH:2]=1.[ClH:18]>[Pt](=O)=O.C(O)C>[ClH:18].[NH:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:17])[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2cc1-c1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccccc2CC1C1CCNCC1
Reaction time: 4 h

Procedure:
A mixture of 1.1 g (4.949 mmol) of 3-(4-pyridinyl)-2(1H)-quinolone (D. R. Bragg and D. G. Wibberley, J. Chem. Soc. 1961, 5074-5077), 100 ml of ethanol, 5 ml (5 mmol) of 1N hydrochloric acid and 0.2 g platinum (IV) oxide was hydrogenated for 4 hours at room temperature. The catalyst was filtered off, the filtrate evaporated down in vacuo and the residue was triturated with isopropanol. The precipitated crystals were suction filtered, washed with isopropanol and diethylether and dried in vacuo. Yield: 0.64 g (56.2% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CCC(=O)OC(C)(C)C)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(CCC(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 5-(2-tert-butoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester (1.6 g, 5 mmol) in dichloromethane (12 mL) was added 8 mL of 40% trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, dissolved in toluene, concentrate, dissolved in dichloromethane and concentrated to give 1.3 g (99%) of 5-(2-carboxy-ethyl)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:29])(=[O:26])=[O:25])=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]>S(=O)(=O)(O)O>[C:6]([NH:13][C:14]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:21]([S:24]([NH:27][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:29])(=[O:26])=[O:25])=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1ccc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Potassium nitrate (0.24 g, 2.3 mmol) was added to a solution of 5-ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydronaphthalene (1.0 g, 2.3 mmol) in 12 ml of conc. sulfuric acid with stirring at 0° C. Stirring was continued for 2 h at this temperature, and then the mixture was poured into 75 ml of ice-water. The separated product was isolated by suction and washed repeatedly with water to give 0.64 g (58%) of sufficiently pure title compound. M.p. 140°-142° C. (ethanol); 1H-NMR (DMSO-d6): 1.20 (t,J=7Hz, 3H, CH3), 1.30 (t,J=7Hz, 3H, CH3), 1.58-1.90 (m, 4H, 2CH2), 2.60-2.90 (m, 2H, CH2), 3.05-3.33 (m, 2H, CH2), 3.95-4.60 (m, 4H, 2CH2), 8.27 (s, 1H, ArH), 10.9 (broad s, 1H, NH, only one exchangeable proton could be seen).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[CH:8]=2)[CH:19]=1
Reactant: Clc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Chlorobenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95)and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanamine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino ]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=1[NH2:13])[CH3:2].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:13]=[C:17]([C:18]([Cl:21])([Cl:20])[Cl:19])[NH:12][C:7]=2[CH:8]=[CH:9][C:10]=1[F:11])=[O:14])[CH3:2]
Reactant: CCOC(=O)c1c(F)ccc(N)c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: CCOC(=O)c1c(F)ccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
5-Fluoro-2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid ethyl ester was prepared by a procedure according to example 5 (i) starting from 150.0 mg (0.76 mmol) 2,3-Diamino-6-fluoro-benzoic acid ethyl ester and 133 μl (1.06 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: CN(C)CCCCCCN
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(C)CCCCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 6-(dimethylamino)-hexylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 510 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.CC1(C)C(C)(C)OB([C:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[CH2:31][N:25]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[S:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[C:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=1)=[N:13][CH:14]=[CH:15]2)(=[O:23])=[O:24]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)nccc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.063 g, 0.095 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.044 g, 0.142 mmol), Pd(AmPhos)2Cl2 (6.71 mg, 9.48 μmol), and potassium phosphate (0.070 g, 0.332 mmol). Dioxane (0.474 ml) and water (0.158 ml) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford tert-butyl 4-(2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as an off-white solid. m/z (ESI) 767.3 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.OC1C2N=NNC=2C=CC=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (6.3 mL) at room temperature was added sequentially -hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 4-chlorobenzyl amine (53.5 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (50 mL). The organic layer was washed with aq. NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the crude mixture. Flash column chromatography of the crude (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.3 mg, 94%): m.p. 110-111° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:31])[CH:15]([N:26]1[CH2:29][CH2:28][C:27]1=[O:30])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([OH:31])[CH:15]([N:26]1[CH2:29][CH2:28][C:27]1=[O:30])[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCC(=O)C(C(=O)OCc1ccccc1)N1CCC1=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Benzyl 5-benzyloxycarbonylamino-3-oxo-2-(2-oxoazetidin-1-yl)valerate (6.9 mg, 16 μmol) in tetrahydrofuran (1.5 ml) was treated with sodium borohydride (2.2 mg, 58 μmol). After one hour the reaction mixture was analysed by high pressure liquid chromatography using similar conditions to those described in Example 10. The reaction mixture contained the fast moving diastereoisomer of the title compound and slow moving diastereoisomer of the title compound in the ratio 55:45 respectively together with unreacted starting material.
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:14](=[O:15])[C@@H:13]([N:11]2[CH2:12][C:8]3[CH2:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=4[O:22][C:9]=3[C:10]2=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4c(Cl)cccc4C3)C2=O)nc1
Yield: 33.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.27 mmol), commercially available 6-aminonicotinic acid methylester (109 mg, 0.71 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (125 mg, 0.66 mmol), and N-hydroxybenzotriazole (HOBt) (88 mg, 0.66 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoyl-amino]-nicotinic acid methyl ester (42 mg, 15%), as a white solid. 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.88 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.08-7.16 (m, 1H), 5.10 (d, J=7.3 Hz, 1H), 4.42 (d, J=19.1 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.86 (s, 3H), 3.83 (br. s., 2H), 1.76-2.02 (m, 1H), 1.69 (t, J=9.3 Hz, 1H), 1.48 (br. s., 1H), 0.87-0.99 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([OH:7])[NH:4][N:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C(O)(=O)C>C1COCC1>[OH:7][C:5]1[NH:4][N:3]=[C:2]([N:1]2[C:11](=[O:12])[C:10]3[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:13])[CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)[nH]n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)[nH]n1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
To a solution of 3-amino-1H-pyrazol-5-ol (10.00 g, 101 mmol) in THF (300 mL) at RT was added phthalic acid anhydride (14.9 g, 101 mmol) followed by acetic acid (69.3 ml, 1.21 mol). The mixture was heated to reflux. After 4 days, the mixture was concentrated in vacuo to afford a slurry that was cooled to 0° C. and filtered. The solid was rinsed with Et2O and dried in vacuo to afford 2-(5-hydroxy-1H-pyrazol-3-yl)isoindoline-1,3-dione as a yellow solid that was advanced without further purification. MS: Found M+H+=230.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH2:28][C:29](O)=[O:30]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5]2)=[O:30]
Reactant: CC(C)(C)OC(=O)CC1CCc2cc(N)ccc2C1
Reactant: O=C(O)CCNc1ccccn1
Product: CC(C)(C)OC(=O)CC1CCc2cc(NC(=O)CCNc3ccccn3)ccc2C1

Procedure:
Following the procedure of Example 32(a), except substituting tert-butyl (6-amino-tetralin-2-yl)acetate, Fisher, et. al., EO 0635492, Scheme 12 and Example 28, parts A-D, for the compound of Preparation O(d) and substituting N-(2-pyridinyl)-β-alanine, Chowdhary, et. al., Indian J. Chem., 1990, 29A, 280-284, for the compound of Preparation V, gives the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[C:11](O)=[O:12].[OH-].[Na+]>>[Br:20][C:16]1[CH:15]=[C:14]([CH:10]2[NH:8][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:7][C:11]2=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(Br)c1cccc(Br)c1
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2NC1c1cccc(Br)c1
Temperature: 60 °C

Procedure:
Ortho-phenylenediamine is treated with a suitably substituted bromoacetic acid derivative, such as 2-bromo-2-(3-bromophenyl)acetic acid, in basic medium, such as aqueous sodium hydroxide, which upon warming to 60° C. and then maintaining at this temperature for 30 minutes, affords the product 3-(3-bromophenyl)-1,2,3,4-tetrahydro-2-quinoxalinone as a precipitate.
Reaction SMILES: C(C(NC([C:12]1[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=1[C:14]([N:16]([S:25]SC1C=CC=CC=1)[CH:17]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:18]([OH:20])=[O:19])=[O:15])=O)C(C)CC)(O)=O.BrBr>ClCCl>[CH3:24][CH:21]([CH2:22][CH3:23])[CH:17]([N:16]1[C:14](=[O:15])[C:13]2[CH:33]=[CH:34][CH:35]=[CH:36][C:12]=2[S:25]1)[C:18]([OH:20])=[O:19]
Reactant: CCC(C)C(NC(=O)c1ccccc1C(=O)N(SSc1ccccc1)C(C(=O)O)C(C)CC)C(=O)O
Agent: BrBr
Solvent: ClCCl
Product: CCC(C)C(C(=O)O)n1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5.3 g (10.0 mmol) of [S-(R*,R*)]-2-[2-[2-(1-carboxy-2-methylbutylcarbamoyl) phenyldisulfanylbenzoylamino]-3-methylpentanoic acid (from Preparation 19) in 200 mL of dichloromethane was added dropwise 2.4 g (15.0 mmol) of liquid bromine. The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness in vacuo. The residue was triturated with dichloromethane. The dichloromethane was removed by evaporation in vacuo to remove excess bromine. The residue was partitioned between dichloromethane/5% aqueous sodium bicarbonate (200 mL each). The aqueous layer was separated, washed with fresh dichloromethane, and acidified to pH 1.5 with 6.0M hydrochloric acid. The acidic aqueous solution was extracted with dichloromethane (2×75 mL). The organic layers were combined, washed with water, dried (MgSO4), filtered and concentrated to dryness in vacuo to give 4.8 g of the title compound, mp 50°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26]1([CH2:32]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: ClCC1CCCCC1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC3CCCCC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 45 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclohexylmethyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 45.0%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:13]Br>C(Cl)Cl>[Br:13][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: BrBr
Reactant: COc1cccc(CC(=O)O)c1
Solvent: ClCCl
Product: COc1ccc(Br)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-methoxyphenyl)acetic acid (4.50 g, 27.1 mmol) in DCM (25 ml), was added bromine (1.40 ml, 27.1 mmol) dropwise at 0° C. (ice-water bath). The mixture was stirred overnight at RT and quenched by addition of 5% sodium thiosulfate solution. The organic layer was washed with brine, dried with MgSO4 and concentrated under a stream of nitrogen to give the titled compound, 2-(2-bromo-5-methoxyphenyl)acetic acid as white crystalline solid.