Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:33])[N:5]=[CH:4][N:3]=1.[N:34]([C:37](C)([CH3:39])[CH3:38])=[C:35]=[O:36].N(CC)=C=O.N(C1CCCC1)=C=O>>[CH:37]([NH:34][C:35]([N:24]1[CH2:23][CH2:22][CH:21]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18][N:14]2[CH2:15][CH:16]3[CH:12]([CH2:11][N:10]([C:8]([C:7]4[C:6]([CH3:33])=[N:5][CH:4]=[N:3][C:2]=4[CH3:1])=[O:9])[CH2:17]3)[CH2:13]2)[CH2:26][CH2:25]1)=[O:36])([CH3:39])[CH3:38]
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCNCC3)CC2C1
Reactant: CC(C)(C)N=C=O
Agent: CCN=C=O
Agent: O=C=NC1CCCC1
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)NC(C)C)CC3)CC2C1

Procedure:
V-2, V4 and V5 were prepared analogously from (4,6-dimethyl-pyrimidin-5-yl)-[5-(3-phenyl-3-piperidin-4-yl-propyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone using 2-isocyanato-2-methyl-propane, isocyanato ethane and isocyanato cyclopentane respectively.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:8](O)=[O:9])=[O:4].NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O.C(I)CC.B.C1COCC1>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCCN(c1cc(C(=O)O)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: B
Agent: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCN(c1cc(CO)cc(C(=O)OC)c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of: 3-(methoxycarbonyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (12.0 g, 38.1 mmol, prepared from dimethyl 5-aminoisophthalate and propyl iodide using a similar procedure as described for the preparation of intermediate A) in THF (250 mL) cooled to 0° C. was added BH3-THF (190.3 mL, 190.3 mmol, 1 M in THF). After 10 min, the reaction mixture was allowed to warm to rt and stirred for 15 h. The reaction mixture was cooled back down to 0° C. and carefully quenched with MeOH. The mixture was concentrated to half its original volume and diluted with EtOAc and water. Following dilution, the organic layer was extracted, washed with sat. aq. NaHCO3 and brine, dried over sodium sulfate and concentrated in vacuo to provide methyl 3-(hydroxymethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 4.79 (d, J=5.7 Hz, 2H), 3.94 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 2.90 (s, 3H), 1.87 (br t, J=5.7 Hz, 1H), 1.55-1.45 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:15](=O)[CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C[Si]([N:39]=[N+:40]=[N-:41])(C)C>C(#N)C>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[N:14]2[C:15]([CH:16]([CH3:18])[CH3:17])=[N:41][N:40]=[N:39]2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CC(C)c1nnnn1-c1cc([N+](=O)[O-])c(F)cc1C1CC1
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 81.3 %

Procedure:
N-(2-Cyclopropyl-4-fluoro-5-nitrophenyl)isobutyramide (1.90 g, 7.14 mmol, 1 equiv) was dissolved in acetonitrile (40 mL) under argon and cooled to −5° C. (external temperature). While maintaining the temperature at −5° C., trifluoromethanesulfonic anhydride (2.40 mL, 4.03 g, 14.27 mmol, 2 equiv) was added slowly dropwise and stirred for 1-2 minutes. Then trimethylsilyl azide (3.75 mL, 28.54 mmol, 4 equiv) was added slowly dropwise while maintaining the temperature at −5° C. TLC, LCMS indicated the reaction was complete in less than 1 minute. While maintaining the temperature at −5° C., the reaction was slowly quenched with ice-cold saturated NaHCO3 and diluted with EtOAc. The layers were separated, and the organic layer was washed with brine 1×, dried over Na2SO4, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with hex:EtOAc=100:0 to 25%-30% EtOAc using 5% EtOAc increments to afford 1-(2-cyclopropyl-4-fluoro-5-nitrophenyl)-5-isopropyl-1H-tetrazole (1.69 g, 78%) as a yellow solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[NH:5][C:6]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:7][C:8]=1[C:9]#[N:10].CCCCCC.C(OCC)(=O)C>O1CCOCC1>[Br:1][C:7]1[C:8]([C:9]#[N:10])=[C:4]([Cl:3])[NH:5][C:6]=1[C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(Cl)s2)[nH]c1Cl
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: N#Cc1c(Cl)[nH]c(-c2ccc(Cl)s2)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromine (0.70 g, 4.3 mmol) in p-dioxane is added dropwise to a solution of 2-chloro-5-(5-chloro-2-thienyl)pyrrole-3-carbonitrile (1.00 g, 4.1 mmol) in p-dioxane. The reaction mixture is stirred overnight at room temperature and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a (6:1) hexane/ethyl acetate solution gives the title product as a yellow solid, mp >200° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc3cc(OC)cc(-c4ccccc4)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7-Bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (200 mg, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.03 mmol) were dissolved in toluene (5 mL) and stirred for 10 min at room temperature under a nitrogen atmosphere. Benzene boronic acid (110 mg, 0.90 mmol) was added, followed by aqueous sodium carbonate (2 M, 1.5 mL) and ethanol (2 mL). The mixture was refluxed for 12 h, diluted with water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (20%-40% EtOAc/petroleum ether) gave the title compound as a light pink solid, mp 92° C.; MS m/e 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:43])=[C:4]([S:9]([N:12]([CH2:27][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[CH:29]=[C:28]([CH:42]=[CH:41][CH:40]=1)[CH2:27][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:43])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 3-[(3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl]-2-hydroxyphenylsulfonamido) methyl)benzylcarbamate (1.0 g, 1.5 mmol, 1 eq) was dissolved in dry DCM, stirred for 10 minutes and cooled to 0° C. Trifluoroacetic acid (3.5 g, 309 mmol 20 eq) was added slowly at 0° C. The reaction mixture was stirred for 10 min and slowly brought to rt. After 4 h, the solvent was evaporated under reduced pressure, and ethyl acetate and 10% aq. NaHCO3 solution were added. The mixture was stirred for 10 minutes and the aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The crude salt (0.7 g, 82%) was used immediately in the next step. 1H NMR (400 MHz, DMSO-d6) δ 3.52 (s, 2H), 4.44 (s, 2H), 4.46 (s, 2H), 6.9-6.99 (t, 2H), 7.08-7.10 (d, 2H), 7.17-7.20 (m, 4H), 7.22-7.27 (m, 2H), 7.44-7.46 (d, 2H), 7.6-7.65 (t, 2H). MS (ESI): 546.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([CH2:27][CH2:28][CH3:29])[C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([OH:12])[CH2:10][C:9](=[O:13])[C@@H:8]1[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:23](C)C)=[O:21].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:30])([CH2:27][CH2:28][CH3:29])[C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([OH:12])[CH2:10][C:9](=[O:13])[C@@H:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of 15-dehydroxy-17,17-difluoro-13,14-dihydro-16-oxo-PGE2 isopropyl ester (20) (0.303 g) obtained in Example 3 in ethyl acetate (20 ml) was subjected to hydrogenation with a catalytic amount of 5% Pd-C and hydrogen gas. The reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was chromatographed on a Rober column to give the titled compound (35).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7](=O)[CH2:8]2)[CH2:3][CH2:2]1.[NH3:11].C(O)C.[H][H]>[Pd]>[NH2:11][CH:7]1[CH2:8][CH:9]2[N:4]([CH2:3][CH2:2][CH2:1]2)[CH2:5][CH2:6]1
Reactant: O=C1CCN2CCCC2C1
Reactant: N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCN2CCCC2C1
Yield: 97.5 %

Procedure:
(±)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (5.0 g, 35.9 mmol) was dissolved in a solution of 2M ammonia/ethanol (54 ml, 108 mmol calculated in terms of ammonia). The resulting solution was stirred at room temperature in an atmosphere of hydrogen in the presence of 10% palladium on charcoal (500 mg) for 4 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound (4.91 g) as a colorless oil (yield 98%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28](O)=[O:29]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][CH:28]=[O:29])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=CO
Agent: Cl
Product: O=CN[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (17 mg, 30%), MS (ISP) m/z=359.4 [(M+H)+], mp 170.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (70.4 mg, 0.16 mmol) and formic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(F)(F)F
Product: O=C(Cl)c1ccccc1C(F)(F)F

Procedure:
A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-2-hydroxybenzaldehyde (1.5 g, 9.3 mmol), tert-butylcarbazate (1.25 g, 9.3 mmol) and acetic acid (0.54 mL, 9.3 mmol) in CH2Cl2 (50 mL) was stirred under a N2 atmosphere for 30 min at RT. Then sodium triacetoxyborohydride (6.20 g, 27.9 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was thoroughly quenched with 2 M HCl (15 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (50 mL) and CH2Cl2 (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with water (2×75 mL), dried (Na2SO4) and evaporated to dryness to give hydrazine 1 as a white solid, 2.6 g (100%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:38][CH:39]([OH:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([Br:37])=[CH:31][CH:30]=3>ClCCl.CCOC(C)=O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][C:32]([Br:37])=[CH:31][CH:30]=3
Reactant: OC(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Yield: 74 %

Procedure:
Dess-Martin periodinane (58.2 mg, 0.137 mmol) was charged to a solution of the title compound of Example 3b (45.0 mg, 0.095 mmol) in dichloromethane (1.0 ml, 0.095 M). After two hours the reaction mixture was diluted with EtOAc and washed with saturated sodium thiosulfate solution, water and brine. The organic layer was dried over Na2SO4, filtered and condensed. The crude product was used without additional purification. Yield=74%
Reaction SMILES: [CH3:1]CN([CH2:6][CH3:7])CC.Cl[C:9]([O:11][CH2:12][CH:13](C)C)=[O:10].N.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH3:13][CH2:12][O:11][C:9]([CH3:1])=[O:10].[CH3:21][CH2:17][CH2:18][CH2:19][CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: CC(C)COC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CCCCCC
Product: CCOC(C)=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Pseudopeptide Boc--Nalψ[CH2S]Ala--OH (1.33 g; 3.4 mmol) was dissolved in THF (25 ml) and the solution was cooled to -30° C. Et3N (0.48 ml; 3.4 mmol) was added, followed by isobutyl chloroformate (0.46 ml; 3.5 mmol). After 15 min an excess of NH3 in CHCl3 was added and the reaction was stirred for 30 min at -30° C. and at room temperature for 3 h. The solvent was removed in vacuo and the residue was dissolved in AcOEt (250 ml). The organic solution was washed with H2O (1×50 ml), NaHCO3 5% (2×50 ml), H2O (1×50 ml), 0.5M citric acid (2×50 ml) and saturated NaCl, then was dried over Na2SO4 and filtered. After evaporation in vacuo of AcOEt, the residue was crystallized from AcOEt/hexane (1.2 g; 90% yield).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:30][C:31]1[N:32]=[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]2[CH:39]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][C:31]3[N:32]=[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]4[CH:39]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cn2ccccc2n1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3cn4ccccc4n3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 using methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-(chloromethyl)imidazo[1,2-a]pyridine. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.33-8.40 (m, 1H) 8.18-8.25 (m, 1H) 8.10-8.17 (m, 1H) 7.70-7.79 (m, 1H) 7.59-7.65 (m, 1H) 7.51-7.56 (m, 1H) 7.44-7.50 (m, 2H) 7.34-7.41 (m, 1H) 7.29-7.34 (m, 1H) 6.18-6.25 (m, 1H) 6.00-6.05 (m, 1H) 5.88-5.98 (m, 1H) 5.35 (s, 1H) 3.67 (s, 3H) 1.02 (s, 9H); LCMS (m/z) ES+=519 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])C.[CH3:24][O-:25].[Na+]>>[CH3:1][O:3][C:4](=[O:23])[C:5]1[C:10]([O:25][CH3:24])=[CH:9][C:8]([C:12]2[C:13]([CH2:20][CH3:21])=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:18][CH3:19])=[N:7][C:6]=1[CH3:22]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Temperature: 65 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (165 mg, 0.5 mmol) and sodium methoxide (0.5 M in methanol, 4 mL, 2.0 mmol) is heated at 65° C. for 16 hours. The volatile material is removed in vacuo and the residue is partitioned between ethyl acetate (50 ml) and water (20 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 mL). The combined organic extract is dried and concentrated in vacuo. The crude product is purified by PTLC (hexanes/ethyl acetate 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester. 1H NMR: (CDCl3) 7.26 (m, 2H), 7.13 (d, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 2.56 (s, 3H), 2.32 (m, 4H), 1.04 (t, 6H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].O=C1C2C(=CC=CC=2)C(=O)[N:8]1[CH2:17][C:18]1[C+:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]1[CH2:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]1[C:21]2([CH3:33])[CH3:32].O.NN>C(Cl)Cl.CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:8][CH2:17][C:18]1[C+:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]1[CH2:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]1[C:21]2([CH3:33])[CH3:32]
Reactant: CC1=CCN2C3=CC=C(CN4C(=O)c5ccccc5C4=O)[C+]=C3C(C)(C)C2=C1
Agent: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1=CCN2C3=CC=C(CN)[C+]=C3C(C)(C)C2=C1
Reaction time: 8 h

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-8,10,10-trimethyl-10H-pyrido[1,2-a]indolylium perchlorate (36 g, 0.077 mol; Sigma-Aldrich) was added to a conical 1-L flask equipped with magnetic stir bar, followed by 480 mL of CH2Cl2—CH3OH mixture (3:2). Stirring was started and hydrazine monohydrate (25 g, 0.50 mol; Aldrich) was added to the reaction mixture at once. Stirring was continued until all solid was dissolved. The flask was closed with a stopper and let to stand at room temperature overnight without stirring. After about 16 hours the precipitated solid phthalhydrazide was filtered off, washed with 100 mL of CH2Cl2—CH3OH mixture (3:2) and discarded. The combined filtrates were evaporated and the resulted solid was washed with Ether-CH3OH. The solid was filtered, washed with ether and dried. The yield was 26 g (100% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:19])[C:12](C2C=COC=2CO)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N(C(OC(C)(C)C)=O)C1C=CC=C(OS(C2C=CC(C)=CC=2)(=O)=O)C=1C(OC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1O
Agent: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)cccc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: COC(=O)c1c(O)cccc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 4, starting from methyl 2-[bis-(tert-butoxycarbonyl)amino]-6-(4-methylbenzenesulfonyloxy)benzoate (Intermediate 56)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:24]([C:21]2[CH:20]=[CH:19][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:23][CH:22]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30](=[O:31])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:38][CH:39]=2)=[O:12])[CH:5]=1
Reactant: CC(C)(C)c1ccc(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.50 mmol 3-isocyanatobenzoic acid methyl ester dissolved in 5 mL dichloroethane was added to the above resin 4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (500 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with dichloromethane (2×10 mL), DMF (2×10 mL) and THF (3×10 mL) afforded the resin bound title compound.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](Cl)=[O:34]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:33](=[O:34])[C:32]2[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:31]=2[F:30])/[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)s/c2=N\C(=O)c2cc(C(F)(F)F)ccc2F)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of the product of Example 42A (4.1 g, 12.5 mmol) in tetrahydrofuran (40 mL) was added triethylamine (5.2 mL, 37.6 mmol) followed by 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.0 mL, 13.2 mmol). This mixture was warmed to 50° C. and was allowed to stir for 90 min then the mixture was cooled to ambient temperature and was stirred for 16 h. The mixture was quenched with saturated, aqueous NH4Cl (20 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in ethyl acetate) to give the title compound (5.2 g, 10.0 mmol, 80% yield). MS (DCI/NH3) m/z 516 (M+H)+.