Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]([CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]([CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][NH2:15])=[CH:6][CH:5]=1
Reactant: NCCN(CCN)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: NCCN(CCN)Cc1ccc(N)cc1
Reaction time: 24 h
Yield: 103 %

Procedure:
In 60 mL of absolute ethanol was dissolved 1 g of 4-(p-nitrobenzyl)diethylenetriamine (prepared in Example B) and 100 mg of palladium on activated charcoal (10% Pd) was added. The mixture was hydrogenated at 40 psi (275.8 kPa) for 24 hours. The catalyst was removed by filtration and the filtrate evaporated to give 0.9 g of product as an oil. The oil solidified upon cooling and the solid was crystallized from ethanol to provide 4-p-aminobenzyl)-diethylenetriamine and further characterized by:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=2[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]([NH:1][CH:2]([CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=3[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:39])=[CH:30][CH:29]=1
Reactant: NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (127 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole-hydrate (102 mg, 0.67 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (290 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:20]([O:22]C)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])=[C:5]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])=[C:5]3[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)C[C@H](NC(=O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc2n1C)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 1 Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 0.78 (d, J=6.3 Hz, 3H, 0.79 (d, J=6.0 Hz, 3H, 1.24 (s, 9H, 1.30-1.60 (m, 3H, 3.74 (s, 3H, 4.25-4.35 (m, 1H), 7.08 (dd, J=8.8, 2.0 Hz, 1H, 7.25-7.32 (m, 4H, 7.33-7.40 (m, 2H, 7.45 (d, J=7.9 Hz, 1H), 7.54 (d, J=7.8 Hz, 2H, 7.59 (d, J=8.7 Hz, 2H, 8.76 (d, J=7.8 Hz, 1H, 9.85 (s, 1H, 12.64 (br s, 1H; MS (ESI) m/z 576 (MH+); MS (ESI) m/z 574 [M-H]−; HRMS calcd for C32H38N3O5S: 576.2530; found (ESI+): 576.2518; Anal. calcd for C32H37N3O5S.0.5H2O: C, 65.73; H, 6.55; N, 7.19. Found: C, 65.41; H, 6.45; N, 7.16.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:15])(=[O:14])[C:12]3[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:23]=1)([O-:3])=[O:2].C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:11]2[CH:10]=[CH:9][C:8]3[CH:23]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[S:13](=[O:14])(=[O:15])[C:12]=2[CH:16]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=[N+]([O-])c1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-nitrodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[CH2:19](OC(OCC)OCC)C>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:9][C@H:10]3[CH2:11][CH2:12][C@H:13]([CH3:16])[CH2:14][CH2:15]3)[CH:19]=[N:17][C:6]=2[CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: C[C@H]1CC[C@H](CNc2c(N)cc(Cl)nc2Cl)CC1
Solvent: CC(=O)OC(C)=O
Product: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1

Procedure:
A solution of 2,6-dichloro-N3-((trans-4-methylcyclohexyl)methyl)pyridine-3,4-diamine (126 g, 0.386 mol) in triethylorthoformate (1.0 L) and acetic anhydride (1.0 L) was stirred at 90° C. for 3 h. The solution was concentrated in vacuo, and the residue was dissolved in DCM/10% NaOH (2.0 L/1.0 L). The organic layer was separated and concentrated. The crude product was purified by a silica gel column, eluting with DCM/petroleum ether (1:1), to give 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C14H17Cl2N3 [M+H]+ 298. found 298. 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H); 7.66 (m, 1H); 4.28-4.26 (d, 2H); 1.85-1.79 (m, 1H); 1.73-1.71 (d, 2H), 1.70-1.61 (d, 2H), 1.34-1.33 (m, 1H) 1.12-1.02 (m, 2H), 0.94-0.84 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[C:26]([CH3:30])=[N:27][NH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1n[nH]cc1-c1ccc2c(c1)C(C)NCC2
Product: Cc1n[nH]cc1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].CC1C=CC(S(O[CH2:31][C@@H:32]2[CH2:34][O:33]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:31][C@@H:32]2[CH2:34][O:33]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Cl)C2(C)C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H]3CO3)c(=O)c1Cl)C2(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Chloro-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (120 mg, 0.425 mmol) in N,N-dimethylformamide (2 mL) was mixed with (2S)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (117 mg, 0.513 mmol) and potassium carbonate (71 mg, 0.0514 mmol) at room temperature and stirred at 80° C. for 3 hours. After cooling, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The resulting crude product was used for the next reaction without purification.
Reaction SMILES: F[C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:3]=1[NH2:4].SC1SC2C(F)=CC=C(C(F)(F)F)C=2N=1.[Cl:29][C:30]1[S:31]C2C=CC(Cl)=CC=2N=1>>[Cl:29][C:30]1[S:31][C:2]2[C:8]([F:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1c(C(F)(F)F)ccc(F)c1F
Agent: Fc1ccc(C(F)(F)F)c2nc(S)sc12
Product: Fc1ccc(C(F)(F)F)c2nc(Cl)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2,3-difluoro-6-trifluoromethylaniline via 2-mercapto-7-fluoro-4-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:22])=[CH:18][CH:17]=1
Reactant: NCCCCCCCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)s1
Product: O=C(NCCCCCCCCn1ccnc1)c1ccc(Cl)s1

Procedure:
When 1H-imidazole-1-octylamine is treated with 5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36, the title compound, m.p. 95°-97° C., was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:53]=1[NH2:54]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:54][C:53]1[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=1[F:51])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38 mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) and DIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657 mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled to room temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl (200 ml). The organic phase was washed with 0.5M HCl (2×50 ml), saturated NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4, and evaporated to dryness to afford 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide as light brown solid. Yield: 1.5 g, 100%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]1)[CH3:12].Cl>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][CH:20]([OH:21])[CH2:19][CH:16]2[CH2:17][CH2:18][CH:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)=[CH:4][CH:5]=1)[CH3:10]
Reactant: C#Cc1ccc(CC)cc1
Reactant: CCC1CCC(CC=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(C#CC(O)CC2CCC(CC)CC2)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
4-Ethylphenylacetylene (1.3 g) was dissolved in THF (20 ml), followed by dropwise adding an n-butyllithium-hexane solution (1.61M, 0.62 ml) under ice cooling with stirring, further stirring the reaction solution under ice cooling for 30 minutes, dropwise adding a solution of 2-(4-ethylcyclohexyl)acetaldehyde (1.5 g) in THF (10 ml) , raising the temperature of the reaction solution up to room temperature after completion of the addition, stirring it for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (50 ml), washing the organic layer with water, drying over anhydrous MgSO4 and concentrating under reduced pressure, to obtain a brown oil, which was then recrystallized from an ethyl acetate-heptane mixed solution, to obtain white crystals of 1-(4-ethylphenyl)-4-(4-ethylcyclohexyl)-1-butyn-3-ol (2.3 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14]
Reactant: C#CC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 104.3 %

Procedure:
A solution of compound of Step 6 (0.926 g, 2.85 mmol) and trifluoroacetic acid (5.49 mL, 71.3 mmol) in CH2Cl2 (5.49 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in 1.0N KOH (7 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over MgSO4 and then concentrated to give the title amine as an off-white solid (0.67 g, 100% yield) 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[OH-].[Na+].C([Br:17])(=O)C>>[Br:17][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cc([N+](=O)[O-])ccn1
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Br)ccn1
Temperature: 75 °C
Yield: 62 %

Procedure:
A mixture of 2-ethyl-4-nitro-pyridine (2.3 g, 15.1 mmol) and acetyl bromide (9 mL) were heated together at 75° C. for 16 hours. More acetyl bromide (10 mL) was added and the reaction was heated to 100° C. for 5 hrs. The reaction mixture was poured into ice, made basic with 20% NaOH and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to a black oil. Purification by flash silica gel chromatography (0% to 25% EtOAc) gave the product as an oil (1.72 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J=7.6 Hz, 3H), 2.81 (d, J=7.6 Hz, 2H), 7.28 (dd, J=5.3, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 8.34 (d, J=5.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:18][CH2:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CO>[CH3:31][CH:29]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:32]([CH3:33])[CH3:34])[C:23]=1[NH:22][C:20](=[O:21])[CH2:19][NH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:35])=[O:3])=[CH:10][CH:9]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(C(NCC(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by the hydrolysis of the product of Example 152 by NaOH in aqueous methanol, mp 245°-246° C.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=O)=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[NH:2][N:1]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)c2ccccc2C(=O)O)cn1
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
24 ml (121 mmol) of hydrazine was added to an ethanol solution (200 ml) of 28.0 g of 2-[(6-methoxypyridin-3-yl)carbonyl]benzoic acid, and the reaction liquid was stirred at 60° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 21.50 g (yield: 77%) of 4-(6-methoxypyridin-3-yl)-2H-phthalazin-1-on as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[S:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([S:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CSc1ccc(C(=O)Cl)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.33 h

Procedure:
A solution of 4-amino-3,5-dichloropyridine (0.46 g) in dry dimethylformamide (20 mL) is treated with sodium hydride (0.23 g of a 60% dispersion in mineral oil; 2.8 mmol) and the mixture is stirred for 20 minutes. It is then treated with a solution of 3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g; that is prepared as described in Reference Example 20 in dimethylformamide (10 mL) and stirred at 600C for 2 hours. The solution is then concentrated and the resulting residue is partitioned between water (30 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (50 mL) and the combined organic layers are dried, concentrated, and subjected to flash chromatography on silica gel, eluting with a mixture of diethyl ether and pentane (1:1 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (0.7 g) in the form of a white crystalline solid, m.p. 157°-159° C. [NMR (CDCI3):8.57 (s,2H), 7.69 (bs,1H), 7.47 (dd,1H,J=8Hz,J=2Hz), 7.43 (d,1H,J=2Hz), 7.17 (d,1H,J=8Hz), 4.95 (m,1H), 2.46 (s,3H), 1.98-1.6(m,8H); Elemental analysis: C,54.0; H,4.5; N,7.0; Cl17.8%; calculated: C,54.4; H,4.6; N,7.05; Cl,17.85%].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9](O)=[O:10])[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CC2CC2)C(=O)O)cc1Cl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
268 mg (0.68 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 192 mg (51% of theory)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:44])[NH:13][CH2:14][C:15]([N:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH:18]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].O.CO>[OH-].[K+]>[C:40]([O:39][C:37]([CH:18]1[CH2:19][CH:20]([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:12](=[O:44])[NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([OH:4])=[O:2])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)Nc3ccccc3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CC(C(=O)Nc2ccccc2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 14.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 4 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(methoxycarbonyl)phenyl)ureido]acetyl}-5-phenyl-4-(phenylcarbamoyl)pyrrolidine-2-carboxylate in a mixture of 6.7 cm3 of a normal aqueous potassium hydroxide solution, 30 cm3 of distilled water and 120 cm3 of methanol. After treatment, there is obtained 0.55 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-phenylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([Br:21])=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(N)cnc1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(N)c(Br)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of ethyl 5-amino-2-methylnicotinate (Fanta, P. E. J. Am. Chem. Soc. 1953, 75, 737) (4.1 g, 22.78 mmol) in DMF (50 ml) was added NBS (4.46 g, 25.06 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, the residue was triturated with ethanol to give ethyl 5-amino-6-bromo-2-methylnicotinate. (5.2 g, 88% yield). 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.40 (q, J=6.8 Hz, 2H), 4.05 (br, s, 2H), 2.75 (s, 3H), 1.39 (t, J=6.8 Hz, 3H). MS (EI) for C9H1BrN2O2: 259.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1)=[O:8]
Reactant: COc1cc2sc(C(=O)Cl)c(Cl)c2cc1OC
Reactant: OC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2sc(C(=O)N3CCC(O)CC3)c(Cl)c2cc1OC
Reaction time: 2 h

Procedure:
3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonyl chloride (2.0 g) and 4-hydroxy-piperidine (1.60 g) was suspended in tetrahydrofuran (15 ml) and triethylamine (0.96 ml) was added and stirring continued at room temperature for two hours. Water was added, pH adjusted to 3 by HCl and the precipitate filtered.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].Cl.[OH:13][C:14]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:34][C:15]=1[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]>C(Cl)Cl>[OH:13][C:14]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:40][CH2:41][N:42]([S:8]([CH3:7])(=[O:10])=[O:9])[CH2:43][CH2:44]2)=[CH:34][C:15]=1[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, pyridine (0.5 mL) and methanesulfonyl chloride (9.9 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.5 mL) were added to the residue, followed by stirring at 70° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid (5 mL) was added thereto. The solid substance was collected by filtration and the obtained solid substance was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 8.0 mg of 2-(2-hydroxy-5-(1-(methylsulfonyl)piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid as a white solid.