Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CC1OC(=O)OC=1C[O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH2:73])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C.[Li+].[OH-].O>>[Cl:72][C:68]1[CH:67]=[C:66]([C:63]2[CH:62]=[CH:61][C:60]([CH2:59][C@@H:58]([NH:73][C:13]([C:4]3[CH:3]=[C:2]([OH:1])[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)[N:5]=3)=[O:15])[CH2:57][C@@H:56]([OH:74])[C:55]([OH:75])=[O:54])=[CH:65][CH:64]=2)[CH:71]=[CH:70][CH:69]=1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cc(O)n(-c2ccccn2)n1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
5-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (59.0 mg, 287 μmol) and HCTU (131 mg, 316 μmol) were combined in DMF (1.3 mL, 17.2 mmol). and stirred at room temperature for 15 minutes. (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (100 mg, 0.3 mmol) and DIPEA (150 μL, 862 μmol) were added, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction was evaporated under reduced pressure. The residue was dissolved in EtOH and a solution of 1 M LiOH in water (1.4 mL, 1.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound (85 mg). MS m/z [M+H]+ calc'd for C26H23ClN4O5, 507.14. found 507.1.
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:11]=1)=[O:8])(=O)C.Cl.CCOC(C)=O>C1COCC1>[OH:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Oc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Oc1cccc(CO)c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To a solution of Compound 5 (9.4 g, 0.024 mol) in THF (120 ml) was added a solution of hydrochloric acid (HCl) (100 ml, 6 N HCl in water) at RT. The reaction mixture was stirred at RT for 2 days. Then, the reaction mixture was mixed with EtOAc (300 ml) and the resulting layers were separated. The organic layer was washed with aqueous saturated NaHCO3 (3×100 ml) and brine (1×100 ml). The aqueous layer was neutralized to pH 7 with aqueous saturated NaHCO3, and extracted with EtOAc (2×100 ml). These EtOAc extracts were combined and washed with brine (1×100 ml). Then, all the organic layers were combined and dried over anhydrous Na2SO4. The crude product obtained upon concentration was purified by column chromatography (elution solvent: 30% EtOAc in hexanes) to yield 5.0 g of Compound 6 in 87% yield.
Reaction SMILES: C[C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([O-:20])=[O:19])[CH:3]=1.[OH-].[Na+].C(O)C>O>[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([OH:20])=[O:19])[CH:3]=1
Reactant: Cc1cc(C(=O)[O-])cc2c1CCc1ccccc1S2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1CC2

Procedure:
520 Mg. methyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylate 5-oxide is stirred at 65° C. in a mixture of 20 cc. 20% aqueous sodium hydroxide and 20 cc. ethanol until a clear solution results (1 hour). The mixture is diluted with water, extracted with ether, then acidified with hydrochloric acid. The white precipitate is filtered and dried to yield 245 mg. of material which is recrystallized from methanol to yield 180 mg., m.p. 261°-265° C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([S:48]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:62]=[CH:61][C:60]([C:63]3[CH:64]=[C:65]4[C:71]([C:72]5[CH:73]=[N:74][N:75]([CH2:77][C:78]6[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=6)[CH:76]=5)=[CH:70][N:69](S(C5C=CC(C)=CC=5)(=O)=O)[C:66]4=[N:67][CH:68]=3)=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)(=[O:50])=[O:49])[CH3:47].[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([S:48]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:62]=[CH:61][C:60]([C:63]3[CH:64]=[C:65]4[C:71]([C:72]5[CH:73]=[N:74][N:75]([CH2:77][C:78]6[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=6)[CH:76]=5)=[CH:70][NH:69][C:66]4=[N:67][CH:68]=3)=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)(=[O:49])=[O:50])[CH3:47]
Reactant: CCS(=O)(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 57.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(6-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.143 mmol) was hydrolyzed with lithium hydroxide (30 mg, 0.715 mmol) in THF/methanol/water (3/2/1 mL) to yield 45 mg (58.4% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.51-8.49 (m, 2H), 8.44-8.43 (d, 2H), 8.41-8.40 (d, 1H), 8.36-8.35 (d, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.48-7.45 (d, 1H), 7.38-7.36 (m, 1H), 7.12-7.09 (d, 1H), 7.08-6.96 (m, 2H), 5.44 (s, 2H), 3.85-3.83 (t, 4H), 3.53-3.50 (t, 4H), 3.15-3.05 (q, 2H), 1.38-1.33 (t, 3H). MS: m/z=546.1 (M+1), HPLC: 94.35% in method A.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1>O1CCCC1>[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:16])[CH2:10][CH2:9]1
Reactant: NC(=O)[C@H]1CC[C@H](O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
To a suspension of 11.4 g (0.3 mol) lithium aluminum hydride in 500 ml anhydrous tetrahydrofuran are introduced 21.6 g (0 15 mol) solid trans-4-hydroxycyclohexanecarboxylic acid amide and heated under reflux for 24 h. After decomposition with 45 ml saturated common salt solution, it is filtered off with suction and the filtrate distilled The residue is triturated with ether and the crystals filtered off with suction. There remain 11 g of amine, i.e. 57% of theory, of the m.p. 137°-139° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:22]([CH3:23])=[CH:21][C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>COCCOC.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>[CH3:23][C:22]1[C:8]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:9][C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C(=O)Nc2cccnc2)c(OCc2ccccc2)cc1Br
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: COCCOC
Product: Cc1cc(C(=O)Nc2cccnc2)c(OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
Sodium carbonate (0.30 ml, 0.30 mmol) was added to 4-bromo-5-methyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 9; 59 mg, 0.15 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37.1 mg, 0.18 mmol) and palladium tetrakis (10.30 mg, 8.91 μmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated in a microwave at 120° C. for 1 hour, the solvent was removed in vacuo and the solid purified by MDAP to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3cccc([N+](=O)[O-])c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.7 mmol) and 3-nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 (1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of 1-(3-nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester as light orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:18])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[F:26][C:27]([F:31])=[C:28]([F:30])[F:29].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:28]([F:30])([F:29])[CH:27]([F:31])[F:26])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(S)[nH]c2-c2cccs2)cc1
Reactant: FC(F)=C(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: Fc1ccc(-c2nc(SC(F)(F)C(F)F)[nH]c2-c2cccs2)cc1

Procedure:
A solution of 14.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 g of diisopropylamine was pressured in a bomb with 4 g of tetrafluoroethylene. The pressure dropped from 160 psi to 0 in 1.5 hrs. The solution was poured into water, stirred until most of gum solidified, filtered and washed with water. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, concentrated and diluted with 1-chlorobutane. The crystalline product was collected; yield 2.5 g, m.p. 164°-168° C. The residue from the filtrate was chromatographed on silica gel (Silicar CC-4) using chloroform to give 4.1 g, m.p. 167.5°-170° C. The combined 6.5 g was crystallized from 1-chlorobutane to give 5.6 g, m.p. 167°-168.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20]/[C:21](/[NH2:24])=[N:22]/[OH:23])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:25].[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31](Cl)=O.C(O)C>C1COCC1>[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]1[O:23][N:22]=[C:21]([NH:20][C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]3[C:3](=[O:25])[N:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=4)[CH:14]=2)[N:24]=1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(Cl)c1nccs1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4nccs4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 (0.1 mmol) in THF (1 mL) was added thiazole-2-carbonyl chloride (0.1 mmol). The reaction mixture was stirred at rt for 30 min. Then ethanol (1 mL) was added and heated at reflux for 3 h. After filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(thiazol-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A9) MS m/z 431.1 (M+1).
Reaction SMILES: [N:1]1([C:5](=[O:18])[C@@H:6]([NH:10]C(=O)OC(C)(C)C)[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.O1CCOCC1.CO>Cl>[NH2:10][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:5]([N:1]1[CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N1CCC1
Reaction time: 5 h
Yield: 73.2 %

Procedure:
(S)-Tert-butyl 1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound D) (23.56 g, 90.07 mmol) was stirred in 4M HCl in dioxane (56.3 mL, 225 mmol) for 30 min. Additional dioxane and MeOH was added until the reaction mixture became a clear solution. The solvent was removed under reduced pressure and conc. HCl (3.00 mL, 30.4 mmol) was added. The mixture was stirred for 5 h before the solvent was removed. The residue was purified via Biotage (gradient; EtOAc:MeOH (2% TEA), 99:1 to 90:10, then EtOAc:MeOH (2% TEA) 90:10 to 0/100 KP-SIL 340 g. The solvent was removed under reduced pressure to give the title compound (10.3 g, 70.3%). 1H NMR (600 MHz, CH3OD) δ 1.03, 1.06, 2.07-2.16, 2.33-2.41, 3.71, 3.99-4.07, 4.07-4.14, 4.25-4.33, 4.33-4.41. Total no of protons: 14. LCMS (M+H)+: 157.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:51]([O:53][CH:54]([Cl:56])[CH3:55])=[O:52].O>C(Cl)Cl>[Cl:56][CH:54]([O:53][C:51]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:33]=[CH:32][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:52])[CH3:55]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)Cl)CC3)CC2=O)cc1
Temperature: 0 °C

Procedure:
To a suspension of 99.6 mg of n-butyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 2 ml of methylene chloride were added 151 mg of proton sponge and 26 μl of 1-chloroethyl chloroformate with stirring at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture thus obtained was poured into 2 ml of water, and extracted three times with 4 ml of ethyl acetate. The organic layer collected was dried over magnesium sulfate, and the solvent was removed by distillation to give 82.7 mg of n-butyl 4-[[4-[1-(1-chloroethyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate as a crude crystalline product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([C:34]([OH:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42]O.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([C:34]([O:36][CH2:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])=[O:35])[CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(-c2c(C(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(C(=O)OCCCCN(C)C)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (prepared in Example 132) (153 mg) in acetonitrile (5 ml) was added 4-dimethylaminobutanol (0.21 ml), 1-hydroxy-7-azabenzotriazole (126 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg) and the resulting mixture was stirred at room temperature for sixteen hours. To the reaction solution were added saturated aqueous sodium hydrogen carbonate solution (10 ml) and ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-(dimethylamino)butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate (137 mg). UPLC/MS 595 (M+H)/0.73 min (measurement condition 9)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([O:10]CC)=[O:9])=[C:3]1[CH2:13][C:14]([O:16]CC)=[O:15].[OH-].[Na+].Cl>>[C:8]([C:4]1[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[C:3]=1[CH2:13][C:14]([OH:16])=[O:15])([OH:10])=[O:9]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cn(C)c(CC(=O)O)c1C(=O)O

Procedure:
A mixture of 176 g. (0.7 mole) of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate and 1760 ml. of 25% sodium hydroxide solution is heated under reflux for 3 hours and then cooled and acidified with dilute hydrochloric acid. The precipitated solid is filtered and air dried. There is obtained 3-carboxy-1,4-dimethylpyrrole-2-acetic acid as a gray solid, m.p. 220-222° C.
Reaction SMILES: Br[CH:2](Br)[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C([O-])(=O)C.[Na+].[NH:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1)[NH2:16]>O>[Cl:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([NH:15][N:16]=[CH:2][C:3](=[O:4])[C:5]([F:8])([F:7])[F:6])=[N:18][CH:19]=1
Reactant: NNc1ncc(Cl)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1ncc(Cl)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
6.75 g 1,1-dibromo-3,3,3-trifluoroacetone were stirred for 30 min. at 80° C. in a solution of 9.0 g sodium acetate in 250 ml water. Then the solution was cooled at 0° C. and 4.0 g 2-hydrazino-3-fluoro-5-chloropyridin were added. Stirring was continued for 3.5 hrs. Then the reaction mixture was extracted with ethyl acetate, the extracts were washed with water and dried. After evaporation, the remaining residue was purified on silcagel (hexane-ethyl acetate 8:2) to give the title compound as brownish residue which was directly used for the next step. MS: (M−H )=268.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:21][C:6]2[NH:7][C:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=3)[C:15](O)=[O:16])=[N:9][C:5]=2[CH2:4]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[CH2:4][C:5]2[NH:9][C:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=3)[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:16])=[N:7][C:6]=2[CH2:21]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC1Cc2nc(-c3cc(C(=O)O)c(C)cc3C)[nH]c2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1Cc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
Into around-bottom flask, was placed a solution of 5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoic acid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equiv), 4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equiv), and EDC.HCl (80 mg, 0.42 mmol, 2.00 equiv) were added and the mixture was stiffed overnight at room temperature. The resulting solution was diluted with ethyl acetate (30 mL) and washed with brine (3×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue (40 mg) was purified by preparative-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (15.0% CH3CN up to 55.0% in 7 min, up to 100.0% in 1 min, down to 15.0% in 1 min); Detector, Waters 2489 254 & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (8.9 mg, 11%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45](=[O:53])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[NH2:52])=[N:42][CH:43]=1>C(Cl)Cl.CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:16]([C:17]([NH:52][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[C:45]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([Cl:37])=[CH:43][N:42]=2)=[O:53])=[O:19])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:23]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoic acid (507 mg, 2.05 mmol) was diluted with methylene chloride (20 mL). DMF (4 drops) and pyridine (0.2 mL, 2.47 mmol) were added, followed by oxalyl chloride (0.2 mL, 2.29 mmol). Vigorous bubbling occurred. After 1.5 hours, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (20 mL). N-(5-Chloropyridin-2-yl)-2-aminobenzamide (507 mg, 2.05 mmol) was added, followed by pyridine (0.2 mL, 2.47 mmol). After stirring overnight, the reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the desired product (992 mg, 1.74 mmol, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5](C)=[C:6]([CH:9]=1)C#N.[CH3:14][C:15]([OH:17])=[O:16]>O.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:6])=[C:14]([CH:9]=1)[C:15]([OH:17])=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Temperature: 120 °C
Yield: 84 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) in AcOH (10 mL), water (10 mL) and conc. sulphuric acid (10 mL) was heated to 120° C. for 5 h. Water (100 mL) was added and the solid was removed by filtration and dried to give 5-chloro-2-methyl-4-nitrobenzoic acid (905 mg, 84%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M−H]−=214 at 2.12 min. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.76 (s, 1H), 2.70 (s, 3H).