Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@:24]2([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]2)[O:23][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH:14]=[CH:13][C:12](=[O:22])[CH2:11]2.[O:31]1CCCC1.[OH-].[Na+].OO>C(OCC)(=O)C.CO>[O:31]1[C@H:13]2[C:12](=[O:22])[CH2:11][C@H:10]3[C@:15]([CH3:16])([C@@H:14]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@H:3]1[C@@H:2]([C@:24]4([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]4)[O:23][C@H:4]1[CH2:5]2)[CH3:1])[CH2:8][CH2:9]3
Reactant: C1CCOC1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)C=C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@@H]6O[C@@H]6[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of (5α,25R)-spirost-1-en-3-one (2.87 g, 6.96 mmol), tetrahydrofuran (30 mL), methanol (50 mL) and 15% sodium hydroxide (1 mL) was stirred under nitrogen atmosphere. The mixture was cooled to 0° C. and 30% hydrogen peroxide (5 mL) was added. The reaction mixture was gradually warmed to room temperature and stirred for 4 hours. The reaction was diluted with ethyl acetate, cooled to 0° C., and then quenched with saturated sodium bisulfite solution. The mixture was washed with saturated sodium bisulfite (2×), brine (1×), dried (sodium sulfate), filtered and concentrated in vacuo to give 2.64 g, (88%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH:11]=2)=[CH:6][CH:5]=1)(=O)C.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[O:33]=[C:28]1[NH:29][C:30](=[O:32])[C:31](=[CH:1][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])[CH:11]=3)=[CH:8][CH:9]=2)[S:27]1
Reactant: CC(=O)c1ccc(-c2cccc(CC(=O)N(C)c3ccccc3)c2)cc1
Reactant: O=C1CSC(=O)N1
Product: CN(C(=O)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccc1
Yield: 70 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1 g (4 mmol) of 2-(4′-acetylbiphenyl-3-yl)-N-methyl-N-phenylacetamide with 460 mg (4 mmol) of 2,4-thiazolidine dione, 1.2 g (71%) of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[CH3:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1ccccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and 1-bromo-2-methyl-benzene (13 μl) instead of 4-chloropicolinic acid t-butylamide, in the same manner as in Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-7-o-tolyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-174) as a pale yellow powder (9 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([N:18]3[CH2:22][C@@H:21]4[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@@H:20]4[CH2:19]3)[CH:15]=[N:16][CH:17]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([N:18]3[CH2:22][C@@H:21]4[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@@H:20]4[CH2:19]3)[CH:15]=[N:16][CH:17]=2)=[S:42])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=S)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1
Temperature: 110 °C
Reaction time: 18 h
Yield: 191.6 %

Procedure:
The product from Example 42A (60 mg, 0.14 mmol) and Lawesson's reagent (27 mg, 0.068 mmol) were combined with toluene (3 mL) and stirred at 110° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (EtOAc, Rf=0.35) to provide the title compound (60 mg, 97%). MS (APCI) m/z 387 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH:26]3[CH2:28][CH2:27]3)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([NH:35][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28]3)[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Reactant: NC1CCCC1
Product: O[C@@H]1[C@H](O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(NC3CCCC3)nc(Cl)nc21

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-cyclopropyl-β-D-ribofuranosyl)-purine (65, 543 mg, 1.22 mmol) and cyclopentylamine (1.83 mmol, 180 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 400 mg (0.98 mmol, 80%), mp 104–106° C.; Rf 0.51 (10% MeOH in CH2Cl2). The product was re-crystallized from (C2H5)2O; 1H NMR (DMSO-d6) δ 8.34 (bs, 1H, NH), 8.28 (s, 1H, H-8), 5.81 (d, 1H, J=5.15 Hz, H-1′), 5.53 (d, 1H, J=5.84 Hz, OH-2′), 5.29 (d, 1H, J=5.15 Hz, OH-3′), 4.50 (q, 1H, J=5.15 Hz, H-2′), 4.50–4.47 (m, 1H, CH), 4.09–3.99 (m, 2H, H-3′,4′), 3.68–3.63 (m, 2H, H-5′), 1.94–1.89 (m, 2H, cyclopentyl), 1.71-1.50 (m, 4H, cyclopentyl), 0.46–0.41 (m, 4H, OCHCH2CH2); MS m/z 410 (M+H)+; Anal. (C18H24ClN5O4.0.2(C2H5)2O) C, H, N.
Reaction SMILES: Br[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=Cc1cscc1Br
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
Product: CCc1ccc(-c2cscc2C=O)cc1
Temperature: 128 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-formylthiophene (0.62 g, 3.18 mmol) and 4-ethylphenylboronic acid (0.95 g, 6.36 mmol) in toluene (12 mL), EtOH (12 mL) and aqueous Na2CO3 solution (2 M, 3.18 mL, 6.36 mmol) in a seal tube was deoxygenated under reduced pressure and flushed with argon for 3 times, followed by addition of Pd(PPh3)4 (184 mg, 0.16 mmol) and deoxygenated again. The resulting solution was stirred at 128° C. in an oil bath for 5 hour. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The reaction was partitioned between ethyl acetate and water. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 440 mg (64%) of 4-(4-ethylphenyl)thiophene-3-carbaldehyde as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2OC)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=587 (M+1); 1H NMR (CDCl3) δ: 11 (S, 1H), 8.63 (s, 1H), 8.54 (d, 1H, J=9 Hz), 8.49 (d, 1H, J=5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 3H), 6.82 (dd, 1H, J=3, 9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.05 (d, 6H), 4.01 (q, 2H, J=8 Hz), 3.85 (s, 3H), 1.45 (t, 3H, J=8 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:17]([O:19][CH3:20])=[O:18].[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][N:27]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:28]=4)[C:5]=3[C:4]([C:17]([O:19][CH3:20])=[O:18])=[C:3]([S:2][CH3:1])[CH:8]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1c(SC)cc(-c2ccc(F)cc2)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(F)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(4-fluorophenyl)-2H-pyran-3-carboxylate (294 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 52% of methyl 6-(4-fluorophenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate. White solid; mp-182-184° C.; 1H NMR (300 MHz, CDCl3) δ 2.48 (s, 3H, CH3), 2.82-2.90 (m, 4H, 2CH2), 4.01 (s, 3H, OCH3), 7.10-7.19 (m, 3H, ArH), 7.27-7.36 (m, 3H, ArH), 7.42-7.51 (m, 2H, ArH), 7.67 (d, J=7.62 Hz, 2H, ArH), 7.98 (s, 1H, ArH); MS (ESI) m/z 445 (M++1).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[N:11]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][CH2:3]1)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCCS2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCSc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 3,4-dihydro-2H-1,4-benzothiazine (50.0 g, 330.8 mmol) in acetic acid (170 mL.), cooled at −10° C. in an ice/acetone bath, was added sodium nitrite (27.4 g, 397.1 mmol) in 75 mL of water over 35 min. After the addition, the mixture was warmed to room temperature and stirred for additional 1.5 hours. Cold water (150 mL) was added and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine as a semi-solid (60.26 g, 101%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ2.99-3.05 (m, 2H), 4.16-4.24 (m, 2H), 7.15-7.31 (m, 3H), 7.88-7.97 (m, 1H) ppm.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: CCCCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 4-(n-butyl)benzoyl chloride (1.967 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 6 hours. The reaction mixture was treated in the same manner as described in Example 120 to obtain 863 mg of the title compound (yield: 32%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].S(Cl)([Cl:17])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:17])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccsc1NC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)sc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 19.9 parts of methyl 2-acetamidothiophene-3-carboxylate in 200 parts by volume of chloroform, 8.2 parts by volume of sulfuryl chloride is added dropwise at below 30° C. The mixture is stirred at room temperature for 30 minutes and then cooled with ice. To the mixture, about 300 parts by volume of saturated aqueous sodium bicarbonate solution is cautiously added with stirring. The chloroform layer is separated, washed with water and dried over sodium sulfate. Evaporation of the solvent gives methyl 2-acetamido-5-chlorothiophene-3-carboxylate as crystals. Recrystallization from methanol gives needles melting at 110°-110.5° C. This compound is identical with that obtained in Reference Example 17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:38][CH2:39][Cl:40]>O>[Cl:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: ClCCBr
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 62.1 %

Procedure:
To a mixture of 0.371 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 1.63 g (5 mmole) of cesium carbonate and 3 mL of dimethylformamide was added 0.249 mL (3 mmole) of 1-bromo-2-chloro-ethane. The mixture was heated at 100 degrees for 30 minutes. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration and then air dried. The solid was triturated with acetonitrile to give 0.269 g of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][CH2:27][CH:26]=[CH2:25])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCBr
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(=O)n(-c2ccccc2)c2ncccc12

Procedure:
To a mixture of 62 g. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one, 39.6 g. of anhydrous potassium carbonate and 1,800 ml of acetone, there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 ml. of chloroform. The organic extract is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3×400 ml of boiling isopropyl ether and filtered, yielding the insoluble product, wt. 38.5 g., m.p. 171°-174°. Recrystallization from methanol produces the product as a colorless solid, m.p. 176°-177° C.
Reaction SMILES: C[CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[N:10]1([CH:16]2CCCN2CC(O)=O)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:16][N:10]1[CH2:15][CH2:14][N:13]([C:7](=[O:9])[CH2:8][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:12][CH2:11]1
Reactant: O=C(O)CN1CCCC1N1CCNCC1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 8 h
Yield: 171 %

Procedure:
1.6 g of 3-methylglutaric anhydride and then 2.62 g of piperazin-1-ylcarboxymethylpyrrolidine are added to 20 cm3 dioxane. After stirring for 8 hours, an additional 320 mg of 3-methylglutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure and then the resulting oil is dried at 45° C. (90 Pa) to give 4.5 g of 5-(4-methylpiperazin-1-yl)-5-oxopentanoic acid in the form of an orange-colored oil which is used as it is.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:49])([OH:47])[CH2:42]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>CC(N(C)C)=O>[C:48]([C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1)(=[O:49])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: NC1CCCC(O)(C(=O)c2ccccc2)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol, 49.5 mg), HCl salt of (3-amino-1-hydroxycyclohexyl)(phenyl)methanone (0.1 mmol, 25.5 mg), HATU (0.1 mmol, 38 mg) and DIEA (0.15 mL) in DMA (0.65 mL) was stirred at room temperature for overnight. The product, N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after rotary evaporation of solvent.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([NH2:29])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:30])[NH:6]2.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.[BH4-].[Na+]>CCO>[CH:31]1([CH2:34][NH:29][C:26]2([CH2:25][O:24][C:18]3[CH:17]=[C:16]4[C:21]([C:12]([O:11][C:10]5[C:2]([F:1])=[C:3]6[C:7](=[CH:8][CH:9]=5)[NH:6][C:5]([CH3:30])=[CH:4]6)=[CH:13][CH:14]=[N:15]4)=[CH:20][C:19]=3[O:22][CH3:23])[CH2:27][CH2:28]2)[CH2:33][CH2:32]1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(N)CC1
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(NCC2CC2)CC1

Procedure:
The compound of Example 24 (100 mg) was refluxed with cyclopropanecarbaldehyde (2 eq) in EtOH (8 ml) for 4 hours. To the reaction was added NaBH4 (2.2 eq), the reaction was refluxed for 20 minutes and evaporated. The residue was purified with silica gel column to give the titled product (50 mg). Mass: (M+1), 462
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28]>>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:28])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The titled compound was synthesized from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide and TMSCHN2. HPLC purification afforded a white solid. LCMS method [11], retention time=7.322 min; MS(ESI) 403.2 (MH+, 35Cl); 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.1 Hz, 1H), 6.94 (s, 1H), 4.98 (s, 2H), 3.98 (s, 3H), 3.36 (t, J=7.5 Hz, 2H), 2.97 (dd, J=8.2, 6.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:24]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[NH2:24][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 4-[1-(tert-butoxycarbonyl)-4-piperidyl]benzoic acid (3.64 g) and 1-hydroxybenzotriazole (2.73 g) in dichloromethane (40 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HCl) (4.56 g) and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added water (20 ml) and an organic layer was separated and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. A solution of the resulting residue in THF (30 ml) was added to a solution of conc. ammonium hydroxide (10 ml) in THF (30 ml) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. To a reaction mixture was added ethyl acetate (200 ml) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The precipitate was chromatographed on silica gel (200 ml) eluting with a mixture of dichloromethane and methanol (9:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-[4-(aminocarbonyl)phenyl]-1-piperidinecarboxylate (3.34 g).