Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][O:27][CH3:28])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[O:27][CH3:28])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C(=O)OC(C)(C)C)cc1
Product: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 93 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with 4-(methoxyamino-methyl)-benzoic acid tert-butyl ester as described in the preparation of compound 1-C gave the title amide as white crystals (93% yield): mp 137-138° C. (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (9H, s, t-Bu), 1.76 (6H, s, CH3), 3.67 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.40 (1H, s, CH), 7.39 (2H, d, J=8.2 Hz, aromatics), 7.95 (2H, d, J=8.2 Hz, aromatics). Anal. calcd for C20H25NO7: C, 61.37; H, 6.44; N, 3.58. Found: C, 61.23; H, 6.25; N, 3.52.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][N+:23]([CH3:26])([O-:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(NC4CCN(C)CC4)nc23)c1
Reactant: OO
Product: Cc1cccc(Nc2ncnc3cnc(NC4CC[N+](C)([O-])CC4)nc23)c1

Procedure:
Prepared from compound 62 of Example 1 by reaction with hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[F:27])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.CO.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2Br)c(F)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Temperature: 50 °C
Yield: 96.9 %

Procedure:
To a 3000 mL flask is added 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (250 g, 573.1 mmol) followed by MeOH (1000 mL) and MeSO3H (1 12.71 mL,1.72 mol) and heated to 50° C. for 14 hours. Solid crystallizes out of solution. The mixture is then cooled to RT. The reaction mixture is concentrated under vacuum at 45° C. to dryness to get solid. The solid is diluted with DCM (2000 mL) and treated with water (1000 mL) and 5N NaOH (about 350 mL) until the pH is 8-9. The organic layer is separated and the solvent is removed followed by azeotrope with toluene to give 195.6 g of the yellow solid material. MS (m/z): 354.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:21][C:22]([N:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]2=[O:33])=[CH:23][C:24]=1[CH3:25])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:21][C:22]([N:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=3)=[CH:28][C:27]2=[O:33])=[CH:23][C:24]=1[CH3:25])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-fluorobenzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a pale yellow solid in 43% yield: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (t, J=6.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.55-7.49 (m, 2H), 7.37-7.20 (m, 8H), 6.28 (dd, J=7.9, 2.7 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 162.4, 160.9, 139.6, 138.8, 137.2, 135.2, 135.1, 131.7 (d, JC-F=3.0 Hz), 130.4 (d, JC-F=8.4 Hz), 128.2, 127.3, 127.1, 126.6, 120.6, 115.3 (d, JC-F=21.5 Hz), 102.5, 97.3, 69.3, 42.5, 15.5; MS (ES+) m/z 449.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCC(=O)c1ccccc1)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
250 mL of concentrated HCl were added 1-(3,4-dichloro-phenyl)-3-(2-oxo-2-phenyl-ethyl)urea (1 equiv., 56 mmol, 18.0 g) at room temperature. The reaction mixture was stirred for one week until starting material disappeared giving a white foam which was filtered off. This foam was purified by recrystallization in ethanol affording 1-(3,4-dichloro-phenyl)-5-phenyl-1,3-dihydro-imidazol-2-one (14.4 g, 85%) as a white solid. Rf 0.2 (n-heptane/ethyl acetate 2:1). δH NMR (DMSO, 300 MHz) 10.68 (1H, br s, NH), 7.62 (1H, d, J=8.6 Hz, H arom), 7.53 (1H, d, J=2.4 Hz, H arom), 7.32-7.20 (3H, m, H arom), 7.09-7.06 (2H, m, H arom), 7.03 (1H, dd, J=8.6, 2.5 Hz, H arom), 6.89 (1H, s, ═CH); m/z (EI) 309.2 (21%), 307.2 (97), 306.1 (24), 305.1 (100, M+H+).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])=[O:7])(C)(C)C.[OH-].[K+]>C(O)C.O>[C:18]([O:17][C:15]([CH2:14][N:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:10]1=[O:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)O)C1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetate (1.14 g) in ethanol (10 ml) and water (10 ml) was added potassium hydroxide (0.22 g) and then the reaction mixture stirred at 70° C. for 5 hours. After the ethanol was removed under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The precipitate was recrystallized with ethyl acetate and filtered off to give 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetic acid (0.30 g) as a colorless solid.
Reaction SMILES: [H][H].[C:3]1([CH:9]2[C:21]3[NH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1.C(Cl)Cl>[Pd].CO>[C:3]1([CH:9]2[C:21]3[NH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[CH2:22][C:23]([OH:25])=[O:24])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CN1CCc2c([nH]c3ccccc23)C1c1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CN1CCc2c([nH]c3ccccc23)C1c1ccccc1
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A catalytic amount of 10% w/w palladium on charcoal was added under a stream of hydrogen to a solution of 260.2 mg (0.656 mmol) of benzyl (1-phenyl-1,2,3,4-tetrahydro-β-carbolin-2-yl)acetate, as obtained in Example 71, in 2 ml each of methanol and of tetrahydrofuran, and hydrogenation was allowed to proceed for 3 hours. The palladium on charcoal catalyst was removed from the reaction mixture by filtration, and the solvent was removed by evaporation under reduced pressure to give 0.32 g of a crude mixture. The resulting residue was subjected to column chromatography using 5 g of silica gel with a 19:1 by volume mixture of methylene chloride and methanol as the eluent, to yield 0.05 g of the title compound as a pale yellow powder, melting at 157°-164° C. (with decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:15][S:16]([C:19]2[S:20][C:21]([C:24]#[C:25][Si](C)(C)C)=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C:12]([OH:14])=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CO>[C:24]([C:21]1[S:20][C:19]([S:16]([NH:15][C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:12]([OH:14])=[O:13])(=[O:18])=[O:17])=[CH:23][CH:22]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a solution of crude (R)-3-(1H-Indol-3-yl)-2-(5-trimethylsilanylethynyl-thiophene-2-sulfonylamino)-propionic acid 115 (0.126 g, 0.282 mmol) in dichloromethane/methanol mixture (1:1, 10 mL) was added K2CO3 (0.047 g, 0.34 mmol) and allowed to stir for 60 minutes. The reaction mixture was then filtered and retentate washed with dichloromethane-methanol mixture. The combined filtrate was concentrated under reduced pressure and then purified using a SAX column to obtain (R)-2-(5-Ethynyl-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid 116 (52 mg, 49%). LC-MS (ES+) 375; (ES−) 373.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH:11]=2)=[O:6])[CH3:3]>C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(N)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
Concentrated hydrochloric acid (1 mL, 2.5 volumes) was added to a solution of 7-(benzhydrylidene-amino)-quinoline-3-carboxylic acid ethyl ester (400 mg, 1.05 mmol, 1 equiv) in ethanol (4 mL, 10 volumes). The solution was stirred at room temperature for three hours and then concentrated. The residue was dissolved in ethyl acetate (20 mL, 50 volumes) and the organic layer was washed with 1 N hydrochloric acid (5×25 mL). The pH of the combined aqueous layer was then adjusted to about 8 with solid sodium hydroxide. The aqueous layer was then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide 7-amino-quinoline-3-carboxylic acid ethyl ester (155 mg, 68%) as a yellow solid. The crude solid can be further purified by flash column chromatography using silica gel (EM Science, Gibbstown, N.J., 230-400 mesh) in 60% ethyl acetate in hexanes if desired.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[C:30]([CH3:39])([CH3:38])[CH2:29]2)=[O:27])[CH:23]=[C:22]([O:40][CH3:41])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[CH:23]=[C:22]([O:40][CH3:41])[N:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=1)=[O:27])[CH2:29][C:30]2([CH3:39])[CH3:38]
Reactant: COc1cc(C(=O)N2CC(C)(C)c3cc(F)ccc32)cc(Cl)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CC(C)(C)c3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
0.26 g (0.9 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.30 g (0.9 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-methanone and 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL NMP for 12 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[N:29]([C@H:37]3[CH2:42][CH2:41][C@H:40]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:28]=2)=[CH:23][C:22]=1[O:50][CH3:51]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([C@H:37]3[CH2:42][CH2:41][C@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)[N:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:13])=[C:22]([O:50][CH3:51])[CH:23]=3)[C:35]=12
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 8 h

Procedure:
To 1-methyl-1H-2-indolecarboxylic acid (0.802 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in Dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid was collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (0.545 g, 80%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.02 (m, 6H), 2.17 (s, 3H), 2.36 (m, 5H), 2.55 (m, 4H), 3.96 (s, 3H), 4.04 (s, 3H), 4.66 (m, 1H), 7.15 (m, 1H), 7.28-7.35 (m, 4H), 7.58 (d, J=8.42 Hz, 1H), 7.70 (d, J=7.96 Hz, 1H), 8.11 (d, J=8.14, 1H), 8.24 (s, 1H), 9.43 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cnn(C)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cn1cc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.11 mmol), β-alanine (804 mg, 9.0 mmol) and NaOMe solution (13 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 31 mg of the title compound as a yellow solid. MS: (+) m/z 448.29 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:15]1[C:10]2[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]3[N:5]([CH:4]=[N:3][C:2]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(Br)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.26 g (10 mmol) of 3-bromo-7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux overnight with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine and 15 ml of methylene chloride. The reaction mixture was evaporated and the residue was dissolved in methylene chloride. After chromatography of the solution on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 194°-195°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, sodium salt, and 4-benzyl-piperidine were condensed to give the title compound, mp=164-165° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[Br:26][C:14]1[C:13]([OH:16])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C(N1CCc2cc(O)c(Br)cc2CC1)C(F)(F)F
Temperature: 80 °C
Yield: 68.4 %

Procedure:
Into a 100 ml flask, the product of step (d) (1.65 g, 6.37 mmol) dissolved in acetonitrile (25 ml) was added. To this stirred solution, NBS (1.07 g, 6.05 mmol) was added. The reaction mixture was heated to 80° C. for 15 minutes and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a yellow solid (1.4 g). MS: ESI (positive): 338, 340 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O[C:15]1[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[CH2:22]([O:21][C:19]([C:18]1[CH:29]=[CH:30][C:15]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:16][CH:17]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol) in tetrahydrofuran (38.1 ml) was added benzyl 4-hydroxybenzoate (1.341 g, 5.87 mmol) and triphenylphpsphine polymer bound (4.45 g, 8.01 mmol). The reaction mixture was cooled to 0° C. and a solution of (E)-diisopropyl diazene-1,2-dicarboxylate (1.367 ml, 6.94 mmol) in tetrahydrofuran (5 mL) was added dropwise over 15 minutes. The reaction was allowed to stir at room temperature for 16 hours and the mixture was filtered. The solids were washed with dichloromethane, and the combined filtrates were concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[O:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:13]1[CH2:12][CH2:11][CH2:10][OH:9]
Reactant: O=C1CCCO1
Reactant: Nc1ccccc1N
Agent: Cl
Product: OCCCc1nc2ccccc2[nH]1
Yield: 95.5 %

Procedure:
A mixture of 5.4 g of 1,2-phenylenediamine and 4.5 g of dihydro-furan-2-one in 50 mL of 4N hydrochloric acid was heated to reflux for 20 h, 1 teaspoon of decolorizing carbon added, and after another 15 min reflux, filtered hot. The filtrate was concentrated under reduced pressure to near dryness, the residue made basic (pH=8) with saturated sodium bicarbonate and extracted into 3×80 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. After drying under vacuum, 8.4 g of 3-(1H-benzimidazol-2-yl)-propan-1-ol was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8](CC3C=CC(OC)=CC=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:22][CH:23]1[CH2:32][CH2:31][C:26]2(OCC[O:27]2)[CH2:25][CH2:24]1.CO>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:22][CH:23]1[CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]1
Reactant: COc1ccc(Cn2ccc3cc(OC4CCC5(CC4)OCCO5)c(Cl)cc3c2=O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
800 mg (1.94 mmol) of 7-chloro-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (65) were dissolved in 3 mL of TFA and heated in a microwave oven at 150° C. for 3 h. Methanol was added and the reaction mixture was evaporated. The crude product was purified by silica gel chromatography to yield 230 mg of 7-chloro-6-(4-oxo-cyclohexyloxy)-2H-isoquinolin-1-one (67). Rt=1.02 min (Method C). Detected mass: 292.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[N:17][C:16]=1[CH3:26]>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:20]([C:18]2[S:19][C:15]([CH2:14][CH2:13][O:12][CH3:11])=[C:16]([CH3:26])[N:17]=2)([OH:25])[C:21]([F:24])([F:23])[F:22])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1scnc1C
Reactant: COCCc1sc(C(=O)C(F)(F)F)nc1C
Solvent: CS(C)=O
Product: COCCc1sc(C(O)(c2nc(C)c(CCOC)s2)C(F)(F)F)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and 5-(2-methoxyethyl)-4-methyl-2-trifluoroacetylthiazole. M.p. 68°-69° C. 13C Nmr (d6 -DMSO) 14.6, 26.0, 57.7, 71.4, 77.0 (q, J 30 Hz), 123.1 (q, J 286 Hz), 131.4, 148.1 and 162.0 ppm.