Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[CH3:14][O:15]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1NC(=O)CC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
8-Methoxy-3,4-dihydro-1H-quinolin-2-one (5 g) was dissolved in dichloromethane (100 ml), and dichloromethyl methyl ether (6.4 ml) was added at room temperature, followed by cooling in an ice water bath. Titanium tetrachloride (85 ml) was added dropwise at a temperature not higher than 10° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and the aqueous layer was subjected to extraction with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether was added to the residue and the produced solid was collected by filtration and dried to thereby obtain 5.2 g (yield: 90%) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:33]=4[Cl:32])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred at room temperature for 2 hours and 2 ml of 1N NaOH is added. The volatiles are removed under vacuum and to the residue is added 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred at room temperature for 2 hours and the volatiles removed. To the residue is added 2 ml of 1N NaOH and 5 ml of H2O.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(benzyloxy)-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (200.0 mg, 0.47 mmol) in EtOAc (21 mL) was added a suspension of Pd/C (171.3 mg, 0.16 mmol, 10% by weight) in EtOH (21 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting suspension was filtered through a pad of celite. The filtrate was concentrated in vacuo and then purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 120.0 mg. 1H NMR (CDCl3, 200 MHz): δ=11.63 (s, 1H), 8.51 (s, 1H), 8.13 (d, 1H, J=9.0 Hz), 7.30 (d, 2H, J=6.6 Hz), 7.06 (d, 1H, J=9.0 Hz), 6.94-6.82 (m, 3H), 4.39 (s, 2H), 4.04 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: CS(C)=O.[OH2:5].[Br:6][C:7]1[C:8]([F:34])=[CH:9][C:10]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:29]=1)[CH:12]([C:15]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)C#N>CN(C=O)C>[Br:6][C:7]1[C:8]([F:34])=[CH:9][C:10]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:29]=1)[C:12]([C:15]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: COCOc1cc(F)c(Br)cc1C(C#N)c1ncccc1OCc1ccccc1
Reactant: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(F)c(Br)cc1C(=O)c1ncccc1OCc1ccccc1

Procedure:
By using DMSO/water (10:1), in place of DMF in Reference Example 40, 2-(5-bromo-α-cyano-4-fluoro-2-methoxymethoxybenzyl)-3-benzyloxypyridine (2.53 g) was subjected to oxidative decyanation to afford 2-(5-bromo-4-fluoro-2-methoxymethoxybenzoyl)-3-benzyloxypyridine (2.46 g) (Compound F-9). Physico-chemical properties and spectrum data are shown in Table 22 and Table 23.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Cl)c1
Yield: 94.5 %

Procedure:
2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-chlorobenzylamine (2.6 g, 18.1 mmol) and N,N-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.25 (dd, 1H), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:17]([C:19]1[NH:20][C:21]2[C:22]([N:29]=1)=[N:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH3:18].O.[OH-].[Li+]>CN(C=O)C>[CH2:17]([C:19]1[N:29]([CH2:2][C:3]2[CH:16]=[CH:15][C:6]([C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:8])=[CH:5][CH:4]=2)[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Commercially available 4-bromomethylbenzophenone (5.00 g, 18.2 mmol) was dissolved in DMF (100 mL), and 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (3.82 g, 21.8 mmol) and lithium hydroxide monohydrate (0.920 g, 21.9 mmol) was added to the solution, followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), and recrystallized from ethanol to obtain Compound 1 (5.33 g, yield 79%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[S:19][C:18]([S:20]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[S:19][C:18]([S:20]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)(=[O:21])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2ccc(C(F)(F)F)cc2)s1)n1cccc1
Yield: 75 %

Procedure:
N-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C using 4-trifluoromethylbenzene boronic acid and N-(5-bromothiophene sulfonyl)-pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide as a white powder in 75% yield.
Reaction SMILES: [O:1]=[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:1])=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:8]
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 52.1 %

Procedure:
Following the method of Menozzi et al. (J. Heterocyclic Chem. 1987, 24, 1669), a mixture of 5.3 g (29.1 mmol) ethyl beta-oxo-2-furanpropionate and 7.7 ml (57.8 mmol) N,N-dimethylformamide dimethyl acetal was stirred for 6.5 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 3.6 g (52%) 3-dimethylamino-2-(furan-2-carbonyl)-acrylic acid ethyl ester as a yellow oil. EI-MS m/e (%): 237 (M+, 36), 163 ([M—EtOH—CO]+, 100), 95 (86).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:18]([O:21][CH3:22])([O:19][CH3:20])=[O:23])=[CH:12][CH:11]=1
Reactant: COP(OC)OC
Reactant: BrCc1ccc(-c2nc3ccccc3s2)cc1
Product: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)cc1)OC
Temperature: 25 °C

Procedure:
6.08 g (0.2 mol) of 4-(benzothiazol-2-yl) bromomethylbenzene was reacted with 10 ml of trimethyl phosphite in nitrogen gas at 130°-160° C. for 15 minutes. The reaction mixture was allowed to cool down to room temperature and the resulting crystals were crystallized from n-hexane to give 3.9 g (83%) of colorless flakes of 1-(benzothiazol-2-yl)-4-dimethoxyphosphinylmethylbenzene melting at 129.5°-130.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[S:12][C:13]=1[CH3:14].[BH4-].[Na+].[OH-].[Na+]>CCOCC>[CH2:15]([C:11]1[S:12][C:13]([CH3:14])=[C:9]([CH3:8])[CH:10]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(C(O)c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1cc(Cc2ccccc2)sc1C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Trifluoroacetic acid (50 mL) was added dropwise over a 60 minute period to a stirred, 0° C. suspension of 4, 5-dimethylthiophene-2-yl-(phenyl)-methanol (7.7 g, 35.3 mmol), sodium borohydride (6.67 g, 177 mmol) and ether (600 mL). After an additional 1.5 hours the reaction mixture was added to 10% aqueous sodium hydroxide (600 mL) and stirred for 30 minutes. The layers were separated and the ether phase was washed with 10% aqueous sodium hydroxide, brine and dried (magnesium sulfate). The ether phase was concentrated to provide the tide compound as a an oil (6.73 g, 94%): NMR (CDCl3); δ 7.33-7.19 (m, 5H), 6.47 (s, 1H), 4.03 (s, 2H), 2.27 (2,3H), 2.06 (s, 2H); MS (EI) (M+) 202 (45%, MI).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1=[CH:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.Cl.C[OH:16]>>[CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1([OH:16])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CO
Reactant: CC1(C)CCOC1=Cn1cncn1
Agent: Cl
Product: CC1(C)CCOC1(O)Cn1cncn1
Yield: 93 %

Procedure:
30 g (0.17 mole) of (3,3-dimethyl-tetrahydrofuran-2-ylidene)-(1,2,4-triazol-1-yl)-methane and 100 g of concentrated hydrochloric acid are stirred in 300 ml of methanol at room temperature for 4 hours. The reaction mixture is concentrated in vacuo, the residue is taken up in water, the pH value is adjusted to 7 to 8 with dilute sodium hydroxide solution and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. 30.7 g (93% of theory) of 3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-tetrahydrofuran of melting point 93°-95° C. are obtained. ##STR99##
Reaction SMILES: [CH3:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:9](=[O:26])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+:28]>CO.O>[CH3:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:9](=[O:26])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:28]
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)cc(-c2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)[O-])c(=O)c(-c2ccc(Cl)cc2)cn1-c1ccccc1

Procedure:
35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 350 g. of 5% NaOH in 1:1 methanol/water and refluxed for 6 hours. The reaction mixture was cooled. This yielded a precipitate of sodium 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate which was collected by filtration and resuspended in dilute aqueous HCl to provide 5.3 g. of 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinic acid, m.p. (acetonitrile)=209°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1)=[O:9]
Reactant: Cc1cnc(N)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: Cc1cnc(NC(=O)c2cc(Br)ccc2O)s1
Yield: 12.9 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-tert-butylsulfanyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-c2nc[nH]n2)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2nc[nH]n2)ccc1N
Yield: 82.5 %

Procedure:
A solution of Na2S.8H2O (171.89 g) in methanol (690 ml) and water (173 ml) was added dropwise to a refluxing suspension of 3-(3-methyl-4-nitro-phenyl)-1,2,4-triazole (36.8 g) in methanol (170 ml). After two hours of refluxing, the solution was filtered through charcoal and evaporated to dryness. The residue was dissolved in 10% hydrochloric acid, the solution was washed several times with ethyl acetate and neutralized with NaHCO3 solution. The solid which separated out was filtered off and dried to give 25.9 g of the title compound; M.p. 183°-186° C. 3-(3-Methoxy-4-amino-phenyl)-1,2,4-triazole; M.p. 191°-194° C., was prepared in analogous manner.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Li+].[OH-]>O1CCOCC1.O>[CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Reaction time: 1 h
Yield: 35.5 %

Procedure:
A solution of methyl 3-methyl-2-phenylquinoxaline-6-carboxylate (90 mg, 0.32 mmol, 1.00 equiv) and LiOH (20.7 mg, 0.90 mmol, 5.00 equiv) in 1,4-dioxane/H2O (9/3 mL) was placed in a 50-mL round-bottom flask and allowed to react, with stirring, for 1 hr while the temperature was maintained at reflux in an oil bath. The resulting mixture was concentrated under vacuum, and the pH adjusted to 4 with HCl (1M). The solids were collected by filtration and dried in an oven under reduced pressure, yielding 30 mg (33%) of 3-methyl-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:27]1(I)[CH2:31][CH2:30][CH2:29][CH2:28]1>O>[CH:27]1([N:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2CCCC2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a solution of methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (780 mg, 3.8 mmol, Bionet), potassium carbonate (650 mg, 4.7 mmol, Aldrich), and 6 mL of DMF was added cyclopentyl iodide (0.52 mL, 4.5 mmol, Aldrich). The solution was stirred at RT for 4 h, then diluted with 50 mL of water. The solids were filtered and washed with CH2Cl2 and EtOAc. The filtrate was concentrated in vacuo and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 15% EtOAc:hexane to give 240 mg (23%) of methyl 2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate as an off-white solid. MS m/z: 272.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH:8]([CH3:9])[C:4]=2[C:3]=1[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:21]=1[C:22]([NH:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH:8]([CH3:9])[C:4]=2[C:3]=1[C:11]([CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[O:23]
Reactant: CC1OCc2sc(N)c(C(=O)C3CCOCC3)c21
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: CC1OCc2sc(NC(=O)c3c(F)cccc3C(F)(F)F)c(C(=O)C3CCOCC3)c21

Procedure:
The title compound was prepared from the product of Example 52A and 2-fluoro-6-trifluoromethylbenzoyl chloride by the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.33 (d, J=6.1 Hz, 3H), 1.64-1.71 (m, 4H), 3.01-3.10 (m, 2H), 3.34-3.43 (m, 1H), 3.82-3.93 (m, 2H), 4.89-5.04 (m, 2H), 5.36-5.45 (m, 1H), 7.75-7.85 (m, 3H), 12.08 (br s, 1H). MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:12][C:10]1[S:11][C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:14][C@@H:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:16]3[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:8][C:7]=2[C:9]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.3 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4; 2.36 g, 10.0 mmol), trans-2-amino-1-{N-[(1,1-dimethylethoxy)]carbonylamino}indan (Method 6; 2.5 g, 10.0 mmol), DIPEA (1.7 ml, 10.0 mmol) and HOBT (1.35 g, 10.0 mmol) was stirred in DCM (75 ml) at room temperature for 2 minutes. EDCI (2.4 g, 12.5 mmol) was added and the mixture stirred at room temperature for 20 hours during which time the product precipitated. The reaction was filtered, washed with DCM (2×25 ml) and dried to give the title compound (3.7 g, 80%) as a pale green powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[CH:12]1([C:4]2[CH:3]=[C:2]([N:1]3[CH2:16][CH2:17][CH2:18][S:19]3(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(N)cc1C1CC1
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1C1CC1

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (871 mg), bis(tricyclohexylphosphine)palladium(II)dichloride (136 mg), tripotassium phosphate (3.98 g) and cyclopropylboronic acid (863 mg) were added toluene (10 mL) and water (0.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (ethyl acetate:hexane) to give methyl 2-cyclopropyl-4-nitrobenzoate (285 mg). The obtained methyl 2-cyclopropyl-4-nitrobenzoate (285 mg) was dissolved in a solution of ethyl acetate and ethanol, and catalytic hydrogenation was performed using palladium carbon to give methyl 4-amino-2-cyclopropylbenzoate (189 mg). Using the obtained methyl 4-amino-2-cyclopropylbenzoate (189 mg) and 3-chloropropane-1-sulfonyl chloride (0.156 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (168 mg) was obtained.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:24][CH2:23][S:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:19]1=[O:31]>C(Cl)Cl>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:24][CH2:23][S:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:19]1=[O:31])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: CCOC(=O)CN1CSCCC(N)C1=O
Solvent: ClCCl
Product: CCOC(=O)CN1CSCCC(NP(=O)(CCCCc2ccccc2)OCC)C1=O

Procedure:
A mixture of crude chloro(4-phenylbutyl)phosphinic acid, ethyl ester, dry methylene chloride and 5-amino-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester are reacted as set forth in Example 1(f). Work up of the reaction mixture according to Example 1(f) yields 5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester.