Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][CH:9]2[C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][CH:7]=1.O[Li].O.CO>O>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][CH:9]2[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCC(=O)N1c1cccc(O)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)C1CCC(=O)N1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of methyl 1-(3-hydroxyphenyl)-5-oxo-2-pyrrolidinecarboxylate (10.00 g, 42 mmol), LiOH.H2O (5.36 g, 128 mmol), MeOH (200 mL) and H2O (50 mL) was stirred at room temperature for about 1 hour. The MeOH was removed in vacuo and the residue diluted with H2O and 2N HCl solution to pH=1. The solid was filtered off, dried in air and suspended in hot CH3CN (200 mL). Filtration gave 1-(3-hydroxyphenyl)-5-oxo-2-pyrrolidinecarboxylic acid (8.06 g, 85%), mp 183-185° C. IR (KBr) 3600-2300 (OH), 1710 (CO2H), 1695 (CONH) cm-1. 1H NMR (DMSO-d6/CDCl3) δ2.05 to 2.15 (1H, m, pyrrolidine ring H), 2.30-2.50 (3H, m, pyrrolidine ring H), 4.58 (1H, dd, J=9 Hz, J'= 2 Hz, CHCO2H), 6.52 (1H, dd, J=8 Hz, J'=2 Hz, aromatic H), 6.81 (1H, dd, J=8 Hz, J'=2Hz, aromatic H), 7.02 to 7.08 (2H, m, aromatic H), 9.16 (1H, bs, OH); MS m/z 222 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH:12](C)[CH2:13][CH2:14][N:15]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:23]=3)[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-].O.Cl.[CH2:39]1COCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:39])[CH2:12][CH2:13][CH2:14][N:15]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:23]=3)[CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CCOC(=O)CN(CCC(C)NCc1ccc2c(c1)OCO2)c1cc(C)nc(-n2ccnc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N(CCCN(C)Cc2ccc3c(c2)OCO3)CC(=O)O)nc(-n2ccnc2)n1
Reaction time: 16 h

Procedure:
To 2-[[3-[(1,3-benzodioxol-5-ylmethyl)amino](methyl)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, ethyl ester (2.2 g, 4.6 mmol) (a compound of formula (Yc10)) dissolved in THF (50 mL) was added LiOH (0.34 g, 8.1 mmol) and water (10 mL). After stirring for 16 hours, the solvent was removed in vacuo and 1 N HCl (8.1 mL, 8.1 mmol) was added. The solvent was removed in vacuo to give 2-[[3-[(1,3-benzodioxol-5-ylmethyl)(methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, a compound of formula (Yc11).
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].CN([CH:24]=[O:25])C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:6]([C:7]([CH3:15])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[CH:24]([OH:25])[C:16]=2[CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)NC(C)(C)c2ccccc2)c(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc2c(c(Cl)n1)C(=O)N(C(C)(C)c1ccccc1)C2O
Yield: 59.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 2-chloro-6-methyl-N-(1-methyl-1-phenylethyl)nicotinamide (500 mg, 1.73 mmol) was dissolved in THF (20 mL), and the solution was treated with n-butyllithium-hexane solution (2.71 mol/L, 4.33 mL, 3.23 mmol) and DMF (0.335 mL, 4.33 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=80/20 to 75/25) to obtain 4-chloro-1-hydroxy-6-methyl-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (326 mg, yield 59%).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]([CH3:32])[C@H:20]2[CH2:24][CH2:23][C@@H:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)[CH2:21]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]([CH3:32])[C@H:20]2[CH2:24][CH2:23][C@@H:22]([N:25]3[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]3)[CH2:21]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: CC1CCN([C@@H]2CC[C@H](N(C)S(=O)(=O)c3cccc(OCc4ccccc4)c3)C2)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1CCN([C@@H]2CC[C@H](N(C)S(=O)(=O)c3cccc(O)c3)C2)CC1
Yield: 90.1 %

Procedure:
cis-3-Benzyloxy-N-methyl-N-(3-(4-methylpiperidin-1-yl)cyclopentyl)benzenesulfonamide hydrochloride (Example 8) (64.7 mg, 0.135 mmol) in methanol (10 ml) was hydrogenated over 20% palladium hydroxide on carbon (38 mg) at 45 psi for 3.5 hours. The mixture was filtered and concentrated in vacuo. Recrystallization from methanol-ethyl acetate gave the title compound (47.3 mg, 90%) as a white solid; δH (400 MHz, CD3OD) 1.00 (3H, d, J 6.4 Hz), 1.44 (2H, m), 1.65-1.82 (5H, m), 1.91 (2H, m), 2.07-2.08 (2H, m), 2.79 (3H, s), 2.90 (2H, m), 3.50 (3H, m), 4.40 (1H, m), 7.04 (1H, m), 7.19 (1H, t, J 2.0 Hz), 7.26 (1H, m), 7.39 (1H, t, J 8.0 Hz); m/z (ES+) 353 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:11]
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Reactant: C1CCNCC1
Product: NC(=O)C(CCC(=O)O)(CCC(=O)N1CCCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
0.3 g of 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid of S configuration is treated with piperidine as described in Preparation 3 to give 0.3 g of the expected compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: Cc1c(C)n(Cc2ccccc2)c2c(Cl)nccc12
Yield: 42 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 42%)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH2:13][C:14]1[CH:22]=[CH:21][C:17]2[NH:18][N:19]=[N:20][C:16]=2[CH:15]=1.C([BH3-])#N.[Na+].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl.[OH-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[NH:18]1[C:17]2[CH:21]=[CH:22][C:14]([NH:13][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:15][C:16]=2[N:20]=[N:19]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1ccc2cc(CNc3ccc4[nH]nnc4c3)ccc2c1

Procedure:
The general procedure employed was as follows. Naphthalene-2-carbaldehyde (624 mg, 4 mmol) in methanol (25 ml) was added to a solution of 5-amino-1H-benzotriazole in methanol (25 ml) that had been adjusted to pH 6 by the addition of glacial acetic acid (1 ml). Sodium cyanoborohydride (1.89 g, 30 mmol) was added and the resulting mixture was stirred at room temperature overnight by which time TLC (A) and ninhydrin development indicated the conversion of starting materials. Hydrochloric acid (50% HCl/H2O, 5 ml) was added and the solution was neutralised to pH 7 by addition of NaOH (1M). Methanol was removed in vacuo to afford an aqueous residue that was dissolved in ethyl acetate (50 ml) and extracted with sodium chloride solution (4×20 ml). Purification by column chromatography, eluting with methanol (0-10%) in dichloromethane afforded [11] as a pale yellow oil. Trituration from diethyl ether afforded [11] as a white solid (880 mg, 80%). Rf (A) 0.42 δH(400 MHz; DMSO-d6 {D2O shake}) 4.50 (2H, s, CH2) 6.45 (1H, s, BT) 6.89 (1H, s, NH, disappeared) 6.91 (1H, d, J8.9, BT) 7.43-7.49 (2H, m, Ar—H) 7.54 (1H, d, J8.6, Nap) 7.65 (1H, d, J8.9, BT) 7.82-7.89 (4H, m, Nap) 14.72 (1H, s, NH, disappeared); m/z (EI−HR) 274.12177 [(M calc. for C17H14N4 274.12185].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 10.88 g (0.16 mol) of imidazole in 150 ml of dry DMF at 0° C. under argon was added 6.4 g (0.16 mol) of 60% NaH, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. The mixture was cooled to 0° C., and 25 g (0.16 mol) of p-methoxybenzyl chloride was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, concentrated in vacuo to yield 35.6 g of a crude product which was purified by chromatography on silica (methylene chloride/methanol 9:1) to afford 25.3 g (84.2%) of 1-(p-methoxybenzyl)-imidazole.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:13]=O)[C:11]=1[OH:12].[CH:16](B(O)O)=[CH:17][CH2:18][CH2:19][CH3:20].C(NCC1C=CC=CC=1)C1C=CC=CC=1.O>O1CCOCC1>[F:15][C:3]1[C:2]([F:1])=[C:11]2[C:10]([CH:13]=[CH:16][CH:17]([CH2:18][CH2:19][CH3:20])[O:12]2)=[C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=12
Reactant: CCCC=CB(O)O
Reactant: Cc1cc2c(C=O)c(O)c(F)c(F)c2o1
Agent: c1ccc(CNCc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
4.0 g (18.9 mmol) of 6,7-difluoro-5-hydroxy-2-methylbenzofuran-4-carbaldehyde are stirred for 20 h at 90° C. together with 2.79 g (24.5 mmol) of 1-penteneboronic acid and 0.72 ml (3.73 mmol) of dibenzylamine in 95 ml of 1,4-dioxane. Water is added to the reaction mixture, which is then extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is firstly purified by column chromatography (SiO2, 1-chlorobutane) and subsequently crystallised from methanol, giving 4,5-difluoro-2-methyl-7-propyl-7H-furo[3,2-f]chromene as a yellow, crystalline solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:19][CH2:20][CH2:21][C:22](=O)[CH2:23][C:24]([O:26][CH3:27])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:20]([OH:19])=[CH:21][C:22]([CH2:23][CH2:24][O:26][CH3:27])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Reactant: COCCC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: COCCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Yield: 61 %

Procedure:
A solution of 2.69 g (10 mmol) of) 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 1.6 g (10 mmol) of methyl 5-methoxy-3-oxo-valerate in 10 ml of acetic acid was heated at reflux for 4 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 80 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 2.40 g (61%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+]=[N-].CO.[Cl-].[NH4+]>[Zn].O1CCCC1>[NH2:1][C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[N:8]=1
Reactant: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1sc(N)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 0.6727 g (2.147 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 20 mL of methanol and 20 mL of tetrahydrofuran was added 1.42 g (21.8 mg-atom) of zinc and 2.84 g (53.1 mmole) of ammonium chloride. The mixture was stirred vigorously for 1 hour and then filtered through Diatomaceous earth, washing the pad with methanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure and then diluted with 350 mL of ethyl acetate, washed three times with 75 mL of water, once with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 0.6276 g of 2-amino-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.47) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH:4]([C:6]([C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)=[CH:7][CH3:8])[CH3:5].Cl>[Pd].C(O)C>[CH3:26][N:2]([CH3:1])[CH2:3][CH:4]([CH3:5])[CH:6]([C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=1)[CH2:7][CH3:8]
Reactant: CC=C(c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1)C(C)CN(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCC(c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1)C(C)CN(C)C
Reaction time: 10 h
Yield: 87 %

Procedure:
A mixture of [1RS]-toluene-4-sulfonic acid 3-[1-(2-dimethylamino-1-methyl-ethyl)-propenyl]-phenyl ester (10 g, 0.03 mol), ethanol (38 ml), concentrated hydrochloric acid (4.5 ml, 30%) and Pd/C (10%, 3 g) was hydrogenated at 5 kg/cm2 for 10 hours. The reaction mixture was filtered through hyflo bed and the filtrate was distilled off to remove ethanol. Water (40 ml) was added to the resulting residue at ambient temperature and reaction mixture was washed with isopropyl ether (2×15 ml). Aqueous sodium carbonate (23 ml, 20%) was added to the reaction mixture till pH 7-8 and saturated with sodium chloride (3.5 g). Resulting product was extracted with dichloromethane (3×50 ml). All organic extracts were combined, washed with brine, dried and solvent distilled off to give 9.8 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:15])[CH2:12][O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])[CH2:12][O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@@H](N)CCOCc1ccccc1
Reactant: COC(C=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CO
Solvent: CC(=O)O
Product: COC[C@H](CCOCc1ccccc1)NCC(OC)OC
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a solution of (S)-3-benzyloxy-1-methoxymethyl-propylamine (1.34 g, 6.40 mmol) in methanol (25 mL) were added dimethoxyacetaldehyde solution (45% in tert-butyl methyl ether, 1.81 mL, 7.04 mmol), magnesium sulfate (6.94 g, 57.6 mmol), acetic acid (1.54 g, 25.6 mmol), and sodium cyanoborohydride (551 mg, 8.32 mmol), then after 4 h the reaction mixture was cooled to 0° C. and treated with another portion of dimethoxyacetaldehyde solution (45% in tert-butyl methyl ether, 0.22 mL, 0.96 mmol). The ice bath was removed, then after 2 h the reaction was stopped by careful addition of sat. aq. sodium hydrogencarbonate solution. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate, the organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol 19:1) furnished the title compound (1.60 g, 84%). Light yellow liquid, MS (ISP)=298.3 (M+H)+.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[CH:18][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[N:19]1[C:12]2=[C:11]3[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=[C:16]3[CH:15]=[CH:14][N:13]2[CH2:17][CH:18]=1
Reactant: CCOC(=O)C(=Cc1cccn2ccnc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC=N3

Procedure:
From 6a (yield: 84%); mp 154-156° C.; IR (KBr) 3276, 2924, 1684, 1252 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.38 (t, 3H, J=7 Hz), 4.38 (q, 2H, J=7 Hz), 7.05 (d, 1H, J=7 Hz), 7.36 (s, 1H), 7.40 (s, 1H), 7.88 (s, 1H), 8.32 (d, 1H, J=7 Hz), 12.53 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 60.4, 101.5, 106.5, 113.5, 113.7, 124.5, 125.6, 130.3, 133.0, 140.7, 160.6; MS m/z 229 (M+, 73), 183 (100), 155 (20), 129 (9). Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 63.11; H, 4.75; N, 18.22.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[C:4]([N:13]([CH3:15])[CH3:14])=[N:5][CH:6]=[N:7]2.[H-].[Na+].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[C:18]([O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][N:5]=[C:4]2[N:13]([CH3:15])[CH3:14])(=[O:21])[CH:19]=[CH2:20]
Reactant: CN(C)c1ncnc2c(O)ccc(Cl)c12
Reactant: C=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CC(=O)Oc1ccc(Cl)c2c(N(C)C)ncnc12
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-chloro-4-(dimethylamino)-8-quinazolinol (0.65 g, 2.91 mmol) in N,N-dimethylformamide is treated in a single portion with a 60% sodium hydride dispersion in mineral oil (0.13 g, 3.25 mmol) at 50° C., stirred for 10 minutes, cooled to 10° C., treated with a solution of acryloyl chloride (0.29 g, 3.20 mmol) in tetrahydrofuran, stirred for 1 hour and diluted with ethyl acetate. The organic solution is washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and an ethyl acetate/heptane mixture gives the title product as a white solid, 0.42 g, mp 95°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#N)[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:12][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2[nH]ccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under a hydrogen pressure of 45 psi, 17.70 g (91.7 mmol) of the compound obtained in Step A and 2.5 g of palladium-on-carbon suspended in 300 ml of ethanol are stirred for 5 hours at room temperature. After filtration over Celite and evaporation, the residue is purified over silica gel (eluant:petroleum ether/ethyl acetate, 4:1) to yield the title product in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-cyano-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K26) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (305 mg, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]2[N:18]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15][CH:16]=2)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (Example 91, 430 mg, 0.95 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (5 mL). The resulting solution was stirred for 30 minutes at room temperature. The mixture was then evaporated to dryness in vacuo to afford the desired product as a pale yellow solid.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]2[NH:25][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:26][CH:27]=1)([O-:19])=[O:18]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccccc1
Yield: 34.9 %

Procedure:
Ethyl 2-hydroxyimino-3-phenyl-3-oxopropionate (36.1 g) and 4-nitrobenzylamine (27.9 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-nitrophenyl)-5-phenylimidazole-4-carboxylate (19.2 g). 18.0 g therefrom was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-nitrophenyl)-5-phenylimidazole-4-carboxylic acid (12.8 g), melting point 175-178° C. (decomposition).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a 500 mL 3-necked flask equipped with reflux condenser, addition funnel, nitrogen inlet and magnetic stirring was added 50.0 g (0.277 mol, 1.0 eq.) 4-iodophenol (Aldrich), 37.69 g (0.2727 mol, 1.2 eq.) potassium carbonate (Fischer) and 250 mL dimethylformamide (DMF) and the mixture was heated to 65° C. for 20 minutes. To the addition funnel was added 48.61 g (0.284 mol., 1.25 eq) benzylbromide (Aldrich) and 50 mL DMF. The heat was turned off and the contents of the addition funnel were added dropwise over 15 minutes during which time an exotherm to 75° C. was produced with salt formation. Heating was resumed at 45° C. for an additional 20 hours after which liquid chromatography (LC) indicated complete conversion. The mixture was poured onto ice and extracted with Et2O, dried over sodium sulfate (Na2SO4), reduced in vacuo and recrystallized from ethanol giving 44.2 g of 1 as tan crystals (m.p.=55°-56° C.) in 63 percent isolated yield (99 percent by LC). It had the following spectral properties. 1H NMR (250 MHz, CDCl3): δ4.82 (s,2H), 6.54 (d), 7.12-7.2 (m), 7.34 (d). 13C NMR (63 MHz, CDCl3 : δ70.1, 117.3, 127.4, 128.1, 128.6, 136.5, 138.2, 158.7. HRMS m/z (EI) calcd (found) for C13H11 OI=309.9855 (309.9851).