Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl>N1C=CC=CC=1>[C:2](=[N:4][O:5][C:7]1[N:9]=[C:10]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:12]=[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:6]=1)([CH3:3])[CH3:1]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)=NO
Solvent: c1ccncc1
Product: CC(C)=NOc1nc(ON=C(C)C)nc(ON=C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a cold (0° C.) solution of acetone oxime (2.92 g, 0.04 mol) in dry pyridine (15 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 35° C. The solution is then stirred for 5 h at room temperature and then poured into 100 ml of ice-cold water. The resulting emulsion is extracted with dichloromethane (5×20 ml), the extracts are dried over MgSO4 and the solvent is evaporated. The residue is chromatographed (silica gel, CH2Cl2—C2H5O(CO)CH3 7:3) and the pure fraction is recrystallized from dichloromethane-hexane to afford 2.79 g of the title compound as a white solid, mp. 156-158° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1>>[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCC1CCC(F)(F)CC1
Product: N#Cc1ccnc(-n2nccc2OCC2CCC(F)(F)CC2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4,4-difluorocyclohexyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.40-1.43 (2H, m), 1.66-1.74 (2H, m), 1.84-1.88 (3H, m), 2.08-2.11 (2H, m), 3.97 (2H, d, J=6.0 Hz), 5.62 (1H, d, J=1.6 Hz), 7.33 (1H, d, J=4.8 Hz), 7.50 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.61 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H16F2N4O, 319. Found, 319.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[C:8]([NH2:34])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1NC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Reaction time: 2 h

Procedure:
A solution of N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (9.10 g, 26.2 mmol) in 200 mL of chloroform was placed under an atmosphere of nitrogen and cooled in an ice water bath. The solution was treated with MCPBA (8.28 g, 28.8 mmol, 77% max) and allowed to slowly come to ambient temperature. After 2 h, LC/MS and HPLC indicated complete conversion to the 5-N-oxide intermediate. The reaction mixture was again cooled in an ice water bath. The reaction mixture was treated with ammonium hydroxide solution (50 mL, 30%) and stirred vigorously. The mixture was treated with p-toluenesulfonyl chloride (5.24 g, 27.5 mmol) and allowed to come to ambient temperature. After 30 min, the reaction was diluted with 50 mL of water, and the phases were separated. The organic portion was washed with water (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown solid. The solid was purified by chromatography (SiO2, 95:5 CHCl3:MeOH) and then recrystallized from acetonitrile to give 4.52 g of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as off white crystals. mp 226–228° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=8.7 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.36 (dd, J=8.7, 2.1 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 6.73 (s, 2H), 3.53–3.40 (m, 1H), 2.90 (s, 2H), 1.93–1.80 (m, 2H), 1.05–1.00 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 154.9, 152.9, 146.3, 132.5, 127.8, 124.2, 123.5, 123.1, 119.7, 114.0, 79.5, 51.4, 28.2, 21.1, 20.6, 14.3; MS (APCI) m/z 362, 364 (M+H)+; Anal. Calcd for C16H20BrN5.0.25H2O: C, 52.40; H, 5.63; N, 19.09; Found: C, 52.03; H, 5.42; N, 19.14.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Br:18])[CH:13]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.CC(C)=O>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:19][C:20]3=[CH:24][CH:23]=[N:22][N:21]23)[CH:15]=[CH:16][C:17]=1[Br:18]
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Br)c(Br)c1
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(Br)c(Br)c1)n1nccc1N2
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A solution of 1,3-cyclohexanedione (0.11 g, 1 mmol), 3,4-dibromobenzaldehyde (0.26 g, 1 mmol) and 3-aminopyrazole (0.11 g, 1.27 mmol) in ethanol (10 mL) was heated at 80° C. in a sealed 20 mL vial for 3 days. After the reaction mixture was allowed to cool to ambient temperature, the resulting solid was isolated by filtration and recrystallization from acetone to provide 0.23 g (56%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(C)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Bromo-2-chloro-6-methylphenol (50 g, 0.225 mole) and K2CO3 (31.8 g, 0.23 mole) were combined in acetone (300 ml). Dimethyl sulfate (32 ml, 0.34 mole) was added dropwise and the mixture stirred 22 hours at room temperature, filtered and concentrated to an oil in vacuo. The oil was taken up in 250 ml ether, washed 2×2N NaOH, 1×saturated NaHCO3, 2×brine, dried over MgSO4, reconcentrated to an oil and distilled to yield purified title product, 42.9 g, b.p. 122°-124°/0.9 mm, pnmr/CDCl3 /delta/TMS: 2.3 (s, 3H), 3.8 (s, 3H), 7.3 (q, 2H).
Reaction SMILES: CN1C(=O)CC(=O)N(C)C1=O.C([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[C:18]([F:31])[CH:17]=1)C=C>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:31][C:18]1[CH:17]=[C:16]([OH:15])[CH:30]=[CH:29][C:19]=1[CH2:20][O:21][CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[N:25]1
Reactant: C=CCOc1ccc(COCCn2ccnn2)c(F)c1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(COCCn2ccnn2)c(F)c1
Reaction time: 24 h
Yield: 56.1 %

Procedure:
To a solution of 10.4 g (66.9 mmol) 1,3-dimethyl-pyrimidine-2,4,6-trione and 774 mg (0.67 mmol) tetrakis-(triphenylphosphine)-palladium in 100 ml dichloromethane was added dropwise a solution of 6.18 g (22.3 mmol) 1-[2-(4-allyloxy-2-fluoro-benzyloxy)-ethyl]-1H-[1,2,3]triazole in 30 ml dichloromethane and stirring was continued for 24 hours at 40° C. It was allowed to cool down over night. The reaction mixture was extracted with three 100 ml portions of sodium bicarbonate solution, the organic extract was dried, evaporated and purified by chromatography on silica (ethyl acetate/dichloromethane 3:7) to yield 2.97 g (56%) 3-fluoro-4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol as oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([OH:18])[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH:7]=[CH:8][CH:9]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([O:18][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: C1=COCCC1
Reactant: COc1cccc([C@H](O)C[C@H]2CCCN2C)c1
Agent: Cl
Product: COc1cccc(C(CC2CCCN2C)OC2CCCCO2)c1

Procedure:
0.3 g of (R*,R*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol-hydrochloride, one drop of etheral hydrochloric acid and 3.5 ml of 3.4-dihydro-2H-pyran are stirred for 24 hours at room temperature and subsequently concentrated to 0.39 g of the oily hydrochloride of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=[N:26][C:20]#[N:21]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)C1CCC2(CC(=NC#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (250 mg, 0.776 mmol) in DCM (10 mL) was added TiCl4 (1.55 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.38 mL, 1.707 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (250 mg, 93%). 1H-NMR (CDCl3): 0.82 (m, 6H), 1.36 (m, 2H), 1.69 (m, 3H), 1.96 (m, 3H), 3.10 (d, 2H), 6.75 (m, 1H), 7.52 (m, 1H), 8.04 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12.O.C(=O)(O)[O-].[Na+].[OH:27][C:28]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]>CO>[OH:27][C:28]1[C:35]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:34][C:31]([CH:32]=[N:2][C@@H:3]2[C:19](=[O:20])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:18])[Cl:17])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]23)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1
Reaction time: 4 h

Procedure:
To 10 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-3-cephem-4-carboxylate hydrochloride was added about 70 ml. of water. About 2.5 g. of sodium bicarbonate was added thereto and, after stirring for a while, the resultant was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated at a temperature below 35° C. The so obtained free base was dissolved in 40 ml. of methanol and 5 g. of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde was added thereto and stirring was continued at room temperature for 4 hours. The insolubles were dissolved by heating briefly and the reaction mixture was concentrated into a half amount thereof, which was then cooled to separate out crystalline substances. The substances were recovered by filtration and washed with cold methanol to give 2,2,2-trichloroethyl 7β-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-methyl-3-cephem-4-carboxylate. Yield 7 g. The product was recrystallized from a small amount of methanol to give the pure product as slightly yellow colored crystals. m.p. 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:23]3[CH2:28][CH:27]([CH3:29])[CH2:26][CH:25]([CH3:30])[CH2:24]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:23]3[CH2:28][C@H:27]([CH3:29])[CH2:26][C@H:25]([CH3:30])[CH2:24]3)[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC1CC(C)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(S(N)(=O)=O)cc3)s2)C1
Solvent: CO
Product: C[C@@H]1C[C@H](C)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(S(N)(=O)=O)cc3)s2)C1

Procedure:
(trans +) 4-(4-(4-chlorophenyl)-2-(3,5-dimethylpiperidin-1-yl)thiazol-5-yl)benzenesulfonamide (Compound 7). [α]23D: 32.32 (c=1.0, MeOH). MS: m/z 462 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[CH3:7].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Cl:1][CH2:2][C:3]([NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:6][CH3:7])=[O:4]
Reactant: CCc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cccc(C)c1NC(=O)CCl
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Chloroacetyl chloride (84.8 g) was added, over 20 minutes, to a solution of 2-ethyl-6-methylaniline (67.5 g), glacial acetic acid (230 ml), sodium acetate (anhydrous 110.5 g) in water (200 ml) at such a rate that the reaction temperature did not exceed 10° C. The resulting suspension was then stirred vigorously for 30 minutes at 10° C. (requiring the addition of further quantities of acetic acid and water to maintain fluidity). The suspension was filtered, the resulting solid was air-dried on the filter and was then recrystallised from ethanol/water to yield the N-chloroacetyl-2-ethyl-6-methylaniline as a colourless solid (58.7 g), m.p. 122°-123° C. This product (10.8 g) was dissolved in toluene and added dropwise to a stirred mixture of N-chloroacetyl-2-ethyl-6-methylaniline (21.2 g), polyethyleneglycol-400 (8.0 g), sodium hydroxide (16.0 g in 15 ml water) and toluene at such a rate to maintain the reaction temperature at 10°-15° C. for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][C:20](Cl)=[O:21]>O1CCOCC1>[OH:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[NH:1][C:20](=[O:21])[CH3:19]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c(O)cccc12
Temperature: 80 °C
Yield: 75.9 %

Procedure:
To a solution of 5-amino-1-naphthol (17.6 g; 0.11 mol) in 500 ml of dioxane, there were added 11 g of calcium carbonate (0.11 mol) and, dropwise, 8 ml of chloroacetyl chloride (0.112 mol), with stirring and under an inert atmosphere. The reaction medium was heated at 80° C. for 2 hours 30 minutes. The suspension was cooled to room temperature, filtered on sintered glass and the inorganic salts were rinsed twice with dioxane. The mixture of the organic solutions was concentrated until an insoluble product appeared, and then poured over 400 ml of ice-cold water. The precipitate formed was drained, washed once with water and once with pentane. The brown powder obtained was dried under vacuum to a constant weight to give 16.8 g of N-(5-hydroxynaphthalen-1-yl)acetamide with a yield of 76%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23](OCC)=[O:24])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23](=[O:24])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCOC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(=O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of ethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was stirred at room temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 29 mg (yield: 28%) of the title compound. Melting point: 142-143° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.[CH2:16]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)[CH3:17]>>[F:14][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH2:16][CH3:17])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:13])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccc(OCC(F)(F)F)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.05 (s, 1H), 8.84-8.80 (m, 2H), 8.25-8.21 (m, 1H), 7.73 (d, J=3.0, 1H), 7.32-7.28 (m, 1H), 7.01 (d, J=8.7, 1H), 4.86 (q, J=8.4, 2H), 4.11 (q, J=6.9, 2H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)cc(-c2cccc(F)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of methyl 3-(3-fluorophenyl)-5-methoxy-benzoate (3 g, 11.5 mmol, 1.0 eq) in a mixture of methanol (20 mL) and THF (20 mL) at 0° C. was added a solution of aqueous KOH (2M aqueous solution, 20 mL, 40 mmol, 3.5 eq). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to remove the methanol and THF then poured into water and the pH adjusted to pH 3-4 by addition of 1M HCl. The precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (2.5 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:31][CH3:32])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CCBr
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(CC)CC2)ncn1
Temperature: 60 °C
Yield: 43 %

Procedure:
To the stirred solution of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.20 g, 0.61 mmol) and potassium carbonate (0.10 g, 0.72 mmol) in DMF (3 ml) was added ethyl bromide (0.07 g, 0.05 ml, 0.61 mmol) at room temperature. The reaction mixture was heated at 60° C. for one hour. The progress of the reaction was monitored by TLC. The reaction mixture was poured onto ice water and extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether (3 ml), filtered and dried under high vacuum to afford 1-ethyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #3A) (0.093 g, 43%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: COc1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.45 g, 0.0033×1.2 mol) and sodium hydride (0.14 g, (ca.60% in mineral oil), 0.033×1.05 mol) in tetrahydrofuran, 2,6- dichloro-4-methoxypyridine (0.59 g, 0.0033 mol) was added and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:12][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 10 g of the above-obtained (tert-butoxycarbonylamino)acetothioamide in 150 ml of ethanol were added 7.3 ml of ethyl bromopyruvate and 2.7 g of calcium carbonate, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a small amount of water, and then dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and isopropyl ether was added to the residue. The crystals precipitated were collected by filtration, and dried under reduced pressure to give 11.2 g (yield 74%) of ethyl 2-(tert-butoxycarbonylamino)methylthiazole-4-carboxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:17]#[N:18])[CH2:11][CH2:10][C:9](=[O:12])[CH:8](C(OC)=O)[CH2:7]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:17]#[N:18])[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: COC(=O)C1CC(C#N)(c2cccs2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2cccs2)CCC(=O)CC1
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 8.0 g. (0.0304 mole) of 4-(2-thienyl)-4-cyano-2-carbomethoxycyclohexanone in 200 ml. acetic acid and 100 ml. 10% aqueous sulfuric acid is heated on the steam bath with mechanical stirring for 24 hours. The mixture is then allowed to cool, diluted with water and extracted thoroughly with benzene. The organic layer is washed in turn with water, aqueous sodium bicarbonate and brine and taken to dryness. The residual solid is recrystallized from methylene chloride:Skellysolve B to afford 4.10 g. (66% yield) of 4-(2-thienyl)-4-cyanocyclohexanone, m.p. 117.5°-119° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[CH:12]=[C:11]([CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[CH:12]=[C:11]([CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.9 %

Procedure:
35 g×2 batches: To a 0° C. solution of 2-(benzyloxy)-4,6-dimethylpyridine-3-carbaldehyde (Cpd X, 35.0 g, 145 mmol) in CH3OH (1000 mL) was added NaBH4 (6.60 g, 174 mmol) in portions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the residue was diluted with NaHCO3 (sat., aq.). After the bubbling had stopped, the aqueous solution was extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (petroleum ether/EtOAc) to give [2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methanol (Cpd Y, 43 g, 61%) as a colorless oil.