Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:22]2[NH:18][N:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide (2.0 g, 6.43 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (1.44 g, 12.9 mmol), Pd(PPh3)4 (0.74 g, 0.643 mmol), and potassium carbonate (2.67 g, 19.3 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (ethyl acetate:hexane, 1:1) to provide 4-methyl-2-(2H-Pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (1.25 g, 66% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.31-7.36 (m, 4H), 7.24-7.27 (m, 1H), 6.78 (d, J=4.0 Hz, 1H), 4.44 (d, J=4.0 Hz, 2H), 2.60 (s, 3H); MS (M+H)+=299.1; Rt=1.06 min; HRMS (M+H)+=299.10.
Reaction SMILES: C1(N[C:8]2[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17](C4C=CC(C(OCC)=O)=CC=4)[CH2:16][CH2:15]3)[N:13]=2)CCCCC1.[C:34]1([N:40]=C=O)C=CC=[CH:36][CH:35]=1>O1CCCC1>[N:14]1([C:12]2[N:13]=[C:8]([CH2:36][CH2:35][CH2:34][NH2:40])[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: NCCCc1nc(N2CCNCC2)nc2c1SCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
0.330 g (1.0 mmol) of cyclohexyl-(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-amine (VI) and 0.115 mL (1.0 mmol) of phenyl isocyanate are placed in 12.5 mL of tetrahydrofuran, then stirred for 1 hour at ambient temperature. Then the reaction mixture is concentrated by evaporation. The residue is stirred with water, suction filtered, washed with water and petroleum ether, then dried. The crude product is purified by chromatography through a 25 g silica gel cartridge with a solvent mixture of petroleum ether/ethyl acetate 1/1. 0.240 g of product VII (53%) is obtained as a powder (m.p. 207-210° C.). 1H NMR (400 MHz, DMSO): 8.51 (1H, s); 7.47 (2H, d); 7.23 (2H, t); 6.92 (1H, t); 6.11 (1H, d); 3.91-3.78 (1H, m); 3.69-3.59 (4H, m); 3.53-3.44 (4H, m); 3.22 (2H, t); 2.98 (2H, t); 1.92-1.78 (2H, m); 1.79-1.67 (2H, m); 1.65-1.56 (1H, m); 1.37-1.21 (4H, m); 1.18-1.04 (1H, m).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])[CH3:41]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])[CH3:41])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: C[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 82.9 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation 2(3) and N-L-alanyl-L-threonine (303 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-alanyl]-L-threonine (164 mg) was obtained as powder according to similar manner to that of Example 12.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([O:7]C(C)(C)C)=[O:6]>Cl.O1CCOCC1>[CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:12][CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](NCC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.022 g, 4.57 mmol) and pivalaldehyde (0.502 mL, 4.57 mmol) were combined in dichloromethane (25 mL). Acetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 5 minutes, then PS-cyanoborohydride (3.90 g, 9.14 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the solvent was removed in vacuo. The crude material was diluted with dichloromethane and basified using saturated aqueous sodium bicarbonate to give (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.04 (t, J=7.4, 1H), 2.40 (d, J=11.1, 1H), 2.09 (d, J=11.1, 1H), 1.86-1.70 (m, 1H), 1.46 (s, 10H), 1.40 (t, J=7.2, 3H), 0.95-0.89 (m, 6H), 0.89 (s, 9H). (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(neopentylamino)pentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89-8.37 (m, 1H), 8.34-8.03 (m, 1H), 3.82 (t, J=6.5, 1H), 2.88 (d, J=12.3, 1H), 2.62 (d, J=12.2, 1H), 1.83-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.00 (s, 9H), 0.97-0.88 (m, 6H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:14])[NH:9][CH2:10][C:11](N)=[O:12].[CH2:16](I)[CH3:17]>>[CH2:16]([S:14][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:15])[C:11](=[O:12])[CH2:10][N:9]=1)[CH3:17]
Reactant: CCI
Reactant: Cc1ccccc1NC(=S)NCC(N)=O
Product: CCSC1=NCC(=O)N1c1ccccc1C
Yield: 57.9 %

Procedure:
The title compound was prepared by the procedure described in Example 6 using 11.2 g of 2-[3-(2-tolyl)-thioureido]-acetamide and 15.6 g of ethyl iodide. Crystallization from ethyl acetate afforded the hydrochloride salt of the title compound as a white solid (6.8 g), m.p. 156°-158° C. (dec.). Anal. Calcd. for. C12H14N2O S . HCl: C, 53.23; H, 5.58; N, 10.34. Found: C, 52.96; H, 5.49; N, 10.25. Mass spectrum (EI, M.+) m/z 234. 1H-NMR (DMSO-d6 ; 400 MHz) 88.75 (broad s, 2 H), 7.43 (m, 2 H), 7.35 (m, 1 H), 7.30 (m, 1 H), 4.53 (q, 2 H), 3.18-3.20 (m, 2 H), and 1.29 ppm (t, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:43]3[CH2:42][CH2:41][N:40]([C:37]4[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=4)[CH2:45][CH2:44]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCN(c4ccc(F)cc4)CC3)cc2F)CC1
Yield: 19.2 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using 1-(4-fluorophenyl) piperazine (5.9 g) as an amine to yield the titled compound (396 mg, 19%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.[NH2:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19]([NH2:21])=[O:20].O[NH-].O=[N-]>>[NH2:21][C:19](=[O:20])[C:18](=[O:22])[CH:17]([NH:16][C:13]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1c1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1c1ccccc1

Procedure:
Coupling of (R)-5-Oxo-1-phenyl-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]2O.[C:26]1([O:32][CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:33][O:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]2
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: COc1ccccc1
Agent: CCCCCON=O
Product: CCOC(=O)C1=NNc2ccc(-c3ccccc3OC)cc2C1

Procedure:
Amyl nitrite (2 ml.) was added to a stirred suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (2 g.) in anisole (250 ml.). The suspension was stirred and heated on a steam bath for 3 hours. The resulting solution was filtered whilst hot and the filtrate was evaporated. The residue was applied to a silica column (100 g. of Kieselgel 60) and eluted with a 10% v/v mixture of dry ethanol and chloroform. The appropriate fractions were evaporated, the residual solid [ethyl 4-hydroxy 6-(methoxyphenyl)cinnolin-3-yl carboxylate] was dissolved in thionyl chloride (50 ml.), and dimethylformamide (5 drops) added. The solution was heated under reflux until gaseous evolution ceased. The solution was then evaporated under reduced pressure, the residue dissolved in dry toluene (20 ml.), and the solution evaporated to dryness. The residue was dissolved in a mixture of dimethylformamide (2 ml.) and ethyl acetate (50 ml.), and sodium borohydride (0.5 g.) was added. The mixture was stirred for 2 hours at room temperature and then added to a mixture of N-hydrochloric acid (10 ml.) and ethyl acetate (50 ml.). The mixture was separated and the ethyl acetate layer was washed with water (3× 20 ml.), dried (MgSO4), and filtered. There was thus obtained the solution of ethyl 6-(methoxyphenyl)-1,4-dihydrocinnolin-3-yl carboxylate (believed to be a mixture of isomers varying in the position of the methoxy radical on the phenyl substituent) which was used as starting material in this Example.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16].Cl>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:15]([OH:16])([CH3:17])[CH3:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(O)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (25 g, 142 mmol) in diethylether (600 ml) was slowly added n-butyllithium (2.5 M in hexane, 56.8 ml, 142 mmol) at −78° C. under a nitrogen atmosphere. The resulting yellow reaction mixture was stirred at −78° C. for 2 hours and dry acetone (11.47 ml, 156 mmol) was added over 30 minutes. Stirring was continued at −78° C. for 1 hour. HCl (2N, 50 ml) was added and the reaction mixture was warmed to 0° C. The pH of the mixture was adjusted to ˜7 with 2N HCl solution. The reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (29.36 g) was chromatographed over silica gel (cyclohexane:ethyl acetate 9:1): 22.3 g (67.1% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.33; LCMS RtH5=0.89 min (ES+ 234, 236). 1H-NMR (360 MHz, DMSO-d6): 7.72-7.62 (m, 2H), 5.27 (s, 1H, OH), 1.50 (s, 6H, 2×CH3).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(-c3ccc(C)cc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccc(OCc3ccc(C(=O)O)o3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid ethyl ester (2.00 g, 5.9 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added to a solution of lithium hydroxide monohydrate (0.476 g, 11.3 mmol) in water (15 mL). Methanol (5 mL) and tetrahydrofuran (10 mL) were added, and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated, and the residue was suspended in water and acidifed to pH 2.5 with 1 M HCl. The resulting white solid was filtered off, and twice suspended in ethyl acetate and evaporated to give 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (1.6 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([NH:10][CH:11]=[C:12]2[C:17](=[O:18])OC(C)(C)OC2=O)=[CH:8][CH:9]=1)=[O:4]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[NH:10][CH:11]=[CH:12][C:17](=[O:18])[C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)o1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2o1
Temperature: 200 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
After adding 5-[(2,2-dimethyl-4,6-dioxo-[1.3]dioxan-5-ylidenemethyl)amino]furan-2-carboxylic acid methyl ester (4.0 g) to Dowtherm A (30 ml), the mixture was heated and stirred at 200° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:42])=[CH:38][CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH:38]=[C:37]([CH3:42])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: CC(C)=CCCO
Agent: N
Product: CC(C)=CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-3-penten-1-ol in place of isobutanol (yield: 0.1165 g, 77%). mp 111-114° C. 1H NMR (300 MHz, DMSO d6) δ 1.46 (s, 3H), 1.56 (s 3H), 2.26 (m, 2H), 3.30 (s, 1H), 4.43 (t, J=7 Hz, 2H), 4.96 (m, 1H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 443 (M+H)+, 460 (M+NH4)+. Anal. calc. for C23H23FN2O4S: C, 62.43; H, 5.24; N, 6.33. Found: C, 62.32; H, 5.30; N, 6.25.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][C:11](OC(C)=O)=[O:12]>CC(O)=O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[CH3:10])=[C:4]([F:9])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1F
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoroaniline (50.0 g, 344 mmol) in AcOH (30 mL) is added Ac2O (60 mL) and the reaction is stirred at room temperature for 2 hours. The mixture is poured into ice water (500 mL) to give a solid precipitate. The mixture is stirred for an additional 1 hour at room temperature. The solid is filtered and washed with water and hexanes, then air dried to give N-(4-chloro-2-fluorophenyl)acetamide.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]=[C:20]2[CH3:44])=[CH:15][CH:14]=1)([CH3:11])[CH3:10].O>CS(C)=O>[CH:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:3][C:4](=[O:7])[O:5][N:40]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]=[C:20]2[CH3:44])=[CH:17][CH:18]=1)([CH3:11])[CH3:10]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a suspension of hydroxylammonium chloride (186 g) in dimethyl sulfoxide (1340 mL) was added sodium hydrogen carbonate (280 g) at 50° C. and stirred for 30 min, and then 4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (160 g) was added to the mixture. After being stirred at 90° C. for 18 hr, the mixture was allowed to cool to room temperature and the mixture was poured into iced water. The mixture was stirred for 30 min and the precipitate was collected. The solid was washed with water and dried in vacuo at 80° C. The solid was dissolved in tetrahydrofuran (1300 mL), N,N′-carbonyldiimidazole (65 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (60 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (152 g, 85%).
Reaction SMILES: [OH:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@@:5]3([OH:23])[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[C:24]([O:28]C(=O)CC)(=[O:27])[CH2:25][CH3:26].C(Cl)(=O)C1C=CC=CC=1>>[OH:23][C@:5]12[C@H:4]3[C@@H:13]([C@:14]4([CH3:21])[C:19]([C:2](=[O:1])[CH2:3]3)=[CH:18][C:17](=[O:20])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C@:9]1([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]2.[C:24]([O-:28])(=[O:27])[CH2:25][CH3:26]
Reactant: C[C@]12CCC(=O)C=C1[C@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12O
Reactant: CCC(=O)OC(=O)CC
Solvent: O=C(Cl)c1ccccc1
Product: CCC(=O)[O-]
Product: C[C@]12CCC(=O)C=C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12O

Procedure:
The above compounds can be synthesized by the methods described in Japanese Patent Application Laid-Open Nos. 192794/1988 and 131193/1989. That is, 14α-hydroxy-4-androstene-3,6,17-trione is synthesized from 6β,14α-dihydroxy-4-androstene-3,17-dione according to an ordinary oxidation reaction (for example, Jones' oxidation reaction) and then is reacted with propionic anhydride or benzoyl chloride to obtain a propionate or a benzoate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1nc(-c2ccccc2)co1
Yield: 92.2 %

Procedure:
To a solution of ethyl 4-phenyl-2-oxazolepropionate (1.4 g) in THF (20 ml) was added sodium borohydride (0.86 g). Methanol (4 ml) was dropwise added to the mixture over a period of 10 minutes under reflux. The reaction mixture was refluxed for further 30 minutes, concentrated, made acidic and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and distilled to obtain crystals of 3-(4-phenyl-2-oxazolyl)propanol (1.07 g, 92%). Recrystallization from ether-hexane gave colorless prism crystals of mp 55°-56° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[F:18])[C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:7])#N.[OH2:19].S(=O)(=O)(O)[OH:21]>>[F:18][C:17]1[C:3]([C:1]([OH:21])=[O:19])=[CH:4][C:5]([C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:7])=[CH:15][CH:16]=1
Reactant: O
Reactant: CCCN(CCC)C(=O)c1ccc(F)c(C#N)c1
Reactant: O=S(=O)(O)O
Product: CCCN(CCC)C(=O)c1ccc(F)c(C(=O)O)c1
Temperature: 150 °C

Procedure:
Dissolve 3-cyano-4-fluoro-N,N-dipropylbenzamide (0.52 g, 2.1 mmol) in a 3:1 solution of concentrated sulfuric acid:water (5 mL). Heat at 150° C. until no starting material remains. Cool to room temperature, pour into water and extract with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound that is used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-:21].[Na+]>CS(C)=O>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([O:9][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:12])=[O:21])=[CH:15][CH:16]=2)[CH:6]([CH3:8])[CH3:7])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)C(Oc1ccc([N+](=O)[O-])cc1)C(C)(C)COc1ccc([N+](=O)[O-])cc1

Procedure:
146 g (1 mol) 2,2,4-trimethyl-1,3-dihydroxypentane, 346.5 g (2.2 mols) 4-nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted using the same procedure described in Example 1 in 600 ml DMSO.