Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#N.[Cl:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1.C([O:22]CC)C>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=1)=[O:22]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: CCOCC
Reactant: Clc1cccc([Mg]Br)c1
Product: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To the stirred solution of 2-amino-5-chloro-benzonitrile (500 mg, 3.28 mmol) in diethyl ether (10 ml) was added 3-chloro phenyl magnesium bromide (freshly prepared 1M solution in ether, 10 ml, 9.83 mmol) drop wise at 0° C. and the resulting reaction mixture was refluxed for 1 h. Then the mixture was stirred for 16 h at 25° C., cooled to 5° C. and quenched with water followed by 2 N HCl solution (20 ml). The reaction mixture was stirred at 45° C. for 5 h and then the pH of the reaction mixture was adjusted to 8-9 with 2N aqueous NaOH solution. The mixture was extracted with diethyl ether (3×30 ml) and the combined organic extracts were washed with brine (25 ml), dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% ethyl acetate in hexane) to yield (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (550 mg, 63%) as a yellow solid. LC-MS (ESI): 266 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]=[C:16]1[NH:20][C@H:19]([CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)[CH2:18][O:17]1>C(O)(=O)C>[OH2:14].[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:25]2[C:24]3[C:28](=[CH:29][CH:30]=[C:22]([CH2:21][C@@H:19]4[CH2:18][O:17][C:16](=[O:15])[NH:20]4)[CH:23]=3)[NH:27][CH:26]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C1N[C@H](Cc2ccc3[nH]ccc3c2)CO1
Solvent: CC(=O)O
Product: O
Product: O=C1N[C@H](Cc2ccc3[nH]cc(C4=CCN(Cc5ccccc5)CC4)c3c2)CO1
Yield: 13.3 %

Procedure:
1-Benzyl-4-piperidone (Aldrich, 2.8 g) was added to a stirred suspension of (R)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indole (1.0 g), the immediate precursor of the product of Synthetic Example 16, in glac. acetic acid (20 ml) and stirred at 100° C. for 3 hours. The cooled mixture was evaporated in vacuo and the residue taken up in methanol, basified with NH4OH and evaporated in vacuo to give a dark tar. The latter was eluted through a silica column using DCM/EtOH/NH4OH (100:8:1) as eluant and treated with DCM. The resulting precipitate was filtered off to give the desired product as yellow crystals (0.25 g), mp 169°-170.5° C. Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:19])=[NH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:27][C:28]([CH3:30])=[O:29]>>[C:28]([OH:2])(=[O:29])[CH3:30].[CH2:6]([NH:14][C:15]1[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:19][C:28]([CH3:30])([CH3:27])[N:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CO
Reactant: CCCCCCCCNC(=N)NC(=N)NCCCCCC
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCCCCCC)N1

Procedure:
120 ml of methanol, 100 ml of acetone and 0.7 ml of concentrated hydrochloric acid were added to 10.0 g (27.0 mmol) of N1-octyl-N5-hexyl-biguanide dihydrochloride. The mixture was refluxed for 40 hours, and the solvent was distilled off under reduced pressure. To half amount of the residue were added 70 ml of ethanol, 46 ml of water and 6 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 3.7 g of colorless crystals having a melting point of 92 to 94° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20][C:21]([C:23]1[C:24]2[S:32][CH:31]=[C:30]([CH2:33]Br)[C:25]=2[C:26]([Cl:29])=[N:27][CH:28]=1)=[O:22])[CH3:19]>C1COCC1.CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1[C:24]2[S:32][CH:31]=[C:30]([CH2:33][O:11][C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[CH3:1])[C:25]=2[C:26]([Cl:29])=[N:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc([N+](=O)[O-])ccc3C)csc12
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-methyl-5-nitrophenol (960 mg, 6.07 mmol) (Avocado) and potassium carbonate powder (913 mg, 6.61 mmol) in dry THF (20 mL) and DMF (10 mL) was stirred at 50° C. for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.997 g, 5.969 mmol) (from Example 1 supra) in THF (20 mL) was added. The reaction was stirred at 50° C. for 10 hours and the resulting precipitate was collected. The filtrate was concentrated to give more precipitate. The combined solid was stirred in water (30 mL), filtered, washed with water and dried overnight to give 4-chloro-3-(2-methyl-5-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 1.647 g, 68%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH2:42]>CO>[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])(=[O:1])=[O:42])[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: COC(=O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [K+]
Solvent: CO
Product: COC(=O)CS(=O)(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 91 %

Procedure:
Oxone (potassium monopersulfate compound)(3.80 g, 6 mmol) suspended in water (20 mL) was added slowly to a stirred solution of methyl [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl)hexyl]thio]acetate (1.00 g, 2 mmol) in methanol (20 mL) maintained at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 5.5 hours before being poured onto water. The mixture was extracted with diethyl ether, the etheral layer washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Crystallization of the residue from a mixture of hexane and dichloromethane (25:1) afforded methyl [[6-(3,4,5-triphenyl 1H-pyrazol-1-yl)hexyl]sulfonyl]acetate (1.17 g, 91%); m.p.=92.5°-94.5° C. MS(CI): m/e=517 (MH+).
Reaction SMILES: [OH:1][C:2]1([C:20]#[C:21]/[C:22](/[C:29]([F:32])([F:31])[F:30])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([CH3:18])([C:14]([F:17])([F:16])[F:15])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:19].O>CC(C)=O.Cl>[OH:1][C:2]1([C:20]#[C:21]/[C:22](/[C:29]([F:30])([F:31])[F:32])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([CH3:18])([C:14]([F:17])([F:16])[F:15])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:19]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Ethyl (2E)-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluormethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (110 mg, 0.23 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 5 drops of conc. hydrochloric acid were added. The resulting reaction solution was stirred at room temperature for 4 h and then water was added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-[1-hydroxy-2,6-dimethyl-4-oxo-6-(trifluoromethyl)cyclohex-2-en-1-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (70 mg, 71% of theory) was isolated in the form of a colorless viscous oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.72/6.71 (s, 1H), 5.98/5.97 (s, 1H), 4.28/3.93 (q, 2H), 3.28 (br. s, 1H, OH), 3.00 (d, 1H), 2.66 (d, 1H), 2.21/2.18 (s, 3H), 1.49/1.37 (s, 3H), 1.32/1.09 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[CH:12]=1.C[Si](Cl)(C)C.[C:31]([Cl:34])(Cl)=[O:32]>ClCCl>[C:22]([O:21][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][C:18](=[O:20])[CH3:19])[C:10]([N:9]([CH3:8])[C:31]([Cl:34])=[O:32])=[O:25])(=[O:24])[CH3:23]
Reactant: CNC(=O)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: O=C(Cl)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)N(C)C(=O)Cl)cc1OC(C)=O

Procedure:
A solution of triethylamine (6.04 g) in anhydrous dichloromethane (20 ml) was added dropwise at room temperature to a solution of N-methyl-3,4-diacetoxybenzamide (15.0 g) and trimethylsilyl chloride (6.49 g) in anhydrous dichloromethane (70 ml). After the mixture was refluxed for 20 minutes, a solution of phosgene (42 ml) in anhydrous dichloromethane (82 ml) was added to the mixture at a temperature of from -5° to 5° C. by allowing its temperature to gradually rise to room temperature. Excess phosgene and the solvent used were evaporated to dryness under reduced pressure to give crude N-(3,4-diacetoxybenzoyl)-N-methylcarbamoyl chloride. The product was dissolved in cold anhydrous dichloromethane (50 ml) and, after removing insoluble substances by filtration, made available for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[CH3:20][S:21]([O:12][CH2:11][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([F:8])([F:9])[F:10])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1sc(Cl)nc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1sc(Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 34.7 g (0.161 mol) of the compound of Example 4 in 150 ml of toluene there was added over a 30 minute period, 18.2 g (0.18 mol) of triethylamine. To this mixture was added 20.5 g (0.18 mol) of methanesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 hours and was allowed to stand in the refrigerator for 4 days. The insoluble salt was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether and the ether solution was washed with water, dried over MgSO4 and concentrated under reduced pressure to give 43.8 g (92%) of crude [2-chloro-4-(trifluoromethyl)thiazol-5-yl]methyl methanesulfonate. A 5.5 g portion of the crude material was dissolved in 50 ml of acetone. To this solution was added 2 g (0.0169 mol) of potassium xanthogenate. The reaction mixture was stirred for 2 hours at room temperature and filtered. The acetone filtrate was concentrated to give 6.9 g of oil which was chromatographed on silica gel using ether petroleum ether (1:9 v/v) as eluant. The earlier fraction was 4.1 g (69.9%) of S-[2-chloro-4-(trifluoromethyl)-5-thiazolyl]methyl O-ethyl carbonodithioate; nD25 1.5497-1.5517.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].CN(C=O)C.O=S(Cl)[Cl:25]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([Cl:25])=[O:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (70 mg, 0.26 mmol) in toluene (5 mL) were added catalytic amount of DMF and SOCl2 (0.2 mL, 2.61 mmol) and the reaction mixture was heated to reflux for 6 hours. The solvent was evaporated and the resulting 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (70 mg, crude) was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=3)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:28]1([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=3)[C:22]([C:23]#[N:24])=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][O:5][C:6]3=[O:32])=[CH:9][CH:10]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OCCCCl)cc3)n(C3CCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4CCCOC4=O)cc3)n(C3CCC3)c2c1
Temperature: 80 °C

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indole-2-yl)-phenyl]-carbamic acid 3-chloro-propyl ester in 5 mL of DMF is added anhydrous K2CO3. The resulting mixture is stirred at 80° C. until complete consumption of the starting material is determined by TLC. After cooling, 10 mL of water is added to the reaction mixture to afford a solid precipitation which is collected by filtration, followed by washing with ether. The desired 1-cyclobutyl-6-ethoxy-2-[4-(2-oxo-[1,3]oxazinan-3-yl)-phenyl]-1H-indole-3-carbonitrile is obtained as a white powder (76.2 mg, 91.8% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].FC(F)(F)C(O)=O>C(OCC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(c1cccs1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 4-[(thiophene-2-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (12.9 g, 43.67 mmol) and trifluoroacetic acid (80 mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and dilute with ethyl ether. Collect the resulting solid by filtration, wash with ethyl acetate and recrystallize (methanol/ethyl ether) to give the title compound as an off-white solid; mp 186°-187° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[F:29][C:28]([F:31])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:32]=[N+:33]=[N-:34])[O:14][C:15]=2[CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C(F)(F)F)O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Yield: 94.1 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-(trifluoromethyl)phenylboronic acid (3.72 g, 17.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (77%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (4.3 g, 9.59 mmol) with sodium azide (2.5 g, 38.46 mmol) generally according to the procedure described for Intermediate 98 gave 2.88 g (94%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide with palladium on carbon (0.28 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.46 g (83%) of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 213-215° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.13; H, 4.65; N, 4.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)[C:42](=[O:43])[O:44][CH3:45])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1cncnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl-N-(5-pyrimidinyl)benzoic acid amide synthesized in Step 1 of Synthetic Example 14, 0.15 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 4 mL of tetrahydrofuran, 0.15 g of methyl chloroformate was added, and stirred at room temperature for 16 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of ethyl acetate was added and insoluble material was filtered off. The solvent was distilled off under reduced pressure and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3OC)nc2n(CC)c1=O
Yield: 34.5 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.04 g (9.19 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.22 g (yield 32%) of Compound 85 as a yellow powder.
Reaction SMILES: CSC.[CH:4](=[N:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:22]1([CH:28]=[N+]=[N-])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OC)(C)(C)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:5]1([CH:4]2[CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]2[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=Cc2ccccc2)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CSC
Product: Cc1ccc(S(=O)(=O)N2C(c3ccccc3)C2c2ccccc2)cc1

Procedure:
To a stirred solution of dimethylsulphide (7 μl, 0.1 mmol), rhodium (II) acetate (2 mg, 0.005 mmol) and N-benzylidene-toluene-p-sulphonamide (131 mg, 0.5 mmol; J. C. S. Perkin I (1981) 2435-2442) in dichloromethane (2 ml) was added phenyldiazomethane (prepared as in Example 36; 8.11 ml of a 0.074M solution in t-butylmethylether) over a period of 12 hours. Upon completion of the addition, the solvent was removed in vacuo and the residue chromatographed using silica gel eluting with 15:85 ethyl acetate:petrol to give the title compound as a 3:1 mixture of trans:cis isomers (144 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(=O)oc2ccc(Cl)cc21

Procedure:
Under an argon atmosphere, to a mixture of 5-chloro-1,3-benzoxazol-2(3H)-one (50.0 g) and acetone (750 mL) were added K2CO3 (61.1 g) and tert-butyl bromoacetate (52.3 mL) at room temperature, followed by heating to reflux for 1.5 hours. The reaction mixture was filtered while hot, and washed with acetone. The filtrate and the washed solution were combined and concentrated under reduced pressure. The obtained solid was stirred with a mixed solvent of Hex/EtOAc (6/1) and collected by filtration, and further stirred with water and collected by filtration to obtain tert-butyl (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (81.1 g).
Reaction SMILES: C(C1C=C([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([O:32]CC)=[O:31])C=C(C(C)(C)C)C=1O)(C)(C)C.[OH-].[K+].C(O)C.Cl>O>[O:29]=[C:18]1[C:17]([C:30]([OH:32])=[O:31])=[CH:16][C:21]2[CH:22]=[C:23]3[CH2:28][CH2:27][CH2:26][C:24]3=[CH:25][C:20]=2[O:19]1
Reactant: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc3c(cc2oc1=O)CCC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3,5-di-tert-butyl-4-hydroxy -phenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta [g] [1]benzopyran-3-carboxylate (1.85 g), potassium hydroxide (1.12 g) and 80% ethanol (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water, adjusted to pH4 with 6N HCl and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 4-3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1]benzopyran-3-carboxylic acid. The crystals were collected by filtration and washed with isopropyl ether (1.13 g, 64.9%). mp. 256°-260° C.