Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:57])[CH2:53][CH:54]([CH3:56])[CH3:55])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:57][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:53][CH:54]([CH3:56])[CH3:55])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 0 °C
Yield: 64 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred in the ice bath for 0.5 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→4:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.14 g, yield 64%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:20])[NH:10][C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:4][N:3]=1.I[CH3:40]>>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:20])[N:10]([CH3:40])[C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NC(C)(C)c1ccccc1
Reactant: CI
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)C(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-(4′-{3-methyl-4-[2-(1-methyl-1-phenyl-ethylcarbamoyl)-ethyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].CCN(C(C)C)C(C)C>C1COCC1.O>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:4]2)=[N:13][CH:12]=1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN([C@@H]1CCN(c2ncnc3[nH]ccc23)C1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (30 mg, 0.138 mmol) in THF (2 mL) were added 4-cyanobenzene-1-sulfonyl chloride (42 mg, 0.208 mmol) and DIPEA (36 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then diluted with water, and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The residue was purified by preparative TLC to give the title compound (13.6 mg, 26%). MS (m/z): 383 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:5]1)[CH:2]=[CH2:3].[OH-:26].[K+]>CO.O>[C:2]1([C:1]([N:4]2[CH2:8][C@@H:7]([CH:9]3[CH2:10][CH2:11]3)[C@H:6]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH2:5]2)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:3]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1cccc2ccccc12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Yield: 41.1 %

Procedure:
A solution of 6 g (48 mmol) of methyl-3-(cyclopropyl)acrylate (Example 1, Step 3) and 5.7 g (100 mmol) of KOH in 25 mL of MeOH and 2 mL of H2O was stirred at 40° C. for 2 h. The reaction mixture was concentrated. Addition of 2N HCl to the residue resulted in its precipitation as a white solid. The solid was collected by filtration and was washed with H2O and dried to give 4.5 g of the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([O:16][CH2:17][C:18]([CH3:20])=O)(=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:18]1([CH2:17][OH:16])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3.[C:13]([O-:16])(=[O:15])[CH3:14]
Reactant: CC(=O)COC(C)=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)[O-]
Product: CC1(CO)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of the starting material, tryptophol (32.2 g, 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is refluxed for 11/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol, acetate is obtained as an oil, nmr(CDCl 3) δ1.52(S,3H), 2.08(S,3H), 4.35(2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22](NC)=[CH:21][CH:20]=1.[CH2:27]([N:29](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:29][CH2:27][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:26][CH:25]=2)=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNc1ccc(OC)cc1
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Product: COc1ccc(CNC(=O)CC(CC(=O)O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.0 g) in CH2Cl2 (100 mL) at 0° C. was treated sequentially with 4-methoxy-N-methylaniline (3.3 g)), triethylamine (3.36 mL) and N,N-dimethylaminopyridine (0.24 g). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (100 mL) and water (2×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (7.3 g).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[O:9][C:10]2[C:16]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])=[CH:15][CH:14]=[C:13]([Cl:30])[C:11]=2[CH:12]=1)([OH:7])=O.[CH2:31]([NH2:33])[CH3:32]>O>[Cl:30][C:13]1[C:11]2[CH:12]=[C:8]([C:5](=[O:7])[NH:33][CH2:31][CH3:32])[O:9][C:10]=2[C:16]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:15][CH:14]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C(=O)O)oc23)c1=O
Reactant: CCN
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reaction time: 3 h
Yield: 77.7 %

Procedure:
10 ml of thionyl chloride was added to 0.37 g (0.96 mmol) of 3-(2-carboxy-4-chlorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, followed by stirring for 3 hours under heating and refluxing. After completion of the reaction, thionyl chloride was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of tetrahydrofuran. To this solution, 0.24 g (3.84 mmol) of ethylamine (70% aqueous solution) was added, followed by stirring for 10 minutes at room temperature. After completion of the reaction, the reaction solution was poured into water, and precipitated crystals were collected by filtration to obtain 0.31 g (yield: 78.3%) of the desired product as white crystals. Melting point: 225-226° C.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>CCOCC>[C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:22])=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Yield: 57.7 %

Procedure:
A solution of 27 m moles(7.3 g) of the above 4-carbobenzoxyoxybenzoic acid and 27 m moles(5.6 g) of phosphorus pentachloride in 50 ml of ether was stirred for 24 hours at room temperature. After the reaction, deetherizing was carried out, and the obtained crystal was recrystallized from hexane, to obtain 4.5 g of 4-carbobenzoxyoxybenzoyl chloride [m.p. 65.5°-67.4° C⟧ (yield: 57%)
Reaction SMILES: C([CH:4]1[CH2:12][C:11]2[C:6](=[C:7](O)[CH:8]=[CH:9][C:10]=2C)[C:5]1=[O:15])(C)C.CC1C2C(=C(OC)C=CC=2C)C(=O)C1>C(O)C>[C:5]1(=[O:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:4]1
Reactant: Cc1ccc(O)c2c1CC(C(C)C)C2=O
Agent: COc1ccc(C)c2c1C(=O)CC2C
Solvent: CCO
Product: O=C1CCc2ccccc21

Procedure:
The above-described aromatic composition according to the present process is added in an amount of 1 ppm to the materials of candies, and candies are prepared therefrom. A 5 % ethanol solution of the mixture (in the ratio 1:1) of 2-isopropyl-4-methyl-7-hydroxyindan-1-one and 3,4-dimethyl-7-methoxyindan-1-one is added to the materials but in an amount to give 10 ppm by weight of said indanone compounds mixture thereto, and candies are prepared therefrom.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)([CH3:13])[CH2:11]OS1(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:12]([CH2:11][C:32]#[N:33])([CH3:13])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCCCCCCOc1ccc(CC[C@]2(C)COS(=O)(=O)N2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CC#N)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of (R)-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-2,2-dioxo-2λ*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (174 mg, 0.40 mMol) in DMF (5 ml) is added sodium cyanide (94 mg, 1.91 mMol). The mixture is stirred at RT for 25 hours. Additional sodium cyanide (37 mg, 0.76 mMol) is added and the mixture is stirred at RT for 18 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: C([CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)C.P(Br)(Br)[Br:27]>CCOCC.CO.O>[C:13]1([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][Br:27])=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)c1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: BrCc1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
7-4 (0.572 g, 1.9 mmol) was dissolved in ether (10 ml). The solution was cooled in ice and phosphorus tribromide (0.204 g, 0.75 mmol) was added. After 1/2 hr. the reaction was diluted with methanol (2 ml) and water (5 ml). The ether layer was separated, washed with sodium bicarbonate and water, dried and filtered. Concentration of the filtrate in vacuo gave 7-5 as a white solid. mp: 70°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([CH:26]=O)[N:23]=[N:22]1.[CH2:28]([O-:30])[CH3:29].[Na+].C(O)C>C(OCC)(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:26]([C:24]3[N:23]=[N:22][N:21]([CH3:20])[CH:25]=3)[C:28](=[O:30])[C:29]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Reactant: Cn1cc(C=O)nn1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1cn(C)nn1)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (698 mg, 2.7 mmol) and 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (334 mg, 3 mmol) in ethyl propionate (35 mL) was cooled to 0° C. Then a solution of sodium ethanolate in ethanol (sodium (248 mg, 10.8 mmol) in ethanol (15 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which then was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (426 mg, yield 39%). LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[OH:61])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:61][C@H:53]1[CH2:54][C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 2971, 2934, 1609, 1562, 1480, 1391, 1294, 1243, 1206, 1184, 1171, 1161, 1119, 1091, 1054 cm−1; OAMS supporting ions at: ESI+ 432.1; MS (EI) m/z 431 (M+); HRMS (FAB) calcd for C27H33N3O2+H1 432.2651, found 432.2650. Anal. Calcd for C27H33N3O2: C, 75.14; H, 7.71; N, 9.74. Found: C, 74.86; H, 7.72; N, 9.67.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1.[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([O:16][C:54]([NH:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:55])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3O)c2)c(C(C)(C)CC)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3OC(=O)Nc3ccccc3)c2)c(C(C)(C)CC)c1

Procedure:
0.01 mole of 1-(2,4,6-trichlorophenyl)-3-[3-{α-(2,4-di-t-amylphenoxy)acetamido}benzamido]-4-hydroxy-5-pyrazolone and 0.01 mole of phenyl isocyanate are dissolved in 100 ml of dehydrated toluene, added with 0.02 moles of pyridine and heated for 5 to 6 hours under reflux. The solvent is eliminated under reduced pressure after the reaction, and n-hexane is added. The solid is collected by filtration, then washed with n-hexane and dried to obtain the coupler (1) in a state of colorless powder with a melting point 72°-77° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH:19]4[CH2:21][CH2:20]4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH:19]4[CH2:21][CH2:20]4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(C3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide (94 mg, 0.23 mmol) was dissolved in CH2Cl2 (0.9 mL). Trifluoroacetic acid (0.7 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (0.9 mL) and ethylenediamine (0.9 mL) was added. The reaction mixture was stirred at room temperature for 2 h then H2O and EtOAc were added. The resultant suspension was filtered, rinsing with H2O and EtOAc and dried under high vacuum to afford 55 mg (85%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide as a white solid. MS: (M+H)+=285; mp>300.0.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](C)=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=O)C.COC1C=C(C=CC=1)C(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Agent: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccccc2)c1

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@H:10]1[NH:26]C(OC(C)(C)C)=O>C(O)C>[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@H:10]1[NH2:26]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Reaction time: 1 h
Yield: 57 %

Procedure:
4N HCl-dioxane (10 ml) was added to a solution of (R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.11 g) in ethanol (15 ml), and the mixture was stirred at 50: for one hour. After allowed to cool, the reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diisopropyl ether was added to crystals so precipitated, washed, and collected by filtration. This was recrystallized from a mixed solvent of ethanol and diisopropyl ether, to thereby obtain 2.1 g of the titled compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(C)c1
Reaction time: 8 h

Procedure:
A mixture of m-cresol (10.8 g), methyl bromoacetate (15.3 g) and potassium carbonate (69 g) in dimethylformamide (200 ml) was stirred overnight and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purified by chromatography eluting with toluene. Yield 12.7 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].C(Cl)(Cl)Cl.O>CN(C=O)C>[CH3:6][CH:5]([CH3:7])[CH2:4][CH2:3][CH2:2][N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)CCCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-methylpentane (5.0 g, 0.030 mol) in DMF (20 mL) was added potassium phthalimide (5.9 g, 0.032 mol) in one portion at room temperature. After stirring at room temperature of 1 hr, the mixture was heated at 55° C. for 16 hr. Chloroform (30 mL) was added to the reaction mixture and the resulting mixture was poured into water (100 mL). The aqueous phase was extracted with chloroform and the combined organic phase was washed with 0.25 M NaOH (aq) and water. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 2-(4-methylpentyl)-1H-isoindole-1,3(2H)-dione as a pale yellow oil. (M+H) 232, 2.80 min. (LC/MS method A).