Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]([OH:25])(=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(C(C)=O)C(C)C>[C:21]([O:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:25]
Reactant: O=C(O)CCCCCCC(=O)O
Reactant: NCCCCCCO
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCCCCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
6.0 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 7.0 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.). After stirring for 10 minutes, 5.2 g of suberic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) suberate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:16])[S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:10]1
Reactant: CN[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CN([C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)S(C)(=O)=O

Procedure:
Prepared analogously to example IV.3 from 0.305 g trans-[4-(5-fluoro-2-nitrophenoxy)-cyclohexyl]-methyl-amine hydrochloride and methanesulfonyl chloride.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][C:10]2=[NH:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([C:29](O)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11]/[C:10]/2=[N:18]\[C:29]([C:19]23[CH2:28][CH:23]4[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]4)[CH2:26]2)[CH2:20]3)=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N=c1sc2ccccc2n1CCN1CCOCC1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: O=C(/N=c1\sc2ccccc2n1CCN1CCOCC1)C12CC3CC(CC(C3)C1)C2
Yield: 25.4 %

Procedure:
The product of Example 108A (0.20 g, 0.76 mmol) and adamantane-1-carboxylic acid (0.15 g, 0.84 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 0-30% methanol/methylene gradient) afforded 82 mg (25%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.67-1.82 (m, 6 H), 1.99 (d, J=2.7 Hz, 6 H), 2.06 (s, 3 H), 2.62 (s, 4 H), 2.78 (s, 2 H), 3.70 (s, 4 H), 4.53 (s, 2 H), 7.22-7.37 (m, 2 H), 7.43 (t, J=7.6 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H); MS (DCI/NH3) m/z 426 (M+H)+. Anal. Calculated for C24H31N3O2S.0.2H2O: C, 67.16; H, 7.37; N, 9.79. Found: C, 66.92; H, 7.59; N, 9.83.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@H:41]2[N:45]([CH3:46])[C:44](=[O:47])[CH2:43][CH2:42]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@H:41]1[N:45]([CH3:46])[C:44](=[O:47])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2C)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CCC(=O)N1C
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (225 mg, 0.7 mmol), (prepared as described in Example 49), in DMF was added powdered potassium carbonate (290 mg, 2.1 mmol) and (5S)-5-(p-toluenesulphonylmethyl)-1-methyl-2-pyrrolidinone (340 mg, 1.2 mmol). The reaction was then heated at 95° C. for 5 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). The product was evaporated, triturated with ether and filtered to give (5S)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(1-methyl-2-oxopyrrolidin-5-ylmethoxy)quinazoline (100 mg, 33%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:7])[CH:5]=[CH2:6]>>[CH3:1][N:2]([CH2:6][CH2:5][C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])[CH3:3]
Reactant: CNC
Reactant: C=CC(=O)OCCN(C)C
Product: CN(C)CCOC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Anhydrous dimethylamine (19.8 grams) was added dropwise to 2-(N,N-dimethylamino)ethyl acrylate (31.5 grams) in a magnetically-stirred, ice-cooled reaction vessel at such a rate that the temperature did not exceed 40° C. The addition of dimethylamine was complete in about 10 minutes. After allowing the reaction mixture to stir overnight at room temperature, it was subjected to reduced pressure (about 20 mm. Hg) to remove unreacted dimethylamine. Gas-liquid chromatographic analysis indicated that the residue product was 96.5 percent pure. The structure of the product, ##STR20## was verified spectroscopically (nuclear magnetic resonance and infrared) and by elemental analysis. Anal. Calc'd. for C9H20N2O2 : C, 57.4; H, 10.6; N, 14.9. Found: C, 57.3; H, 10.5; N, 14.8. This product is designated herein as Amine Catalyst X.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2c3cc(C)cc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of {9-[(3-methylphenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (0.12 g, 0.288 mM) and 1.4 mL (2.8 mM) of 2 N NaOH in 14 mL of ethanol was stirred for 30 minutes at 25° C. The reaction was acidified with 1N HCl to pH=2. After stirring 1 hour, the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 114 mg (95%) {9-[(3-methylphenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ 11.1 (bs, 1H), 7.75 (bs, 1H), 7.6 (d, J=8 Hz, 1H), 7.45 (bs, 1H), 7.35 (dd, J=8 and 8 Hz, 1H), 7.2-7.0 (m, 5H), 6.85 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.6 (s, 2H), 4.8 (s, 2H), 2.4 (s, 3H), 2.2 (s, 3H). MS (ES) m/e 386, 403. Recrystallization from acetone/hexane provided an analytical sample:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17].[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=[O:28]>C(#N)C>[CH:27]([C:26]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([CH:25]=1)[O:23][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[O:28]
Reactant: COc1ccc(C=O)cc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C=O)ccc1OC
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Potassium carbonate (0.35 g, 2.6 mmol) was added to a solution (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (0.5 g, 1.7 mmol) and 3-hydroxy-4-methoxybenzaldehyde (0.32 g, 2.1 mmol) in 20 mL of acetonitrile (CH3CN) which was then stirred for 6 hours under reflux. The reaction solvent was removed by vacuum concentration. The residue was stirred in water (20 mL), and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. Purification through silica gel chromatography afforded the title compound as a white oil (0.3 g, yield 49%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.CN(C)[CH:18]=[O:19].Cl>CCCCCC.C(OCC)C>[S:10]1[CH:11]=[C:7]([CH:18]=[O:19])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]1=2
Reactant: CN(C)C=O
Reactant: Brc1csc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1csc2ccccc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -70° C. was added a solution of 5.3 g of 3-bromobenzo[b]thiophene in 65 ml of diethyl ether. After stirring for about 30 minutes, 2.2 ml of dry dimethylformamide in 2.5 ml of dry diethyl ether were added. The mixture was stirred for about 3.5 hours at -70° C., and then allowed to warm to -5° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction mixture was stirred at 0° C. for 15 minutes. The layers were separated and the aqueous layer was extracted with one liter of ether. The organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was held at 0° C. overnight at which time an orange solid had formed. Approximately 4.6 g of this solid was recovered and identified by proton NMR to be the desired subtitle carboxaldehyde intermediate. The carboxaldehyde intermediate was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=1[NH2:16].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:16][C:15]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:14]=2[F:13])=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1F)Nc1cc(F)ccc1F
Temperature: 20 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (180 mg, 0.775 mmol) and 2,5-difluoroaniline (100 mg, 0.775 mmol) in DCM (20 mL) was added Et3N (0.324 mL, 2.324 mmol) and HATU (884 mg, 2.324 mmol) in portions. Then the mixture was stirred at 20° C. for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness. The crude product which was purified by silica column chromatography (PE/EA 100/1 to 10/1) to afford 2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (103 mg, 0.276 mmol, 35.6% yield). 1H NMR: (400 MHz, CD3OD) δ 7.87-7.82 (m, 1H), 7.39-7.26 (m, 3H), 7.20-7.13 (m, 1H), 6.90-6.82 (m, 1H), 3.83 (s, 2H); ES-LCMS: m/z 343.9 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])(=[O:4])=[O:3].Cl[C:14]1[N:19]=[C:18]([Cl:20])[N:17]=[C:16]2[N:21]([CH3:24])[N:22]=[CH:23][C:15]=12>>[Cl:20][C:18]1[N:17]=[C:16]2[N:21]([CH3:24])[N:22]=[CH:23][C:15]2=[C:14]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[N:19]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: CS(=O)(=O)c1cccc(CN)c1
Product: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(Cl)nc21

Procedure:
Reaction of 3-(methylsulfonyl)benzylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methanesulfonyl-benzyl)-amine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:38]#[C:39][C:40]([OH:43])([CH3:42])[CH3:41])=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[OH:43][C:40]([CH3:42])([CH3:41])[C:39]#[C:38][C:20]1[C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:22][C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: CC(C)(O)C#Cc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C#Cc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
TFA (0.2 mL) was added at room temperature to a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.020 g, 0.041 mmol) dissolved in dichloromethane (2 mL). The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the crude mixture was purified by ion exchange on SCX-II acidic resin (500 mg), eluting with methanol then 2M ammonia-methanol. The basic fractions were combined and solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/19), to give the title compound as a yellow solid (0.008 g, 50%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(C=NOCCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of 0.14 g of 4-(trifluoromethyl)benzaldehyde and 10 ml of pyridine was added 0.30 g of O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.37 g (yield, 95.6%) of 4-(trifluoromethyl)benzaldehyde O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)oxime, nD21.0 1.5387.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([C:14]1[C:15]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([CH3:13])([CH3:12])[CH3:11].[Cl:31][C:32]1[C:33]([Cl:39])=[C:34]([Cl:38])[CH:35]=[CH:36][CH:37]=1>O>[Cl:31][C:32]1[C:33]([Cl:39])=[C:34]([Cl:38])[CH:35]=[CH:36][CH:37]=1.[C:10]([C:14]1[C:15]2[C:23](=[O:30])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17](=[O:18])[C:16]=2[CH:20]=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(=O)O)c1C(=O)c1ccccc1
Agent: Clc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CC(C)(C)c1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To 400 parts of 10.5% oleum there was added a solution of 100 parts of tertiary butylbenzoylbenzoic acid in 600 parts of commercial trichlorobenzene. The solution was added gradually over a 30 minute period to the well-stirred oleum held at 80° to 90° C. After the addition was complete, the reaction mixture was stirred at 90° C for 4 hours, then poured into 2000 parts of cold water. The aqueous and organic layers were allowed to separate, and the aqueous layer was removed by decantation. After washing the organic layer twice with 800 part portions of water, the residual acidity was neutralized by stirring the organic layer with another 800 parts of water, sufficient 30% aqueous sodium hydroxide solution being added to achieve a pH above 7.0. A final 800 part water wash was applied, and the product was fractionally distilled. From 562 parts of crude product there was obtained 480 parts of trichlorobenzene, 80 parts of tertiary butylanthraquinone-containing product and 6 parts of residual high-boiling tar. The product was 98.4 % tertiary butylanthraquinone. The yield was 86% of theory.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[O:9]1[C:22]([CH3:24])([CH3:23])[CH:10]1[CH2:11][C:12]1[C:13]([OH:21])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:18]=1)[OH:17].C(=O)([O-])O.[K+]>CO>[OH:9][C:22]([CH:10]1[CH2:11][C:12]2[CH:18]=[C:16]([OH:17])[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[O:21]1)([CH3:24])[CH3:23]
Reactant: COc1cc(O)c(CC2OC2(C)C)cc1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1O)CC(C(C)(C)O)O2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.1 %

Procedure:
To a solution of 5-(2,3-epoxy-3-methylbutyl)-2-methoxyhydroquinone diacetate (1.848 g) in methanol (36 ml) was added potassium hydrogencarbonate (1.50 g) in one portion. The mixture was stirred for 21 hours at ambient temperature and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (30 ml) and saturated sodium chloride solution (30 ml). The separated organic layer was washed with saturated sodium chloride solution, dried, and evaporated to dryness. The oily residue was crystallized from isopropyl ether to yield 2,3-dihydro-2-(1-hydroxy-1-methylethyl)-6-methoxy-5-benzofuranol (964 mg) as a white solid.
Reaction SMILES: [C:1]([S:4][C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=1)(=O)[CH3:2].CC(C)([O-])C.[K+].ClCC1[O:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][N:26]=1>C1COCC1>[C:27]([C:24]1[O:23][C:2]([CH2:1][S:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=2)=[N:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cnc(CCl)o1
Reactant: CC(=O)Nc1ncc(SC(C)=O)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(SCc2ncc(C(C)(C)C)o2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of 50 mg (0.23 mmol, Applied Chemical Laboratory) of N-[5-(acetylthio)-2-thiazolyl]acetamide in 10 mL of THF was added 0.25 mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol) at rt under argon. The resulting suspension was stirred for 15 min at rt, then a solution of 59 mg of 2-(chloromethyl)-5-t-butyloxazole (0.34 mmol) in 1 mL of THF was added. The resulting mixture was stirred at rt for 16 h, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 25×200 mm, 1:1 EtOAc/hexanes followed by 100% EtOAc) to give 44 mg (0.14 mmol, 61%) of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([CH:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH3:21])[C:18](=[O:28])[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH3:21])[C:18](=[O:28])[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n(C(C)c3ccccn3)c12
Solvent: CCO
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n([C@@H](C)c3ccccn3)c12

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[1-(2-pyridinyl)ethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Example 38, ˜50 mg) was dissolved in 3 ml of ethanol (3 ml) and heptanes (3 ml) with warming (×3). The solutions were purified by chiral HPLC using 6× injection (3 ml) of the above solution onto a Chiralpak IA column (20 um, 5 cm×25 cm) and elution with ethanol/heptanes (30%, flow rate 50 ml/min, wavelength 215 nm). The mixed fractions were reduced to dryness in vacuo and reprocessed as described in the method above. The bulked fractions of the first eluting enantiomer were reduced to dryness in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1S)-1-(2-pyridinyl)ethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (61 mg).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[CH:26]=[CH:25]2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[CH:26]=[CH:25]2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cn3ccc(=O)c4ccccc43)ccc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cn2ccc(=O)c3ccccc32)ccc1F)N1CCNCC1

Procedure:
B1 from step 1 was stirred in a 1:1 mixture of DCM and TFA (0.1M) for 30 min. The solvents were removed under reduced pressure and the residue was dissolved in MeOH. The solution was applied on a SCX cation exchange resin, the resin was washed with H2O and MeOH and the product was eluted with ammonia in MeOH (2N). The solvents were removed under reduced pressure to a afford the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:27][C:28](OCC)=[O:29])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[NH2:26])=[O:7])=[CH:4][CH:3]=1.[N:35]1([C:40]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.[OH-].[Na+].C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][P:18](=[O:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:12][C:11]=3[N:26]([CH2:46][C:45]3[CH:44]=[CH:43][C:42]([C:40]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:41])=[CH:49][CH:48]=3)[C:28](=[O:29])[CH2:27]2)=[O:7])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(Cc1ccc(CCP(=O)(OCC)OCC)cc1N)C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)N2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
240 mg (0.47 mmol) of ethyl ((4-chlorobenzoyl)-(4-(2-(diethoxyphosphoryl)ethyl)-2-aminobenzyl)amino)acetate and 105 mg (0.52 mmol) of 4-(1-pyrrolidinecarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.054 ml (0.94 mmol) of acetic acid was added to the obtained solution. They were stirred at room temperature for 30 minutes. 248 mg (1.18 mmol) of sodium triacetoxyborohydride was added to the obtained mixture and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in a mixture of 4 ml of 1 N sodium hydroxide and 2 ml of ethanol, and the solution was stirred at room temperature for 5 hours. After the treatment with ethyl acetate by an ordinary method, the obtained crude product was dissolved in 10 ml of dichloromethane. 95 mg (0.56 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.14 ml (0.94 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.