Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.045 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 52 as a colorless solid (0.067 g, 54%). LCMS m/z (%)=485 M+H+ (81Br 37Cl, 30), 483 M+H+ (81Br35Cl, 100), 481 M+H+ (79Br35Cl, 72), 1H NMR (400 MHz, CDCl3) δ: 7.7 (s, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.3 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 7.1-6.8 (m, 3H), 4.2 (m, 1H), 3.8 (s, 3H), 1.5 (d, J=6.61 Hz, 3H), 1.3 (d, J=6.61 Hz, 31-1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)[C:39](O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH:23]1[CH2:39][CH2:38][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:22]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(5-bromopentyl)-1-piperidinecarboxylate.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH:14][CH:15]1[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1>C1(C)C=CC=CC=1>[C:8]([O:14][CH:15]1[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: OC1Cc2cccc3cccc1c23
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1Cc2cccc3cccc1c23

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 170 g of 1-hydroxyacenaphthene, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, acenaphthenyl methacrylate.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:23].Cl>C1C=CC=CC=1>[CH3:10][C:11]12[C:12](=[O:23])[CH:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=31)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: BrCCCCCBr
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C1(C)CCCCCC(C2)C1=O
Reaction time: 12 h

Procedure:
Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to a stirred mixture of 1,5-dibromopentane (184 g.) and 1-methyl-7-methoxy-2-tetralone (32 g.) in dry benzene (300 ml.). Stirring is continued for 12 hours at 25° and at reflux for an additional 15 hours. The mixture is cooled, sodium hydride (5.8 g.) in 50 ml. benzene added, stirring continued at 25° for 10 hours, and at reflux for 12 additional hours. After cooling excess base is neutralized with concentrated hydrochloric acid and the inorganic solids which precipitate are removed by filtration. Washing and filtrate with saline, drying over sodium sulfate, concentrating and vacuum distilling gives an oil (21 g.), b.p. 160°-190° C. (0.5 mm.) containing 6.5 g. (27 percent) of the title product by vapor phase chromatographed (3 percent OVI, C200- 225- 250).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31]OC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC[NH:72][S:73]([CH3:76])(=[O:75])=[O:74])=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][NH:72][S:73]([CH3:76])(=[O:75])=[O:74])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: CS(=O)(=O)NCCN=[N+]=[N-]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCNS(C)(=O)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.87 mmol) and compound 413 (1.3 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 65:35 to 85:15 as the eluent to afford the title compound as almost white solid. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.4, 145.3, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.4 (dd), 124.9, 124.1 (dd), 121.9, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 49.8, 42.2, 39.5, 19.4
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[NH3:16]>C(O)C>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:4](=[O:3])[NH2:16])([F:14])[F:13])[CH3:12]
Reactant: N
Reactant: CCOC(=O)CCC(F)(F)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2-difluoropentanedioic acid diethyl ester (21 g) synthesized in Section (1) was dissolved in ethanol (50 mL) and 2.0 M methanolic ammonia was slowly added thereto. The mixture was stirred at room temperature for 30 min and distilled under reduced pressure to afford 18.2 g of the title compound as viscous oil, which was used in the subsequent step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61](O)=[O:62])[CH:57]=1)[CH3:55].C(N(CC)CC)C>CN(C=O)C>[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61]([N:44]2[CH2:43][C:42]3([CH2:41][CH2:40][N:39]([CH2:38][C:37]4[CH:50]=[CH:51][CH:52]=[C:35]([CH2:34][CH2:33][OH:32])[C:36]=4[F:53])[CH2:49][CH2:48]3)[O:47][CH2:46][CH2:45]2)=[O:62])[CH:57]=1)[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.316 g) was added in one portion to a solution at 0° C. of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.271 g) and 5-ethylthiophene-3-carboxylic acid (0.1 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 1.921 mL). The reaction mixture was allowed to stand at 20° C. for 18 hours and the solvent was then removed under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.12 g.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1

Procedure:
264.0 g. of (R)-2-hydoxy-isocaproic acid were dissolved in 1.8 liters of absolute dioxan in a three-necked flask fitted with a stirrer, thermometer and reflux condenser with a calcium chloride tube. The solution was treated successively with 285 ml. of triethylamine and 236 ml. of benzyl chloride and heated at an internal temperature of 100° for 20 hours with stirring in an oil-bath. After cooling, the resulting triethylamine hydrochloride was filtered off and washed with 500 ml. of ethyl acetate. The filtrate was evaporated under reduced pressure at 50°. The residual oil was dissolved in 800 ml. of ethyl acetate and washed twice with 150 ml. portions of 3-N hydrochloric acid, twice with 100 ml. portions of 5 percent sodium chloride solution, twice with 150 ml. portions of 10 percent potassium bicarbonate solution and twice with 100 ml. portions of 5 percent sodium chloride solution. After each of these washings, the oil was rinsed with 200 ml. of ethyl acetate. The ethyl acetate solutions were dried over magnesium sulphate and evaporated under reduced pressure at 50°. The crude product which was thus-obtained was distilled at 0.3 Torr (112°-115°). There was obtained benzyl-(R)-2-hydroxy-isocaproate; [α]D25 = + 18.0° (c = 1 in methanol); nD23 = 1.498.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].[OH-].[K+]>C(#N)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccccc1Cl
Reactant: Cn1cnc2c(Cl)nccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cnc2c(OCc3ccccc3Cl)nccc21

Procedure:
A mixture of 7.5 g of 4-chloro-1-methyl-1H-imidazo(4,5-c)pyridine, 7.1 g of 2-chlorobenzyl alcohol, 3.3 g of KOH and 100 ml of acetonitrile is refluxed for 7 hours. The solvent is removed and the residue is worked up in the customary manner (water/methylene chloride) to give 4-o-Chlorobenzyloxy-1-methyl-1H-imidazo(4,5-c)pyridine, m.p. 132°-135°.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8](I)=[N:7]1.[C:28]([Cu])#[N:29]>CN(C=O)C>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8]([C:28]#[N:29])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Temperature: 170 °C

Procedure:
A mixture of 1-[2,4-bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde (2 mmol) and CuCN (5 mmol) in DMF (5 mL) was heated under microwave irradiation at 170° C. for 30 min. The mixture was partitioned between EtOAc and water. The EtOAc extracts were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes 1:4 v/v) to afford 1-[2,4-bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-carbaldehyde as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15]>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:14](=[O:16])[CH3:15])[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)n1cnc(C)c1

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added triethylamine (NEt3) (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-C1 (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][NH:9][CH2:8][CH2:7][O:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOC2(CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCC2(C1)CNCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 173.4 %

Procedure:
To a of solution 1,1-dimethylethyl 6-oxa-9-azaspiro[4.5]decane-9-carboxylate (200 mg, 0.829 mmol, available from Tyger Scientific Inc) in DCM (3 ml) was added trifluoroacetic acid (TFA) (0.5 ml). The resulting colourless yellow solution was stirred at room temperature for 24 hr. The solvent was evaporated to give the title compound as a grey oil (203 mg).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C.C1(C(C2C=CC=CC=2)C(O)=O)C=CC=CC=1>>[C:5]1([CH:13]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: O=C(O)C(c1ccccc1)c1ccccc1
Product: CC(C)c1ccc(C(=O)C(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with diphenylacetic acid, mp 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ncnc2c1CCC2
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Reaction time: 8 h
Yield: 51.3 %

Procedure:
77.5 g of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were dissolved in 2 liters of chloroform, and then a solution of 259 g of m-chloroperbenzoic acid in 0.1 liter of chloroform was added dropwise. The mixture was stirred overnight, whilst cooling with water, and then a solution of 375 g of sodium thiosulfate in 1.5 liters of water and a solution of 191 g of sodium carbonate in 0.7 liters of water were added successively dropwise, whilst ice-cooling. The chloroform layer was separated, and the aqueous layer was extracted with chloroform. The separated chloroform layer and extracts were combined and dried over anhydrous sodium sulfate. The chloroform was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to give 43.9 g of the title compound as colorless crystals melting at 85°-87° C. (with decomposition).
Reaction SMILES: C[O:2]C(=O)NC(C(N1CCCC1C1NC(C2C=CC3C4C(=C5C=CC(C6NC(C7CCCN7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC5=CC=4)OCC=3C=2)=CN=1)=O)C(C)C.[F:61][C:62]([F:94])([F:93])[S:63]([O:66][C:67]1C=C[C:70]2[C:71]([CH:92]=1)=[CH:72]C=[C:74]1[C:79]=2[O:78][CH2:77][C:76]2[CH:80]=[C:81]([O:84][S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH:82]=[CH:83][C:75]1=2)(=[O:65])=[O:64]>>[F:94][C:62]([F:93])([F:61])[S:63]([O:66][C:67]1[CH:74]=[C:79]2[O:78][CH2:77][C:76]3[C:75]4[C:70]2=[C:71]([CH2:72][O:2][C:83]=4[CH:82]=[C:81]([O:84][S:85]([C:88]([F:90])([F:91])[F:89])(=[O:86])=[O:87])[CH:80]=3)[CH:92]=1)(=[O:65])=[O:64]
Reactant: O=S(=O)(Oc1ccc2c(c1)COc1c-2ccc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Product: O=S(=O)(Oc1cc2c3c(c1)OCc1cc(OS(=O)(=O)C(F)(F)F)cc(c1-3)OC2)C(F)(F)F

Procedure:
(1-{2-{[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5,10-dihydro-chromeno [5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (1-{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting trifluoro-methanesulfonic acid 7-trifluoromethane sulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-yl ester for trifluoro-methanesulfonic acid 2-trifluoromethanesulfonyloxy-6-H-dibenzo[c,h]chromen-8-yl ester.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>O1CCOCC1>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:2]/[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Solvent: C1COCCO1
Product: CN(C)/C=C/C(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A solution of 25 g of 2-[4-(4-acetylphenoxy)butyl]-1H-isoindole-1,3(2H)-dione (Example 42) and 25 ml of dimethylformamide dimethylacetal in 50 ml of dioxane is heated in the steam bath for 16 hours. The volatile components are removed in vacuo, a tacky reddish-brown solid being obtained. A portion is recrystallized from dichloromethane/hexane; m.p. 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([CH:14]([OH:17])[CH2:15][OH:16])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>ClCCCl>[Si:28]([O:16][CH2:15][CH:14]([C:4]1[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:18])[OH:17])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 80 %

Procedure:
1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-fluorophenyl]ethanone (700 mg, 2 mmol) (from Step 2, peak 2) was stirred in 1,2-dichloroethane (6 mL) with N,N-diisopropylethylamine (4.0 mL, 23 mmol) and a 1.0 M solution of tert-butyldimethylsilyl chloride in 1,2-dichloroethane (7.6 mL) was added. The mixture was heated to 80° C. for 3 hours and cooled to rt. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound 800 mg, 80%. LCMS calculated for C18H28ClFO4SiNa (M+Na)+: m/z=413.1; found: 413.1.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH:14]=O.C1(C)C=CC=CC=1>O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[N:4]=[CH:12][CH:13]([CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(C)C=O
Reactant: COC(=O)c1ccccc1N
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(C)C=Nc1ccccc1C(=O)OC

Procedure:
226.5 g (= 1.5 g mole) of methyl anthranilate, 150 g (= 1.5 g mole) of 2-methylpentanal and 400 g of toluene are brought into a 2 liter reaction flask. Then the mixture is agitated under reflux for about 5 hours at a bottom temperature of 100°-120°C, 20 g of water being taken off through the reflux head. Then the solution is concentrated at a 30 cm Vigreux column under reduced pressure (about 20 mm Hg) to a bottom temperature of 110°C. 360 g of toluene are obtained and 347 g of evaporation-residue. The evaporation residue is fractionated at a 30 cm Vigreux column to obtain:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Li]CCCC.CCCCCC.[CH2:21]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29](=[O:30])[C:27]1=[O:28])[CH3:22]>C1COCC1>[CH2:42]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:39])([F:41])[F:40])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29]([OH:30])([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])[C:27]1=[O:28])[CH3:43]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(F)cc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (0.13 mL, 1.15 mmol) in THF (7.5 mL) was added dropwise 1.47 N BuLi in hexane (0.77 mL, 1.13 mmol) at −78° C. and the mixture was stirred for 15 min. To the resulting solution was added dropwise a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (500 mg, 1.14 mmol) in THF (6 mL) over 15 min at −78° C. The mixture was stirred for 40 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (576 mg, 91%).