Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(CCN3CCOC3=O)CC1)C2

Procedure:
15.4 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin are treated with 41 g. of 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone and stirred at 120°-130°C. (internal temperature) for 10 minutes. The cooled mixture is treated with 2N sodium hydroxide and extracted with chloroform. The chloroform solution is washed to neutrality with water and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the base extracted with chloroform. The organic solution is washed with water, dried over magnesium sulfate and concentrated. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone of melting point 177°-179°C. The corresponding maleate melts at 212°-214°C.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][Cl:23])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(OCCCOc2ccc(CO)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OCCCOc2ccc(CCl)cc2)cc1
Temperature: 0 °C
Yield: 106.6 %

Procedure:
1.67 g of 4-[3-(4-tolyloxy)propyloxy]benzyl alcohol were dissolved in 30 ml of chloroform, and the resultant solution was then stirred for 1 hour at room temperature after conducting the dropping of 0.88 g of thionyl chloride into the solution. The solution reacted was then poured into ice-water and extracted with chloroform, and the organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure thereby affording 1.9 g of 4-[3-(4-tolyloxy)propyloxy]benzyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[Li+].C([Mg]Cl)(C)C.[C:13]([CH:16]1[CH2:21][CH2:20][C:19]([CH3:26])([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[OH:15][C:13]([CH:16]1[CH2:21][CH2:20][C:19]([CH3:26])([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: COC(=O)C1(C)CCC(C(C)=O)CC1
Reactant: c1cscn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(C)(O)c2nccs2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of thiazole (0.309 mL, 4.36 mmol) in tetrahydrofuran (5 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex (1.0 M in tetrahydrofuran, 3.36 mL, 4.36 mmol). After 20 minutes, the resulting solution was added to a solution of methyl 4-acetyl-1-methylcyclohexanecarboxylate (864.9 mg, 4.36 mmol) in tetrahydrofuran (10 mL) via syringe over 6 minutes. After 90 minutes, saturated aqueous ammonium chloride solution (5 mL) was added to the reaction mixture and the resulting suspension was partitioned between water (5 mL) and ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chiral chromatography (methanol/supercritical CO2) to give four separate stereoisomers (peak 1, peak 2, peak 3, peak 4) of methyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-methylcyclohexanecarboxylate. MS ESI calc'd. for C14H21NO3S [M+H]+ 284. found 284.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH4+].[Cl-:7].[CH2:8]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[NH:12][C:11]1=O)[CH3:9]>>[Cl:7][C:11]1[N:10]([CH2:8][CH3:9])[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1
Reactant: [Cl-]
Reactant: CCn1c(-c2ccncc2)c(-c2ccc(F)cc2)[nH]c1=O
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c(Cl)nc(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 81 %

Procedure:
35 ml of POCl3 and a small amount of NH4Cl were added to 2.0 g of 1-ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-one, and the reaction mixture was heated under reflux for 9 h. After cooling, most of the excess POCl3 was distilled off, and distilled water was carefully added to the residue. The mixture was neutralized using 20% strength NaOH, resulting in the precipitation of the title compound. The precipitate was filtered off and dried over P2O5 under reduced pressure. Yield: 81%.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:8][O:7][C:6]2=[C:9](C(O)=O)[S:10][C:11](C(O)=O)=[C:5]2[O:4][CH2:3]1.COC(C)(C)C>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[F:18][C:2]1([F:1])[CH2:8][O:7][C:6]2=[CH:9][S:10][CH:11]=[C:5]2[O:4][CH2:3]1
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCC(F)(F)CO2
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Solvent: COC(C)(C)C
Product: FC1(F)COc2cscc2OC1
Yield: 39.9 %

Procedure:
300 mg (1.07 mmol) of 3,3-difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid was heated at 175° C. with 77 mg of copper chromite in 3.0 mL of quinoline for 1.5 hours. After cooling and mixing with 35 mL of tert-butyl methyl ether, the resulting mixture was washed three times with 2N hydrochloric acid, then three times with deionized water, dried with anhydrous magnesium sulphate and finally evaporated to dryness yielding 138 mg of raw product. The raw product was purified by column chromatography using Kieselgel 60 and cyclohexane as eluant. 82 mg of 3,3-difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine (M3) was obtained corresponding to a yield of 40% with a melting point of 66–67° C., as characterized by:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2O[C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.[NH2:31][NH2:32]>C1COCC1.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2[N:31]=[N:32][C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)o2)cn1
Reactant: NN
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nn2)cn1
Temperature: -35 °C
Reaction time: 20 h
Yield: 21.7 %

Procedure:
In a round bottom flask, {1-[5-(1-methyl-1H-pyrazol-4-yl)-furan-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (226 mg, 0.745 mmol) was dissolved in a mixture of THF (12.4 mL) and water (1.3 mL). The flask was cooled to −35° C. in a dry ice/acetone bath (the mixture becomes a thick slurry) and then N-bromosuccinimide (146 mg, 0.819 mmol) was added as a solid in one portion. The reaction immediately turned a bright yellow color. The reaction was stirred for 15 min at this temperature after which time anhydrous hydrazine (0.21 mL, 6.7 mmol) was added in one portion via syringe. The ice bath was removed and the reaction was allowed to stir at room temperature for 20 h. The volatiles were removed at 50° C. under a stream of N2. The resulting residue was purified by flash chromatography (silica, 90→100% EtOAc/hexanes) to give 51 mg of {1-[6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a bright yellow solid, m/z 316.6 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][C:10]=3[CH2:9][C:8]2=[O:23])=[CH:4][CH:3]=1.Cl[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:20](=[O:21])[C:19]3[C:18]([O:22][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][C:10]=3[CH2:9][C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1Cc2cc3cccnc3c(O)c2C(=O)N1Cc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1c2c(cc3cccnc13)CC(=O)N(Cc1ccc(F)cc1)C2=O)(C(C)C)C(C)C

Procedure:
For example, 7-(4-fluoro-benzyl)-9-hydroxy-5H-1,7-diaza-anthracene-6,8-dione A1.6 is reacted with one molar equivalent of chlorotriisopropylsilane and imidazole in dimethylformamide at ambient temperature, as described in Tet. Lett., 2865, 1974, to produce 7-(4-fluoro-benzyl)-9-triisopropylsilanyloxy-5H-1,7-diaza-anthracene-6,8-dione A1.7. The product is then reacted in dimethylformamide solution at about 60° C. with one molar equivalent of a dialkyl 2-bromoethyl phosphonate A1.8 (Aldrich) and lithium hexamethyldisilazide, to yield the alkylated product A1.9. The silyl protecting group is then removed by reaction with tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Org. Chem., 51, 4941, 1986, to give the phenolic product A1.10.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:36])[NH:12][CH:13]2[C:21]3[N:20]=[CH:19][C:18]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([F:29])[C:23]=4[C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:17][C:16]=3[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:26]1[CH:25]=[C:24]([F:29])[C:23]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[C:22]([C:18]2[CH:19]=[N:20][C:21]3[CH:13]([NH:12][C:11]([C:8]4([NH2:7])[CH2:10][CH2:9]4)=[O:36])[CH2:14][CH2:15][C:16]=3[CH:17]=2)[CH:27]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 36) has been treated with trifluoroacetic acid (90%) to give the title compound as light yellow oil. MS: 428.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([OH:22])=O)[CH3:3].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([NH2:25])=[O:22])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(-c3ccccc3)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A suspension of 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxylic acid (173 mg, 0.58 mmol) and 1,1'-carbonyldiimidazole (116 mg, 0.72 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 2 hours. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxamide in 94% yield; mp=192°-130° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][O-:23].[Na+]>CO.O>[CH3:22][O:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccccc2C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (317 mg, 0.998 mmol, prepared as described in the Example 1) in MeOH (5 mL) was added NaOMe (1.99 mL, 0.998 mmol, 0.5 M solution in MeOH). The resulting mixture was stirred at 70° C. overnight. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting residue was purified on silica 0:100-50:50 EtOAc-hexanes to yield 4-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.78 (d, J=7.8 Hz, 1H), 7.61-7.67 (m, 1H), 7.54-7.60 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.46 (s, 1H), 6.27 (br. s., 2H), 3.97 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Br)cc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1
Reaction time: 5 h

Procedure:
To a solution of (2S,4R)-2-(3-bromo-5-methoxycarbonyl-phenylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 1.08 mmol) in MeOH (10 mL), cooled to 0° C. was added LiOH.H2O (271 mg, 6.47 mmol) and the resulting solution was allowed to reach RT and stirred for 5 h. MeOH was concentrated and the residue was diluted in CH2Cl2, HCl 1 M was added (pH=1) and the layers were separated. The aqueous layer was back extracted twice with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the desired material which was used without further purification in the next step. MS (LC-MS): 453.0/455.0 [M+Na]+, 375.1/377.1 [MH−tBu]+, 331.1/333.1 [MH−Boc]+, 429.0/431.0 [M−H]−; tR (HPLC conditions a): 3.27 min.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH:17]=[CH2:18])C(O)=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].[O:28]1CCC[CH2:29]1>CCOCC>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[CH:17][CH2:18][CH2:29][OH:28])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCC=Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A solution of 6.0 gm (0.025 mol) of 4-(4'-biphenylyl- 3-butenoic acid (m.p. 188°C) in 100 ml of absolute tetrahydrofuran was dropwise stirred, at room temperature, into a suspension of 1.0 gm (0.026 mol) of lithium aluminum hydride in 100 ml of absolute ether. The mixture was stirred for a further 2 hours, then were successively added 1 ml of water, 2 ml of 2N sodium hydroxide solution and again 5 ml of water and the obtained precipitate was suction filtered. The solvent was distilled off from the filtrate, and the obtained firm residue was recrystallized from cyclohexane/ethyl acetate. The compound was obtained therefrom in a yield of 3.8 gm (68% of theory), m.p. 142°C, of the formula ##SPC9##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:16]([OH:17])[C:15]4[S:18][CH2:19][CH2:20][S:21][C:14]=4[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27].C(#N)C>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([O:22][C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[C:14]4[S:21][CH2:20][CH2:19][S:18][C:15]=4[C:16]3=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2ccc(Cl)cc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)cc3n2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
6-(7-Chloroquinol-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (9.0 g.) is added over the course of half an hour, at 15°-20°C, to a suspension of sodium hydride (1.35 g.) in anhydrous tetrahydrofuran (250 cc.). The reaction mixture is diluted with anhydrous dimethylformamide (50 cc.). 6-(7-Chloroquinol-2-yl)5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (a further 9.0 g.) is added over the course of half an hour, at 15°C, and then 1-chlorocarbonyl-4-methylpiperazine (25.0 g.) dissolved in anhydrous tetrahydrofuran (150 cc.) is added at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the tetrahydrofuran under reduced pressure (20 mm.Hg), the reaction mixture is treated with water (500 cc.). The gummy precipitate which has appeared is filtered off and taken up in an ice-cold 2N aqueous solution of methanesulphonic acid (350 cc.). The ice-cold aqueous acid solution is filtered and then rendered alkaline by adding 10N sodium hydroxide solution. The oil which separates out is extracted three times with methylene chloride (total 600 cc.). The organic solution is washed three times with distilled water (total 450 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (1.0 g.) and evaporated. The partially crystalline residue obtained (13.3 g.) is dissolved in boiling acetonitrile (170 cc.). After cooling for 2 hours at 2°C, the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 40 cc.) and dried under reduced pressure (20 mm.Hg). 6-(7-Chloroquinol-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.9 g.), melting at 192°C, is thus obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
6-Butyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g) were dissolved in dichloromethane (4 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.37 g, 93%) as a colorless amorphous solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:2]=[C:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN=C2CCc3cc4c(cc3C2)OCC4)cc1

Procedure:
10 g of the compound of Example 2 are brought to reflux in 200 ml of ethanol in the presence of 2.8 g of benzaldehyde. A sample is removed, concentrated and recrystallized in ethanol.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:41])[CH3:42])[NH:17][C@H:16]2[C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (26 mg, 0.411 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 250 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30° C., and 45% of methanol to give two peaks: Peak 1, undesired enantiomer, 78 mg; Peak 2, 77 mg as white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[N:4]([CH3:19])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:18])[N:6]=3)[C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
A mixture of 8-bromomethyl-2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (400 mg, 1.16 mmol), 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (250 mg, 1.17 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (20 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound (150 mg, 27%). 1H NMR (CDCl3, 400 MHz): δ 4.26 (4 H, brd s), 3.82-3.80 (9 H, m), 3.33 (2 H, brd s), 3.22 (2 H, brd s), 2.42-2.35 (2 H, m), 1.45 (9 H, s), 1.15 (6 H, s).