Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>C(Cl)Cl.O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(CO)CO
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCC(CO)NC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
2.75 g of 2-aminopropan-1,3-diol and 5.9 g of 1-benzyl-4-piperidone are dissolved in 60 ml of methylene chloride and while cooling with ice a total of 9.9 g of sodium triacetoxyborohydride are added batchwise. The mixture is left to stand overnight at ambient temperature. 60 ml of methylene chloride and some water are added, then conc. hydrochloric acid is added while cooling with ice until an acid reaction is obtained. The mixture is stirred for about another 15 min. with cooling and then made clearly alkaline with 4 N sodium hydroxide solution. The aqueous phase is separated off, the organic phase is washed with a very little water, dried over sodium sulphate and freed from solvent in vacuo. 8 g of substance are obtained which are chromatographed with methylene chloride/methanol 8:2 over 150 g of silica gel. The uniform fractions according to TLC are combined and freed from solvent in vacuo. 7.3 g of 1-benzyl-4-(1,3-dihydroxyprop-2-ylamino)-piperidine are obtained.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[C:13]([CH3:20])[C:12]=2[N:21]2[CH2:26][CH:25]3[CH:23]([CH2:24]3)[CH2:22]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>O1CCOCC1>[F:28][C:2]([F:1])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:21]3[CH2:26][CH:25]4[CH:23]([CH2:24]4)[CH2:22]3)=[C:13]([CH3:20])[C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: C1COCCO1
Product: Cc1c(N2CC3CC3C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c12

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-aza-bicyclo[3.1.0]hex-3-yl]-3-methyl-4-methylamino-5-amino-benzoic acid amide (80 mg, 0.195 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (62 mg, 0.19 mmol), DIC (36 μL) and dioxane (5.0 mL).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)O[CH2:3][CH2:2]1.C(I)C>>[CH2:2]([O:1][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH3:3]
Reactant: OC1CCC2(CC1)OCCO2
Solvent: CCI
Product: CCOC1CCC(=O)CC1

Procedure:
The title compound was prepared as white solid from reaction of 1,4-dioxa-spiro[4.5]decan-8-ol and EtI (Aldrich) followed by de-protection using the procedure described in Example 34.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12]O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: OCCCc1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: BrCCCc1ccc2c(c1)OCO2

Procedure:
Compound 21-1 (9.72 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (5.27 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 6.5 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.05 g) as a pale-yellow oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:16])[NH:6][C:7]1[O:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][N:11]=1.[CH:19]([C:22]1[N:26]2[CH:27]=[C:28]([O:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:35]([NH2:42])[CH2:34][CH2:33]3)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:12]([C:9]1[O:8][C:7]([NH:6][C:5]([NH:42][C@@H:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:32]([O:31][C:28]3[CH:29]=[CH:30][C:25]4[N:26]([C:22]([CH:19]([CH3:21])[CH3:20])=[N:23][N:24]=4)[CH:27]=3)[CH2:33][CH2:34]2)=[O:16])=[N:11][N:10]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4nnc(C(C)(C)C)o4)c4ccccc43)cn12
Yield: 81.4 %

Procedure:
A solution of Intermediate 5d (83.1 mg, 0.263 mmol), Intermediate 5c (80.6 mg, 0.250 mmol), and DIPEA (54.4 μL, 0.313 mmol) in DMF (2 mL) was stirred at 125° C. for 45 min. After cooling, the mixture was concentrated in vacuo to give a brown oil. This was suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to leave a brown oil. Purification by FCC, using 0-8% MeOH in EtOAc, followed by trituration (diethyl ether) afforded a buff solid (99.6 mg). Further purification by HPLC (10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a flocculent white solid (25.9 mg, 21%). LCMS (Method 5): Rt 3.77 min, m/z 490 [MH+]. 1H NMR (400 MHz, CDCl3): 1.39 (9H, s), 1.52 (3H, d), 1.55 (3H, d), 2.00 (1H, m), 2.21-2.36 (2H, m), 2.43 (1H, m), 3.32 (1H, sept), 5.28-5.34 (2H, m), 7.12 (1H, dd), 7.30-7.38 (3H, m), 7.47-7.50 (2H, m), 7.73 (1H, d), 8.35 (1H, br s), 8.49 (1H, br d).
Reaction SMILES: [Br-].[CH:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCCCCC.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[N:59]=[CH:58][C:57]([CH:60]=O)=[CH:56][N:55]=2)=[CH:50][CH:49]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>COC(C)(C)C.O1CCCC1>[CH:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:60][C:57]2[CH:58]=[N:59][C:54]([C:51]3[CH:52]=[CH:53][C:48]([O:47][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:49][CH:50]=3)=[N:55][CH:56]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCOc1ccc(-c2ncc(C=O)cn2)cc1
Reactant: c1ccc([P+](CCCCCCCCC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2ncc(C=CCCCCCCCC3CCCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3.7 g of (8-cyclopentyl-octyl)-triphenylphosphonium bromide (prepared by heating 3.4 g of (8-bromooctyl)-cyclopentane and 3.9 g of triphenylphosphine in 15 ml of toluene overnight and precipitation of the product from the cooled reaction mixture by addition of hexane) in 20 ml of tert.-butyl methyl ether is treated with 0.8 g of potassium tert.-butylate and the yellow suspension is stirred at room temperature for 45 minutes. Then, a solution of 1.64 g of 2-(4-heptyloxy-phenyl)-pyrimidine-5-carboxaldehyde in 10 ml of tetrahydrofuran is added dropwise at 0° to 5° C. The reaction mixture is stirred at 0° C. for a further 2 hours and then triturated with 10 ml of saturated sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue is partitioned between methanol/water (vol.) 4:1 and hexane and the methanol phase is separated. The hexane phase is washed with methanol/water 4:1 and the filtrate is concentrated. The crude 5-(9-cyclopentyl-non-1-enyl)-2-(4-heptyloxy-phenyl)-pyrimidine obtained is purified by chromatography on 10 g of silica gel with hexane/ethyl acetate 19:1 (v/v).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19]=3[CH:18]=[CH:17]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[S:35]([NH2:38])(=[O:37])=[O:36]>>[S:35](=[O:37])(=[O:36])([O:15][CH2:14][C@@H:13]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][C@H:11]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:19]=3[CH:18]=[CH:17]2)[O:12]1)[NH2:38]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reactant: NS(=O)(=O)Cl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Yield: 48 %

Procedure:
Using essentially the same procedure as example 43 step f, N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide (0.524 g, 1.12 mmol) was reacted with chlorosulfonamide and the product was purified by flash chromatography (20 to 50% EtOAc/hexanes) to afford the title compound as a white foam (0.292 g, 48%).
Reaction SMILES: C([S:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][CH2:40][S:41][CH2:42][CH2:43][CH2:44][S:45]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)Cl>[SH:45][CH2:44][CH2:43][CH2:42][S:41][CH2:40][CH2:39][CH2:38][S:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][S:28][CH2:27][CH2:26][CH2:25][S:24][CH2:23][CH2:22][CH2:21][SH:20]
Reactant: c1ccc(C(SCCCSCCCSCCOCCOCCSCCCSCCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: SCCCSCCCSCCOCCOCCSCCCSCCCS
Temperature: 25 °C
Yield: 58 %

Procedure:
A 2.14 g amount of 1,26 ditrityl-1,5,9,18,22,26-hexathia-12,15-dioxahexacosane was dissolved in a mixture of 9.0 ml of triflouroacetic acid and 9.0 ml of methylene chloride. About 0.7 ml of triethylenesilane was added and stirred at room temperature for a half hour. About 100 ml of methylene chloride was added to the mixture and this was washed with 50 ml of water. The organic layer was then dried with magnesium sulfate and filtered. The solvent was evaporated from filtrate and the residue was purified on silica gel using a mixture of methylene chloride and acetone (5:1 v/v). About 620 mg (58%) of 1,5,9,18,22,26-hexathia-12,15-dioxahexacosane was obtained. The preparation scheme is shown below:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.[Cl-].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:5]2[C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]([NH2:1])=[C:3]([S:19]([OH:22])(=[O:21])=[O:20])[CH:4]=2)=[CH:25][CH:26]=1
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Product: Nc1c(S(=O)(=O)O)cc(Nc2ccc(O)cc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
38.2 parts of 1-amino-4-bromo-2-sulfoanthraquinone (bromamine acid) are condensed in an aqueous suspension with 12.7 parts of 4-aminophenol with the addition of 1 part of copper(II) sulfate at a pH of 8.5 and a temperature of 70° C. over a period of 1 to 2 hours. This results in a dark blue solution. After cooling to 20°-25° C., the reaction mixture is acidified until reaching a pH of about 1, stirred at 60° C. for about 1 h, salted out with sodium chloride, and the dye chromophore 4-(4'-hydroxyphenyl)amino-1-amino-2-sulfoanthraquinone is isolated by suction filtration.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[C:17]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nccs1
Product: CCOC(=O)C(=CNc1nccs1)C(=O)OCC

Procedure:
2-Aminothiazole (10.0 g., 0.10 mole) and diethyl ethoxymethylenemalonate (23.8 g., 0.11 mole) were combined and heated on a steam bath for 1.25 hours. The reaction mixture was cooled and the resulting semisolid recrystallized from hexane to yield purified 2-(2,2-dicarbethoxyethenyl)thiazole (17.2 g. in two crops, Rf 0.6 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[H][H]>CO.Cl.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:14][CH2:15][CH2:16][CH2:17]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(CCC3(O)CCCC3)nc21
Yield: 69 %

Procedure:
To a solution of 300 mg of 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cyclopentanol in 20 ml of methanol were added six drops of 5N hydrochloric acid and 63 mg of 10% palladium/carbon and the mixture was stirred in a hydrogen atmosphere at room temperature for 17 hours. The palladium/carbon was filtered off, the filtrate was concentrated and the residue was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane, dichloromethane/methanol (40:1, 20:1 and 10:1) to give 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopentanol. This was dissolved in methanol and then five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ether was added to the residue and the crystals were collected by filtration and washed with ether to give 6209 209 mg of the product. The yield was 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[C:11]([NH2:18])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[O:27].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][C:10]2[C:11](=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[NH:18][C:26]1=[O:27]
Reactant: CSc1ncc(CNc2ccccc2Cl)c(N)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a stirred solution, cooled to 0° C., of 5-(2-chlorophenyl) aminomethyl-4-amino-2-methylthiopyrimidine (7.0 g, 24.9 mmol) in 200 mL of tetrahydrofuran was added triethylamine (10 mL, 71.7 mmol). This solution was then treated dropwise with a solution of phosgene (14.2 mL of 20% solution in toluene, 27.2 mmol). After stirring for 2 hours, an additional 5.0 mL of triethylamine (35.9 mmol) was added followed by phosgene (6.5 mL of 20% solution in toluene; 12.5 mmol). After stirring for an additional 2 hours, additional triethylamine (21n, 14.3 mmol) was added followed by phosgene (3 mL of 20% solution in toluene; 5.8 mmol). The reaction was stirred for one additional hour then warmed to room temperature, poured onto a heterogeneous solution of 75 mL water and 150 mL ethyl acetate. The mixture was then filtered and the phases separated. The aqueous phase was re-extracted twice with 150 mL ethyl acetate. The combined ethyl acetate extracts were concentrated under reduced pressure. The residue was stirred with ethyl acetate. The product was then collected by vacuum filtration and dried in vacuo to give 3.2 g of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (sulfide 10.1)as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].C[O:29][C:30](=[O:35])[CH2:31][C:32](O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:32](=[O:33])[CH2:31][C:30]([OH:35])=[O:29])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: COC(=O)CC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (103 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) and malonic acid monomethyl ester chloride (42 mg, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was taken up in 20 ml and 2 N NaOH (2 ml) was added. The solution was stirred at room temperature overnight. Thereafter, the mixture was evaporated in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 8:2:0.1, l=15 cm, V=5 ml). The crude product was taken up in CH2Cl2 again, the mixture was filtered with a glass filter crucible G4 and Celite® (kieselguhr from CELITE Corp., Lompoc, USA) and the filtrate was evaporated in vacuo. A colorless solid was obtained.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[O:13]=[S:14]1(=[O:41])[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][C@H:29]([CH2:31][NH:32]C(=O)OC(C)(C)C)[O:28][C:27]3=[O:40])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.C1(C(C2C=CC=CC=2)CCO[C:69](=[S:73])[CH:70]([F:72])[F:71])C=CC=CC=1>ClCCl.CO>[O:41]=[S:14]1(=[O:13])[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][C@H:29]([CH2:31][NH:32][C:69](=[S:73])[CH:70]([F:72])[F:71])[O:28][C:27]3=[O:40])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(N2C=CS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (0.26 mL, 1.41 mmol) is added slowly over 15 min to a solution of the product from Step 7 (0.30 g, 0.71 mmol) and 2,6-lutidine (0.25 mL, 2.1 mmol) in dichloromethane (1.5 mL). The solution is stirred at room temperature for 1 h and then treated with methanol (1 mL). After 30 min, the solution is concentrated and redissolved in methanol (4 mL) and diisopropylethyl amine (0.38 mL, 2.1 mmol) is added. A solution of difluoro-thioacetic acid O-(3,3-diphenyl-propyl) ester (0.325 g, 0.71 mmol) in dichloromethane (0.5 mL) is then added and the solution stirred for 20 h at room temperature. The reaction mixture is then concentrated and the residue purified by column chromatography (0–1% MeOH-DCM) to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:34].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:34])=[O:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reaction time: 0.08 h
Yield: 31 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(10-formyldecyl) quinoline-N-oxide is dissolved in acetone, and 10 m moles of Jones' reagent prepared from chromium trioxide, sulfuric acid and water is added thereto with ice cooling. The mixture is stirred for 5 minutes. After the reaction, water is added thereto, and the reaction mixture is extracted with chloroform. The extract is dried over anhydrous sodium sulfate, and then the solvent is removed therefrom by distillation. The residue is purified by silica gel column procedure, whereby the captioned compound is obtained as colorless crystals (yield: 31.0%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([Cu])#[N:15].N>CN(C)C=O>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:14]#[N:15]
Reactant: COc1cc(I)cc(C(F)(F)F)c1
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1-iodo-3-methoxy-5-(trifluoromethyl)benzene (2.23 g, 7.38 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added CuCN. The reaction mixture was stirred at 100° C. for 24 h, and then poured into aq. NH3 (100 mL) and extracted with ethyl acetate (100 mL). Separated organic portions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. Purification via flash chromatography (ethylacetate/hexanes: 5% to 80%) afforded the title product (1.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[NH:48][CH:46]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)[CH3:47])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CC(N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (0.60 g, 2.32 mmol) and HATU (1.06 g, 2.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then 1-(4-fluorophenyl)ethanamine (0.323 g, 0.3 mL, 2.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.880 g, 99.9% yield): HPLC retention time: 2.098 min (method A). MS (ESD) (M+H)+ 380/382.