Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[Cl:18][C:19]1[C:20](=[O:35])[NH:21][C:22](=[O:34])[N:23]([CH:33]=1)[C@@H:24]1[O:32][C@H:29]([CH2:30][OH:31])[C@@H:27]([OH:28])[C@H:25]1O>>[CH2:1]=[C:25]1[C@H:27]([OH:28])[C@@H:29]([CH2:30][OH:31])[O:32][C@H:24]1[N:23]1[CH:33]=[C:19]([Cl:18])[C:20](=[O:35])[NH:21][C:22]1=[O:34]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1Cl
Product: C=C1[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@H](CO)[C@H]1O

Procedure:
Protection, oxidation, methylidenation and deprotection reactions were carried out similarly as in Example 7 except that the uridine was replaced by 5-chlorouridine to obtain 2'-methylidene-2'-deoxy-5-chlorouridine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:17]=3[C:16]=2[NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[O:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:6]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Reactant: O=C(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
4-chlorobutanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 119 as a white solid (45 mg).). LCMS showed MH+=448, TRET=2.77 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(C)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification. (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M−H) (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 357/359 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C(O)(=O)C.[CH3:23][NH2:24].[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:24][CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g) and molecular sieves in methanol (20 mL) at room temperature was added acetic acid (0.1 mL) and a solution of methylamine (219 mg) in methanol (1 ml). The reaction mixture was stirred at room temperature for 24 h. Then sodium borohydride (542 mg) was added portionwise and the reaction stirred at room temperature for a further 30 min. The reaction was then quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted into dichloromethane (2×10 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine as a white solid (0.95 g).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:26][C:27]([F:36])([F:35])[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46]([CH3:49])=[CH:47][CH3:48])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38].O>ClCCl>[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46](=[CH:47][CH3:48])[CH2:49][C:28]([OH:34])([C:27]([F:35])([F:36])[F:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38]
Reactant: CC=C(C)c1ccc(C(C)C)cc1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(C(C)C)cc1OC

Procedure:
Ytterbium(III) trifluoromethanesulphonate (3.25 g, 5.23 mmol) in 116 ml of dichloromethane is admixed dropwise at room temperature with ethyl trifluoropyruvate (9.55 ml, 78.5 mmol). Following the addition of 4-isopropyl-2-methoxy-1-(1-methylpropenyl)benzene (10.7 g, 52.37 mmol), in solution in 29.5 ml of dichloromethane, the reaction mixture is stirred at room temperature for two days. In parallel a second batch is carried out with the same quantities and under the same conditions. Water (100 ml) is added to each of the two reactions. For further working up, the two batches are combined. The dichloromethane phase is separated off and the aqueous phase is extracted a further time with dichloromethane (300 ml). The combined organic extracts are washed with water (100 ml) and brine (100 ml) and then dried (Na2SO4). After removal of the solvent on a rotary evaporator, the residue is purified by repeated chromatography on silica gel (eluent: ethyl acetate/hexane). The yield of ene product, which is used in the next stage, is 9.08 g, only 40% being the described compound and 60% being the corresponding ethyl 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pent-4-enoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70 mg, 0.309 mmol) in DCM (3 mL) were added acetyl chloride (32 μL, 0.450 mmol) and triethylamine (54 μL, 0.526 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, and washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (41 mg, 79%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(Cl)cc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 3,5-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (40 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-(3,5-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.36 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 9.14 min (96.29%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.86-2.12 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.60 (d, J=16.4 Hz, 1H, CHH), 2.77-3.05 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.38-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.00 (t, J=5.9 Hz, 1H, NH), 7.08 (t, J=1.7 Hz, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.48-7.59 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 9.08 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.83, 47.12, 51.58, 115.78, 120.16, 121.92, 122.94, 126.92, 130.35, 133.93, 142.39, 142.93, 144.43, 154.77, 167.92, 170.98, 172.85; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.61; H, 3.78; N, 11.84; Cl, 15.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:64]=[CH:63][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C@@H:19]([CH2:42][O:43]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:18][C@H:10]2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(O)=O>CCOCC>[CH3:1][O:2][C:3]1[CH:64]=[CH:63][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[C@@H:19]([CH2:42][OH:43])[O:18][C@H:10]2[S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2OCc2ccc(OC)cc2)cc1
Solvent: O=CO
Solvent: CCOCC
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-(4-methoxybenzyl)-6-O-triphenylmethyl-1-thio-β-D-glucopyranoside (7) (3.44 g, 3.93 mmol) in ether (8 ml) was added formic acid (8 ml), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen-carbonate solution and saturated brine, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixture of ethanol (5 ml) and 1N aqueous sodium hydroxide solution (5 ml), and the suspension was stirred overnight at room temperature. Ethanol was evaporated under reduced pressure and the resulting suspension was extracted twice with ether. The combined ether layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1) to give phenyl 2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (8) (1.28 g, yield 51%) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][N:31]([CH2:39][CH:40]=O)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([C:13]1[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][CH2:40][CH2:39][N:31]([CH3:30])[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[N:10]=[C:11]([C:26]([F:28])([F:29])[F:27])[CH:12]=1)=[O:15]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a stirred solution of 58 (200 mg, 0.386 mmol) in MeOH (2.0 mL) was added tert-butyl methyl(2-oxoethyl)carbamate (100 mg, 0.579 mmol) followed by acetic acid (44.2 μl, 0.772 mmol). After stirring for 30 min, sodium cyanoborohydride (61 mg, 0.964 mmol) was added and the resulting solution was allowed to stir at 21° C. for 16 h. The solvent was removed by evaporation and the residue taken in saturated NaHCO3. It was then extracted three times with CH2Cl2, dried over Na2SO4 and evaporated. The residue was purified via silica gel flash chromatography (40% to 100% EtOAc/hexanes). The title product 59 (81 mg, 37% yield) was isolated as a yellow solid. LRMS (ESI): calc. 561.6; found 562.7 (MH)+.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][C:16]#[C:17][CH2:18][S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CO>[C:21]([O:23][CH3:24])(=[O:22])[CH2:20][S:19][CH2:18][C:17]#[C:16][CH2:15][S:13][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCS
Reactant: COC(=O)CSCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
2 ml of a 30% solution of sodium methoxide in methanol were added to a solution of 2 ml of nonanethiol in a 20 ml methanol/5 ml THF mixture, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 2 g of methyl 7-chloro-3-thia-5-heptynoate in 20 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oil thus obtained was chromatographed on a silica gel column (CH2Cl2/heptane 85/15) providing 2.1 g of methyl 3,8-dithia-5-heptadecynoate in the form of an orange-colored oil (yield 64%).
Reaction SMILES: C([O:3][C:4](=[S:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([S:13]C(=O)C)[CH2:10][CH2:11][CH3:12])C.[OH-].[K+].CO>O>[SH:13][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[S:17]
Reactant: CCCC(CCCCC(=S)OCC)SC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(S)CCCCC(O)=S
Yield: 84.5 %

Procedure:
11.9 grams (40.7 mmoles) of 6-acetylthio-8-methylthiooctanoic acid ethyl ester (XI) were added to a solution of 7.5 grams (133.7 mmoles) of potassium hydroxide in l00ml of methanol and 5 ml of water and the mixture heated at reflux for 10 hours under a cover of nitrogen. After a further 10 hours at room temperature the solvent was removed in a vacuum, the residue taken up in 100 ml of 3N hydrochloric acid and extracted three times, each time with 100 ml of ethyl acetate. After drying the combined extracts with magnesium sulfate the solvent was removed in a vacuum. The short path distillation of the residue gave 7.1 grams (78% of theory) of 6-mercapto-8-methylthiooctanoic acid as a pale yellow oil having a boiling point of 150° C. to 170° C. at 0.5 mbar.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:20][CH:21]=3)[C:12]([S:15][CH3:37])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCOCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F45-03, 2.43 g, 4.72 mmol) and potassium carbonate (653 mg, 4.72 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) and then methyl iodide (0.29 mL, 4.72 mmol) were added. After heating at 80° C. stirring for an hour, the reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The reaction system was mixed with water, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium sulfate, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a pale yellow foam (2.18 g) containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F45-04).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:15]([CH2:22][C:23](OCC)=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:28]=1)#[N:2].[CH2:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C:23]([NH:31][CH2:29][CH3:30])=[O:24])[C:7]=2[CH:28]=1)#[N:2]
Reactant: CCN
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Product: CCNC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
The title compound was prepared from (3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]acetic acid, ethyl ester (the title compound of Example 3) and ethyl amine by the same procedure as described for the title compound of Example 7. The product was triturated with hexanes to give the title compound as a colorless solid, mp 213°-215° C. Analysis calculated for C22H25N3O3 : C, 69.64; H, 6.64; N, 11.07. Found: C, 69.31; H, 6.33; N, 10.96. [α]D =+76.6° (c=0.47, CDCl3).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1
Reactant: OCc1cc(-c2ccccc2)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cc(-c2ccccc2)on1
Yield: 58 %

Procedure:
3-Hydroxymethyl-5-phenylisoxazole (2.10 g, 12 mmol) was refluxed with triphenylphosphine (3.14 g, 12 mmol) in carbon tetrachloride (40 ml) overnight. After cooling the solvent was removed under reduced pressure and the residue taken up in ether, the solution filtered and concentrated to give an oil. This material was filtered through a plug of silicagel (5 g, ether-hexane 1:1) to remove triphenylphosphine oxide then crystallised to give the title compound (1.33 g, 6.9 mmol, 58%); m.p. 48°-9° C.; νmax (CHCl3) 3000, 1610, 1590, 1570, 1450, 1265, 945, 690 cm-1 ; δH (CDCl3) 4.55(2H,s,CH2Cl), 6.55(1H,s,CH-het) 7.2-8.0(5H,m,Ph).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]([CH3:25])([CH3:24])[C@@H:21]([NH2:23])[CH3:22]>C(#N)C>[CH3:19][C:20]([CH3:25])([CH3:24])[C@@H:21]([NH:23][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:22]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccc(F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (5.0 g, 0.027 mol) and K2CO3 (7.45 g, 0.054 mol) in acetonitrile (100 mL) was added (S)-3,3-dimethylbutan-2-amine (3.24 g, 0.032 mol), and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (6.40 g, 94%). 1H NMR (CDCl3): 0.82 (s, 9H), 0.91-0.96 (d, 3H), 2.14-2.22 (m, 1H), 2.73-2.82 (m, 1H), 3.01-3.11 (m, 3H), 7.01-7.09 (m, 2H), 7.88-7.96 (m, 2H).