Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(C)=O)cc12)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (3.03 g), pyridine (3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture was added acetic anhydride (1.88 g). The reaction mixture was stirred for 30 minutes under ice-cooling and then for 2 hours and 15 minutes at ambient temperature. Ice water was added to the mixture. The resultant mixture was extracted with chloroform. The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel (developing solvent: chloroform) and recrystallized from chloroform, ethyl acetate and hexane to give crystalline diethyl [(6-acetamido-4-quinazolinylamino)methylene]-propanedioate (2.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22](N2C=CC(=O)NC2=O)[CH2:21]1.[N-]=[N+]=[N-].[K+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:22]2[O:23][C@H:24]([CH2:25][OH:26])[C@@H:20]([F:19])[CH2:21]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1nc(NCc2ccccc2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Product: Nc1nc(NCc2ccccc2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 24 h
Yield: 53.3 %

Procedure:
2-Amino-6-benzylamino-9H-purine (0.64 g, 2.7 mmoles) and 2',3'-dideoxy-3'-florouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer containing 0.04% potassium azide. After the pH was adjusted to 7.0, purified purine nucleoside phosphorylase (15,700 I.U.) and thymidine phosphorylase (4,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) were added to the reaction and the suspension was stirred at 45° C. After 24 hours, purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase immobilized onto 10 ml of DEAE-cellulose were added. After an additional two days, 150 ml of methanol was added to the reaction. The reaction was filtered through Celite and the filtrate was applied to an ionic exchange column (AG1-X2, 2.5×10 cm, OH-- form). After eluting the product with methano, fraction were combined and concentrated. The residue was then purified by flash chromatography on silica gel (5×20 cm column) with dichloromethane:methanol (95:5). Solvent was removed and lyophilization yielded 0.42 g of 2-amino-6-benzylamino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (54%): mp 90°-94° C.; [α]D20 -16.2 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 282 (17.5); at pH13, 282 (17.7); 1H NMR (300 MHz, DMSO-d6) δ7.95 (s, 1H, H8), 7.93 (b, 1H, NH), 7.28 (m, 5H, C6H5), 6.23 (dd, 1H, H1', J=9.4 Hz, J=5.6 Hz), 5.87 (b, 2H, NH2), 5.54 (t, 1H, OH5', J=5.7 Hz), 5.40 (dd, 1H, H3', J=53.7 Hz, J=4.2 Hz), 4.68 (b, 2H, CH2), 4.19 (dt, 1H, H4', J=27.2 Hz, J=4.4 Hz), 3.60 (m, 2H, H5' and H5"), 2.90 and 2.58 (m, 2H, H2' and H2"); MS (ci) 359 (M+1), 339 (M-F), 241 (MH2 --C5H8FO2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[C:16]([Cl:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1>[Cl:25][C:16]1[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=1[S:21]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](=[O:12])(=[O:11])[NH2:13])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1cc(F)c(F)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(F)c(F)cc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
2-Amino-4,5-difluorobenzenesulfonamide (99 mg, 0.48 mmol) and dichlorobenzenesulfonyl chloride (152 mg, 0.62 mmol) were dissolved in anhydrous pyridine (2 mL). The mixture was stirred at ambient temperature under an atmosphere of argon for 24 h. The solvent was evaporated in vacuo, water was added and the product was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. Purification by preparative HPLC gave 107 mg (54% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:18]2[C:17](=[O:22])[CH2:21][CH2:20][CH:19]=2)=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: CCc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: CCc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 97 %

Procedure:
The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 97% yield (2.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH2:70])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH:70][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (28.7 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (37.8 mg, purity 98.5%). MS m/z [M+H]+ calc'd for C29H25ClN4O8, 593.14. found 593.0.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][C:10]([S:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:10]([S:13]([N:15]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:14])([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)S(N)=O
Reactant: COC(=O)CCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)CCC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of commercially available methyl 4-oxobutanoate (4.454 g; 38.36 mmol) in DCM (90 ml) was treated with 2-methylpropane-2-sulfinamide (4.650 g; 38.36 mmol) and with anh. CuSO4 (12.246 g; 76.73 mmol). The resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 12 h. The resulting grey mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained orange filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 4-((tert-butylsulfinyl)imino)-butanoate as a yellow oil. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 220.40 g/mol.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:10]=[C:11](SCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCCCCC>C(Cl)Cl>[NH:10]=[C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=N)SCC
Reactant: Cc1c(N)cccc1F
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(=N)Nc1cccc(F)c1C
Reaction time: 12 h

Procedure:
To a solution of 3-fluoro-2-methylaniline (200 mmol, 25 g) in methylene chloride (70 ml) was added a solution of ethyl imino(ethylthio)acetate hydrogentetrafluorobarate (200 mmol) prepared by a method disclosed in Japanese Patent Laid-open Publication No. 56-39092 in methylene chloride (100 ml), and the mixture was thoroughly shaken and allowed to stand at room temperature for 12 hours. At the end of the period, n-hexane (300 ml) was added to the reaction mixture and the mixture was allowed to stand for 2 hours. After removal of a supernatant by decantation, methylene chloride (200 ml) was added to the remaining mixture, which was then neutralized by addition of an aqueous solution of sodium bicarbonate with thorough stirring. From the resulting mixture an organic phase (a solution in methylene chloride) was separated and dried over anhydrous magnesium sulfate overnight. After removal of inorganic materials by filtration, the filtrate was concentrated under reduced pressure to obtain ethyl imino[(3-fluoro-2-methylphenyl)amino]acetate. The product was dissolved in ethanol (80 ml), and to the resulting solution 37% formalin (30 ml) was added and the mixture was thoroughly shaken and allowed to stand overnight. The crystalline product so produced was filtered and recrystallized from ethanol. A white crystalline product (86 mmol, 18 g) was obtained in a yield of 43%.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)c(F)c1-c1cccnc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.9 %

Procedure:
A mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.37 mmol), 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (132 mg, 0.56 mmol) and 2 M Na2CO3 (0.56 ml) in 1,2-dimethoxyethane (2 ml) was degassed for 10 min with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.022 g) was added and the mixture was stirred under nitrogen at 80° C. for 12 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2.5% MeOH/CH2Cl2), to give 78 mg (55%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.17–7.22 (1H, m), 7.37–7.41 (1H, m), 7.80 (1H, d, J 8.4), 8.10–8.16 (1H, m), 8.56 (1H, d, J 2.6), 8.62 (1H, dd, J 4.6, 1.5), 8.72 (1H, 8.74 (1H, s); MS (ES+) m/z 378 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH3:23][CH:24]([CH2:28][S:29][CH3:30])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH:24]([CH3:23])[CH2:28][S:29][CH3:30]
Reactant: CSCC(C)C(=O)Cl
Reactant: CCNc1sc(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 35 °C
Yield: 90 %

Procedure:
Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc(Br)ccn1
Product: COC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=281.0 (Me) was obtained as a light yellow solid (10% yield) by the reaction of 4-bromo-pyridine-2-carboxylic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5]Br.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(CF)(CF)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(CF)(CF)C(=O)Cn1cncn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
215 g (1 mole) of crude 3,3-bisfluoromethyl-1-bromo-butan-2-one were added dropwise to 84 g (1.2 moles) of 1,2,4-triazole and 165 g (1.2 moles) of ground potassium carbonate in 1 liter of ethanol at 30° to 35° C. The mixture was subsequently stirred at 40° C. overnight, the insoluble material was then filtered off and the filtrate was concentrated. The oily residue was extracted with methylene chloride and water and the extract was dried over sodium sulphate and concentrated. The residue was taken up in methylene chloride and 140 ml of ethereal hydrochloric acid were added. The crystalline product formed was filtered off with suction and extracted by stirring with 1 liter of methylene chloride and 1 liter of saturated aqueous sodium bicarbonate solution, and the extract was washed with 1 liter of water, dried over sodium sulphate and concentrated. 73.8 g (36.4% of theory) of 3,3-bisfluoromethyl-1-(1,2,4-triazol-1-yl)-butan-2-one were obtained as an oil, which could be further reacted directly. ##STR35##
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH2:8][CH2:7]2.[OH-:20].[Na+].OO>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:20])[CH2:8][CH2:7]2
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CCC=C2c1ccccc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Yield: 37 %

Procedure:
Borane in tetrahydrofuran (34 mL of a 1M solution, 34 mmol) was added to tetrahydrofuran (50 mL) and the resultant solution was cooled to 0° C. A solution of 6-methoxy-1-phenyl-3,4-dihydronaphthalene 28 (5.0 g, 21.2 mmol) in tetrahydrofuran (10 mL) was added. The resultant mixture was stirred at ambient temperature for 18 h. A solution of water (5 mL) in tetrahydrofuran (20 mL) was slowly added to the cooled solution which resulted in considerable foaming. Additional water (10 mL) was added followed by 10% aqueous sodium hydroxide (15 mL) and 30% hydrogen peroxide (30 mL). The resultant mixture was stirred at room temperature for 6 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic solutions were washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 30 to 40% ethyl acetate in hexanes as the eluent, to afford trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 as an oil (2.0 g, 37%). 1H NMR(CDCl3) δ1.77 (d, 1H), 1.83-1.97 (m, 1H), 2.13-2.22 (m, 1H), 2.94-3.05 (m, 2H), 3.78 (s, 3H), 3.90 (d, 1H), 3.98-4.07 (m, 1H), 6.59-6.70 and 7.16-7.39 (m, 8H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12].Cl.CN(C)CCCN1C=CN(C(N2C=CN(CC)C2)=O)C1.[F:40][C:41]([F:62])([F:61])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([CH3:53])[CH:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[F:40][C:41]([F:61])([F:62])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:5](=[O:7])[C:4]2[C:3](=[C:2]([I:1])[CH:10]=[CH:9][CH:8]=2)[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12])=[C:48]([CH3:53])[CH:47]=1
Reactant: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)O
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Agent: CCN1C=CN(C(=O)N2C=CN(CCCN(C)C)C2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Iodo-N-((S)-1-methyl-2-methylthioethyl)-phthalamic acid (0.38 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbonyldimidazole hydrochloride (0.2 g) were stirred in methylene chloride (10 ml) at room temperature for 30 minutes. 4-(3,5-Bis-trifluoromethyl-benzyl)-2-methylaniline (0.3 g) and p-toluenesulfonic acid hydrate (0.02 g) were added thereto and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-iodo-N2-((S)-1-methyl-2-methylthioethyl) phthalamide (0.15 g).
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)[Cl:3].[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Mg]Br>O1CCCC1>[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Si:2]([Cl:5])([Cl:3])[Cl:1]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: CC(C)CCCC(C)CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrahydrofuran (100 ml) and tetrachlorosilane (17.0 g, 100 mmol) were placed in a 500 mL four-necked flask in a nitrogen atmosphere, and cooled to −10° C. 3.7-dimethyloctyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 100 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target 3,7-dimethyloctyl trichlorosilane (99-102° C./0.3 Torr, 22.3 g, yield 81%).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[C:26]([CH3:35])[CH:25]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)(=[O:23])=[O:22])=[CH:25][C:26]=2[CH3:35])[CH2:31]1
Reactant: COC(=O)CBr
Reactant: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Triethylamine (0.387 mL, 1.533 mmol) and methyl bromoacetate (0.146 mL, 1.533 mmol) were added at 0° C. to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.445 g, 1.393 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.410 g (84% yield) of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester as a yellow oil.