Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:16](=[O:23])([O:20]CC)[O:17]CC)[P:8](=[O:15])([O:12]CC)[O:9]CC.Br[Si](C)(C)C>C(#N)C.O>[OH2:9].[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:8](=[O:9])([OH:15])[OH:12])[P:16](=[O:17])([OH:20])[OH:23].[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:8](=[O:9])([OH:15])[OH:12])[P:16](=[O:17])([OH:20])[OH:23]
Reactant: CCOP(=O)(OCC)C(NCCCSC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CC#N
Product: CSCCCNC(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
To a solution of tetraethyl 3-methylthiopropylaminomethylenebisphosphonate (5.28 g) in acetonitrile (100 ml) was added bromotrimethylsilane (12.39 g) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water (3.2 ml) and concentrated under reduced pressure. The solid residue was collected by filtration and recrystallized from water-methanol to give 3-methylthiopropylaminomethylenebisphosphonic acid hemihydrate (1.84 g, 47%). Colorless prisms, m.p. 120°-122° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(CO)Cc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Dissolve 3-(hydroxymethyl)-3,4-dihydro-2H-isoquinolin-1-one (6.0 g, 33.86 mmol) in DCM (60 mL) and add triethylamine (7.25 g, 67.72 mmol). Cool to 0° C. and add methanesulfonyl chloride (4.65 g, 40.63 mmol) drop-wise. Stir for one hour; dilute with DCM; and wash with water and then brine. Remove the solvents under reduced pressure to give the title compound (8.0 g, 92%). MS (m/z): 256 (M+1).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[CH3:7].[CH2:13]1[O:15][CH2:14]1.[NH4+].[Cl-]>C1COCC1>[CH2:6]([C:8]1[O:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=1)[CH3:7]
Reactant: C1CO1
Reactant: CCc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
n-BuLi (2.5 M in hexane, 4.4 mL, 11 mmol) was added to a solution of 2-ethylfuran (1.05 mL, 10 mmol) in THF (10 mL) at −25° C. The solution was warmed to rt and stirred for 3 h. Ethylene oxide (0.75 mL) was added at −78° C. The reaction was stirred for 0.5 h at −15° C. and overnight at rt. Aqueous sat. NH4Cl was added and the mixture was extracted with ether (3×). The combined extracts were washed with water (1×) and brine (1×) and dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 30% EtOAc/70% hexane gave 1.12 g (8.02 mmol, 80.2%) of compound 245A as a yellow oil.
Reaction SMILES: [Na].[NH:2]1[C:6]([SH:7])=[CH:5][N:4]=[N:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27]Cl)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27][S:7][C:6]3[NH:2][N:3]=[N:4][CH:5]=3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Sc1cnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnn[nH]3)c2CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Slurry 1H-[1,2,3]triazole-5-thiol sodium salt (465 mg, 3.78 mmol) in anhydrous DMF (20 mL). Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 3.4 mmol) in anhydrous DMF (10 mL) dropwise over 10 min under nitrogen. Stir at room temperature for 3 h. Quench by addition of saturated NH4Cl (100 mL). Extract with EtOAc (3×50 mL) and dry the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain 3-tert-butoxycarbonyl-7-chloro-6-(3H-[1,2,3]triazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.2 g, 90%) as a yellow oil suitable for use without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:39].[N:40]1([C:45](N)=[NH:46])C=CC=N1>CN(C)C=O>[ClH:39].[ClH:39].[CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:45](=[NH:40])[NH2:46])[CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.9 %

Procedure:
To a solution of 1-(pyridin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (8.29 g) in dimethylformamide (50 ml) were added diisopropylethylamine (4.4 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (3.69 g), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether (350 ml) and the supernatant was removed. The obtained oil was dissolved in methanol (20 ml) and thereto was dropwise added diethyl ether (700 ml) with stirring. The supernatant was removed and dried under reduced pressure. Fifty (50) mg from the obtained 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (10.0 g) was dissolved in ethanol and dil. hydrochloric acid was added. The mixture was concentrated and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]1[O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[O:38]1[C:37]2[CH:36]=[CH:35][C:33]([NH:34][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4[C:10]([NH:15][S:16]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=4)=[CH:5][CH:4]=3)=[CH:32][C:31]=2[O:30][CH2:29]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(CNc2ccc3c(c2)OCO3)cc1)c1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-(methylenedioxy)aniline, the title compound was isolated as a yellow solid in 69% yield (96% purity by HPLC).
Reaction SMILES: C1COCC1.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([C:24](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23]>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:24]([C:22]#[N:23])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(Cc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
835 mg of Mg are suspended in 5 ml of abs. THF. A solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. tetrahydrofuran is subsequently added dropwise. When the addition is complete, the cloudy solution is stirred at room temperature for a further 1 hour, a solution of 1.73 g of ethyl 2-cyano-3-phenylacrylate in 10 ml of abs. toluene is subsequently added, and the mixture is refluxed for 16 hours. The solvent is removed, and conventional work-up gives ethyl 4-(4-benzyloxyphenyl)-2-cyano-3-phenylbutyrate (“AA”).
Reaction SMILES: CO[O:3][P:4]([O:9][CH2:10][CH:11]([OH:34])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15])([O:6]OC)=[O:5].C[Si](Br)(C)C>C(#N)C.ClCCl>[OH:34][CH:11]([CH2:10][O:9][P:4]([OH:5])([OH:6])=[O:3])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15]
Reactant: COOP(=O)(OCC(O)COC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)COP(=O)(O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
To a solution of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-2-hydroxy-propyl ester (60 mg, 0.4 mmol) in 1.5 mL of acetonitrile and 1.5 mL of dichloromethane was added 52 μl (0.40 mmol) of TMSBr dropwise. The reaction mixture was stirred for 6 h at room temperature and concentrated. The residue was quenched with 0.05 mL of water followed by 1.5 mL of EtOAc. The resultant mixture was centrifuged and the solvent was decanted. The precipitate was washed twice with ethyl acetate and dried to afford 120 mg (62%) of 3-[1-(3,5-dim ethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-phosphonooxy-propyl ester as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H, NH-1′), 7.84 (dd, J=2.4, 8.0 Hz, 1H, H-4), 7.79 (dd, J=2.2, 6.8 Hz, 1H, H-7), 7.64 (s, 1H, H-vinyl), 7.16-7.21 (m, 2H, H-5, 6), 6.11 (s, br, 1H, H-4′), 4.40 (dd, J=4.0, 10.8 Hz, 1H), 4.32 (dd, J=5.8, 11.2 Hz, 1H), 4.00-4.05 (m, 1H), 3.90-3.93 (m, 2H), 2.37 (s, 3H, CH3), 2.33 (s, 3H, CH3). 31P NMR(162 MHz, d6-DMSO) δ 0.16.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21]O>>[CH3:21][O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Yield: 96 %

Procedure:
In FIG. 6A, the results of using Zn3La1 in esterifying pure oleic acid with methanol using the step-rise heating method (i.e., a heating rate of 2° C./minute, and holding the reaction mixture at the target temperature for 1 minute) is provided. When the temperature is higher than 140° C., Zn3La1 shows activity in regards to the esterification of FAA. At 200° C., a 96% yield of oleic acid methyl ester can be obtained in 10 minutes (see FIG. 6B).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[CH:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]#[CH:7])[CH:9]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: C#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 14 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 8 (1.39 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 20.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15]Br)[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][C:17]#[N:18])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2cc(CBr)ccc2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2cc(CC#N)ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.9 %

Procedure:
Compound 46 (0.254 g, 0.91 mmol) was diluted with anhydrous DMF (10 mL), and NaCN (0.230 g, 4.55 mmol) was added. The orange mixture was stirred at room temperature for 17 h. The mixture was concentrated and partitioned between EtOAc and H2O (50 mL each) and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with H2O (2×80 mL) and sat aq. NaCl (50 mL), and dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2), eluting with a gradient of 15% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 to yield the title compound as a white solid (0.170 g, 83%): mp 154-155° C.; 1H-NMR (500 MHz; CDCl3): δ 8.48 (d, J=8.6 Hz, 1 H), 8.22 (br s, 1 H), 8.20 (d, J=9.0 Hz, 1 H), 7.85 (d, J=8.7 Hz, 1 H), 7.81 (d, J=1.0 Hz, 1 H), 7.61 (dd, J=8.7, 2.1 Hz, 1 H), 3.96 (s, 2 H), 2.30 (s, 3 H); 13C-NMR (126 MHz; CDCl3): δ 169.1 (1 C), 151.3 (1 C), 145.8 (1 C), 138.6 (1 C), 129.8 (1 C), 128.3 (1 C), 126.74 (1 C), 126.64 (1 C), 126.2 (1 C), 117.6 (1 C), 114.9 (1 C), 25.0 (1 C), 23.7 (1 C); ESIMS m/z (rel. intensity) 472 (2M+Na+, 100).
Reaction SMILES: C(Cl)([Cl:3])=O.[CH:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]#[N:13])=[CH:7][CH:6]=1.N#N>C1(C)C=CC=CC=1>[Cl:3][CH:11]([C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1)[C:12]#[N:13]
Reactant: N#CC(O)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: N#N
Solvent: Cc1ccccc1
Product: N#CC(Cl)c1ccccc1
Yield: 967.2 %

Procedure:
150 g of toluene and 7 g (0.02 mol) of Cyanex® 923 are initially introduced into a phosgenation apparatus with attached carbonic acid condenser and heated. At 99° C., 13 g of phosgene are gassed in over the course of 10 minutes. Thereafter, over the course of 2 hours, 192 g (1.44 mol) of benzaldehyde cyanohydrin and a further 149 g (total=172 g or 1.74 mol) of phosgene are added in parallel. The internal temperature is maintained between 99 and 102° C. throughout. After a post-reaction of 60 minutes at 99° C., excess phosgene is stripped out using N2 at 50° C. for 2.5 h. The discharge of 359 g is fractionally distilled on a 30 cm Vigreux column. The main fraction passes over at 0.6 mbar and a head temperature of from 68 to 73° C. 192.7 g (88.3% of theory) of α-chlorophenylacetonitrile are isolated.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>COCCOC>[F:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])=[O:7])=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:44])[F:43])[CH:23]=1
Reactant: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 63.1 %

Procedure:
A solution of thiophene-3-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (251 mg, 0.60 mmol) in DME (5 ml)/2M Na2CO3 (1.05 ml, 2.12 mmol) was with 2-trifluoromethoxyphenylboronic acid (187 mg, 0.91 mmol) and Pd[PPh3]4 (140 mg, 0.12 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (188 mg, 63%). MS m/e 497.41 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[CH:42]=[CH:41][C:10]([C:11]([O:13][C@@H:14]3[CH2:22][C@@H:17]4[O:18][C:19](=[O:21])[CH2:20][C@@H:16]4[C@H:15]3/[CH:23]=[CH:24]/[C@@H:25]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>[Pd].CC#N>[C:1]1([C:7]2[CH:42]=[CH:41][C:10]([C:11]([O:13][C@@H:14]3[CH2:22][C@@H:17]4[O:18][C:19](=[O:21])[CH2:20][C@@H:16]4[C@H:15]3[CH2:23][CH2:24][C@@H:25]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: [Pd]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of a compound [7a] (80.0 g), palladium on carbon catalyst (16 g) and ethyl acetate (1.0 L) was stirred under hydrogen atmosphere at 150 psi for 3 hours at room temperature. The reaction mixture was then filtered and evaporated under reduced pressure. The oily residue was crystallized from a mixture of hexane and ethyl acetate 4:1 v/v to give 71.4 g (89% yield) of compound [9a], mp 103-105° C., [α]D20 −107° (c 1.0, MeCN). 1H NMR (CDCl3) δ: 8.03 (d, J=8 Hz, 2H); 7.60-7.67 (m, 4H); 7.36-7.48 (m, 3H); 7.14-7.24 (m, 5H); 5.20-5.30 (m, 1H); 5.00-5.15 (m, 1H); 4.50-4.70 (m, 1H), 3.89-3.95 (m, 1H); 3.66-3.72 (m, 1H); 3.45-3.50 (m, 1H). 13C NMR (CDCl3) δ: 20.1; 25.4; 28.7; 31.3; 31.9; 36.5; 43.5; 52.8; 63.0; 76.0; 80.1; 84.3; 97.8; 125.7; 127.1; 127.2; 128.1; 128.3; 128.4; 128.9; 130.1; 140.0; 142.4; 146.0; 165.8; 176.7. IR (KBr): 2990; 1771; 1707; 1608; 1277; 1181; 1110; 1026; 751; 698 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O>C1(C)C=CC=CC=1>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:13](=[O:15])[C@H:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@H](CC2CCCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1Cl
Temperature: 80 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 92, 6.07 g, 18.35 mmol), (R)-(+)-4-benzyl-2-oxazolidinone (2.83 g, 15.96 mmol), and triethylamine (6.68 ml, 47.71 mmol) in toluene (50 mL) was heated at 80° C. under argon until a homogeneous solution was obtained. The reaction mixture was then treated with trimethylacetyl chloride (3.55 mL, 28.81 mmol) in toluene (10 mL), and the reaction became yellow in color and a precipitate formed. The reaction mixture was then heated at 80° C. for 36 h. The reaction was cooled to 25° C. and then the toluene was removed in vacuo. The residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a IN aqueous hydrochloric solution (1×100 mL), a 10% aqueous sodium carbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/5/5 methylene chloride/hexanes/ethyl acetate) afforded (1) 4(R)-benzyl-3-[2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.08 g, 23%) as a white foam: [α]23589 =+10.4° (c=0.144, chloroform); FAB-HRMS m/e calcd for C25H28ClNO5S (M+H)+490.1455, found 490.1457 and (2) 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 25%) as a white foam: [α]23589 =−93.9° (c=0.165, chloroform); FAB-HRMS m/e calcd for C25H28CINO5S (M+H)+490.1455, found 490.1443.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>Cl.C(O)(C)C>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[NH:4][CH:5]=[N:6]3)[CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3nc[nH]c23)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 102.8 %

Procedure:
A mixture of 6-chloropurine (1.0 g, 6.47 mmol), 3-bromoaniline (0.78 mL, 7.12 mmol), and conc HCl (4 drops) in isopropanol (10 mL) is stirred at 80° C. for 5 h. Upon cooling, it precipitates. The solid is filtered and washed with isopropanol and air dried to yield N6 -(3-bromophenyl)adenine (1.93 g, 91%) as a light yellow solid. 1H NMR (DMSO) δ 11.38 (1H, s), 8.78 (1H, s), 8.75 (1H, s), 7.90 (1H, d, J=8.0 Hz), 7.38-7.34 (2H, m). ##STR15##
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[N:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.4 mmol) in anhydrous DMF (10 mL) was added sodium azide (285 mg, 4.4 mmol). The resulting mixture was heated at 50° C. for 2 h, cooled, diluted with CHCl3 (100 mL), washed with water (5×50 mL), dried (MgSO4) and concentrated under reduced pressure to yield methyl 3-(azidomethyl)benzoate (0.84 g, quant.), which was used without purification. 1H-NMR (CDCl3): δ 8.01 (2H, m), 7.44-7.54 (2H, m), 4.42 (2H, s), 3.94 (3H, s).
Reaction SMILES: [NH4+:1].[OH-].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]>>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN

Procedure:
The title compound was prepared from 28% NH4OH solution and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 9.64 (s, 1H), 8.81 (s, 2H), 8.00 (d, 1H), 7.83 (br, 3H), 7.21 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 2.79 (m, 2H), 1.75-1.50 (m, 6H); MS (ESI): 437.9.