Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][SH-:7][C:8](=[N:10][C:11]#[N:12])[S-:9])=[CH:4][CH:3]=1.[K+].[K+].[OH:17]O>O>[OH:17][C:11]1[N:10]=[C:8]([S:7][CH2:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9][N:12]=1
Reactant: N#CN=C([S-])[SH-]Cc1ccc(Cl)cc1
Reactant: OO
Agent: [K+]
Solvent: O
Product: Oc1nsc(SCc2ccc(Cl)cc2)n1
Temperature: 65 °C

Procedure:
A mixture of 144 g of potassium S-p-chlorobenzyl-N-cyano-dithioimidocarbonate, 48 ml of 30% hydrogen peroxide and 1000ml of water was heated to 65° C, returned to room temperature and filtered. The filtrate was acidified with 40 ml of concentrated hydrochloric acid and was filtered. The recovered crystals were washed with water and dried to obtain 90 g of 3-hydroxy-5-(p-chlorobenzylthio)-1,2,4-thiadiazole melting at 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([O-])=[O:5].CC(C[AlH]CC(C)C)C.CCOC(C)=O>CCOCC>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH3:14])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCOc1cc(C(=O)[O-])c(Br)cc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1cc(CO)c(Br)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 2-bromo-5-ethoxy-4-methylbenzoate (660 mg, 2.23 mmol) in ether (20 mL) at 0° C. was added DIBAL (5.75 mL, 5.75 mmol, 1 M in toluene). The reaction was stirred at 0° C. for 10 minutes. EtOAc (20 mL) and wet silica gel (˜50 g silica gel and 3 mL of water) were added portion wise at 0° C. The resulting slurry was stirred for ˜15 minutes and was filtered, washed with EtOAc (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with EtOAc/hexanes (20/80) to give the title intermediate (550 mg) as colorless liquid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[NH:25][C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[N:25]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccccc2)C1=O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(Cc4ccccc4)C(=O)[C@@H]3C)nc12
Temperature: 35 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (970 mg, 4.58 mmol) and (3S,5S)-1-benzyl-3,5-dimethylpiperazin-2-one (1.00 g, 4.58 mmol) in DMF (20 mL), was stirred in a 35° C. oil bath. After 16 h, the reaction mixture was heated to 55° C. After 3 h, potassium carbonate (630 mg, 4.58 mmol) was added. The reaction mixture was stirred for 2 h at 55° C. and then at ambient temperature for 17 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 0.5 N HCl (25 mL), H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography (silica gel, 10 to 80% EtOAc in hexanes) gave methyl 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (1.08 g, 60%). 1H NMR consistent.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH2:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>O.ClCCl.C(N(CC)CC)C>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH:54][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.8 %

Procedure:
N-[3-(Trifluoromethyl)benzoyl]glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and triethylamine (1.72 g) were added to an anhydrous dichloromethane (200 mL) solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g). The resulting reaction mixture was stirred at 25° C. for 20 hours, and H2O (100 mL) was then added to the mixture. The obtained mixture was extracted with dichloromethane (50 mLX 2). The extracts were combined, washed with H2O (50 mL×2) and brine (50 mL), dried (over MgSO4) and concentrated to thereby afford a yellow oil. The obtained crude product was purified by column chromatography (SiO2,70% ethyl acetate-hexane) to provide 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (6.39 g, 85%). 1H NMR (CDCl3, 300 MHz) δ 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J=7.2, 7.2 Hz), 7.79 (d, 1H, J=7.2 Hz), 8.0 (d, 1H, J=7.2 Hz), 8.11 (s, 1H). The purity was determined by RPLC/MS (97%). ESI/MS m/e 444.3 (M++H, C21H28N3O4).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8]C=C[C:5]=1[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1.[CH3:33][O:34][C:35](=[O:44])C1C=CC=CC=1CBr.C[OH:46]>>[CH3:33][O:34][C:35]([C:8]1[O:46][C:5]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([S:21](=[O:30])(=[O:31])[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[CH:16][CH:17]=3)[CH2:12]2)=[CH:4][CH:9]=1)=[O:44]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CO
Reactant: COC(=O)c1ccccc1CN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Product: COC(=O)c1ccc(CN2CCc3ccc(S(=O)(=O)Nc4cccc(Cl)c4)cc3C2)o1
Yield: 62 %

Procedure:
Following the procedure of Example 1 to methyl-2-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]benzoate, substituting methyl-5-(chloromethyl)-2-furoate (1.75 g, 10 mmol) for methyl-2-(bromomethyl)benzoate and using corresponding proportions of other reagents, gave methyl-5-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]-2-furoate (2.86 g, 62%), m.pt. 167°-168° C. (from methanol).
Reaction SMILES: [Cl:1][C:2]([Cl:24])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)CCl>[Cl:24][C:2]([Cl:1])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:34](=[O:35])[CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=2)=[CH:16][CH:15]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CSc1ccc(CO)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
2-(4-Hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) was added to a stirred mixture of (4-trifluoromethyl-phenyl) acetic acid (39 mg, 0.190 mmol), EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and DCM (3 mL). The reaction mixture was stirred at rt overnight, according to LC-MS analysis the reaction was uncomplete. Additional EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and 2-(4-hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) were added and the mixture was stirred for 3 h. More DCM was added and the mixture was washed with 0.25M HCl, the organic portion was dried through a phase separator and concentrated to give the titled compound (112 mg, 100%); Mass spectrum: M−H+590.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1F.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]([OH:22])[OH:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]([OH:22])[OH:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OB(O)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 13.2 %

Procedure:
A solution of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.95 g), (4-hydroxyphenyl)boronic acid (0.66 g), and potassium carbonate (1.65 g) in DMSO (5.0 mL) was heated with stirring at 130° C. for 20 hours. The resultant reaction mixture was left to be cooled down and was poured into an ice water, and pH of the resultant reaction mixture was adjusted to around 2 with a 10% hydrochloric acid, followed by extracting the reaction mixture with ethyl acetate. From the organic phase, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 100:0 to 50:50) to obtain the subject compound (0.20 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])[CH:17]=1>C1COCC1.C(Cl)Cl.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])[CH:17]=2)[N:7]=1
Reactant: COC(=O)c1ccc(N)cc1OCCCCl
Reactant: FC(F)(F)COc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (770 mg, 2.79 mmol) in THF (10 mL) was added methyl 4-amino-2-(3-chloropropoxy)benzoate (681 mg, 2.79 mmol) and Hunig'sBase (1.464 mL, 8.38 mmol). The resulting mixture was stirred for 16 h. The reaction was diluted with DCM and water. The organic layer was collected and dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes. The product fractions were collected and concentrated under vacuum to give methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate as a solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[O:9])[CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.[C:22]1(C)[CH:27]=CC=C[CH:23]=1.CS(O)(=O)=O>C1C=CC=CC=1>[CH:22]([N:7]1[C:3]2[C:4](=[CH:5][CH:6]=[C:1]([CH3:11])[CH:2]=2)[CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=2)[NH:10][C:8]1=[O:9])([CH3:27])[CH3:23]
Reactant: Cc1ccccc1
Reactant: Cc1cccc(NC(N)=O)c1
Reactant: COc1cccc(C=O)c1
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Product: COc1cccc(C2NC(=O)N(C(C)C)c3cc(C)ccc32)c1
Temperature: 110 °C

Procedure:
To a vessel equipped with agitation means, thermometer and a reflux condenser is added 6.40 g of N-isopropyl, N-(m-tolyl) urea, 22.21 g of m-methoxy benzaldehyde, and 255 ml of toluene. The temperature of the mixture is slowly raised (about 25 min.) to 110° C to start refluxing. After refluxing for 5 min. the temperature is lowered to 100° C and 0.12 g (0.082 ml) of methanesulphonic acid is added. The temperature is again increased to 110° C and refluxing maintained for 3 hours. The reaction mixture is then allowed to cool to room temperature, washed 4 times with dilute sulfuric acid (20% w/v) resulting in the formation of a brown-orange gummy material (undesirable material). The organic phase is then washed 4 times with 25 ml portion of water (pH of last wash 5), then dried over anh. soidum sulfate and evaporated (steam distilled) to obtain a residue. The residue is taken up in benzene, and chromatographed on a silica column; starting with benzene then increasing proportions of chloroform (20%, 50%, then 100% chloroform). The samples obtained from 100% chloroform are combined, evaporated to dryness, then crystallized from chloroform to obtain 3,4-dihydro-1-isopropyl-4-(3--methoxyphenyl)-7-methyl-2(1H)-Quinazolinone, mp 167-169.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:20])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: CSc1nnc(-c2ccncc2)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccncc2)nnc1S(C)=O
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(4-pyridyl)-4H-1,2,4-triazole (4.54 g, 2.2×10-2 mole) and CH2Cl2 (125 ml) was added portionwise m-chloroperoxybenzoic acid (4.83 g, 2.24×10-2 mole, 80% active MCPBA). After stirring overnight the reaction was diluted with CH2Cl2 until homogeneous. The CH2Cl2 solution was then washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. After drying over anhydrouse Na2SO4, the CH2Cl2 was evaporated at reduced pressure to give the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylate (4.3 g, 11.8 mmol) in methanol:THF (4:1, 100 ml) 10 N sodium hydroxide (15 ml) was added at room temperature. It was stirred for 16 hrs and evaporated to dryness in vacuo. The residue was dissolved in 100 mL water, pH adjusted to 7 with 5N hydrochloric, acid solution. It was extracted with chloroform/methanol (3:1), washed with water, dried and concentrated to give 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylic acid. Yield 4.0 g (98%); White solid, mp. 112-4° C. Electrospray Mass Spec 349 (M−H)−.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][NH:8][C:7](=[O:12])[N:6]=1)[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.N1C=CC=CC=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][N:8]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[C:7](=[O:12])[N:6]=1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccsc1
Reactant: C=CCSc1nc(=O)[nH]cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
This material was prepared by the procedure described in J. Org. Chem. 2006, 71, 9183-9190. To a stirred suspension of dry Cu(OAc)2 (1.02 g, 5.64 mmol), 4-(allylthio)-5-fluoro-pyrimidin-2(1H)-one (700 mg, 3.76 mmol), thiophen-3-ylboronic acid (962 mg, 7.52 mmol), and activated 3 Å molecular sieves (2 g) in dry CH2Cl2 (30 mL) was added pyridine (595 mg, 7.52 mmol) at room temperature. The mixture was stirred for 24 h at ambient temperature in the presence of air. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered through a pad of Celite, and washed with water (50 mL) in the presence of ethylenediaminetetraacetic acid (EDTA; 700 mg, 2.4 mmol). The colorless organic phase was dried over MgSO4 and was concentrated in vacuo. The residue was purified by normal phase chromatography (isocratic, 2:1 petroleum ether:EtOAc) to afford 4-(allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (290 mg, 29%) as a yellow solid: mp 125-127° C.; 1H NMR (301 MHz, DMSO-d6) δ 8.52-8.35 (m, 1H), 7.81 (s, 1H), 7.69-7.55 (m, 1H), 7.32 (d, J=3.5 Hz, 1H), 6.05-5.81 (m, 1H), 5.36 (d, J=16.9 Hz, 1H), 5.18 (d, J=9.8 Hz, 1H), 3.89 (d, J=6.4 Hz, 2H); ESIMS m/z 269 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:30]([CH:27]([N:26]([CH2:20][C:18]1[S:19][C:12]2[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=2[CH:17]=1)[CH3:25])[CH2:28][OH:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CNC(CO)Cc1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C(CO)Cc1ccccc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 73.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), racemic 2-(methylamino)-3-phenylpropan-1-ol (Tetrahedron 2001, 57, 3425)(33 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 10 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[S:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:25]=[CH:26][CH:27]=2)=[CH:18]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:12][C:9]1[C:8]([CH3:13])=[C:7]([NH:6][C:5]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:19]4[CH:20]=[CH:21][S:17][CH:18]=4)[CH:23]=3)[CH2:29][CH2:30]2)=[O:14])[O:11][N:10]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3cccc(-c4ccsc4)c3)CC2)c1C
Yield: 19.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (129 mg, 0.450 mmol), 1-[3-(3-thienyl)phenyl]piperazine (100 mg, 0.409 mmol) and diisopropylethylamine (0.143 ml, 0.818 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound 30.7 mg (19.6%) as solid product.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]([CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (180 mg) in THF (4 mL) was added sodium hydride (32 mg, 60%) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. To the reaction mixture was added methyl iodide (0.107 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]=[CH2:3].[NH3:48]>>[NH2:48][C:9]1[N:10]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=1
Reactant: N
Reactant: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Product: C=CCOc1nc(N)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 13.5 g of 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 250 ml of liquid ammonia is heated at 100° C. for 2 hours and allowed to evaporate in a stream of nitrogen. The residue is dissolved in ethyl acetate and chromatographed over silica gel with ethyl acetate to provide 9.3 g of pure 2-amino-4-allyloxy-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.O(C([CH2:36][O:37][NH2:38])=O)C1C=CC=CC=1.C1C[O:42][CH2:41]C1>>[CH3:36][O:37][NH:38][C:41]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:42]
Reactant: C1CCOC1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Reactant: NOCC(=O)Oc1ccccc1
Product: CONC(=O)N1CCC(N(Cc2ncc(C)cc2C)Cc2ncccc2C(C)C)CC1

Procedure:
(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (125 mg, 0.36 mmol) and N-(phenoxycarbonyl)methoxylamine (120 mg, 0.71 mmol) were stirred in THF (3.5 mL) for 16 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel (20:1:0.2 CH2Cl2MeOH:NH4OH), COMPOUND 300 as a sticky solid (110 mg, 72%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.9 Hz), 1.62 (dq, 2H, J=12.3, 3.8 Hz), 1.89 (br d, 2H, J=12.3 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.64 (br t, 2H, J=12.3 Hz), 2.74 (m, 1H), 2.78 (sept, 1H, J=6.9 Hz), 3.71 (s, 3H), 3.77 (s, 2H), 3.82 (s, 2H), 4.02 (br d, 2H, J=12.0 Hz), 7.13 (br, 1H(NH)), 7.16 (m, 1H), 7.24 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 8.18 (s, 1H), 8.32 (d, 1H, J=3.9 Hz). 13C NMR (CDCl3) δ 18.30, 18.45, 23.59 (2C), 27.30 (2C), 27.38, 44.40 (2C), 54.35 (2C), 57.24, 64.49, 123.20, 132.30, 133.23, 133.88, 139.09, 144.42, 146.05, 146.63, 154.42, 156.24, 159.06. ES-MS m/z 426 (M+H). Anal. Calcd. for C24H35N5O2.0.3CH2Cl2: C, 64.71; H, 7.96; N, 15.53. Found: C, 64.94; H, 8.09; N, 15.88.