Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Yield: 98.9 %

Procedure:
2-Amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (7.96 g, 15.4 mmol) and hydrazine hydrate (3.85 g, 77.0 mmol) in ethanol (250 ml) was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the solid residue was extracted with diethyl ether (3×200 ml). The fractions were combined and the solvent removed in vacuo to give 5.9 g (100%) of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[CH:6][CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Fc1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc3c(ccn3Cc3ccc(F)cc3)c2)cc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To 0.2 g of a 60% dispersion of NaH in mineral oil, suspended in 20 ml of anhydrous THF, was added 0.61 g (2.38 mmol) 5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole from Step 1. The slurry was stirred for 15 min upon which time 0.33 ml (2.6 mmol) 4-fluorobenzylbromide was added. The slurry was stirred overnight. The slurry was concentrated under vacuum and the residue was redissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4 and concentrated. The residue was chromatographed on silica to afford 0.61 g 1-(4-fluoro-benzyl)-5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole as a fluffy powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1)[CH3:2].[CH2:19]=O.[CH:21]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])=[CH2:22]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:19][CH:21]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:35])[F:34])(=[O:24])=[O:25])[CH2:22][N:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:17])[F:16])[CH:8]=1)=[O:18])[CH3:2]
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CNc1cccc(OC(F)(F)F)c1
Reactant: C=O
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 343d, (3-trifluoromethoxy-phenylamino)-acetic acid ethyl ester (CAS Reg. No. 1021237-80-8) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as off-white solid. MS (ESI): m/z=512.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].O.[CH3:20][N:21](C=O)C>>[CH3:20][NH:21][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: O
Product: CNCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Anhydrous methylamine was bubbled into anhydrous DMF (200 mL) at 0° C. for 15 min. A solution of t-butyl 4-bromomethyl-3-nitrobenzoate (5.0 g, 15.8 mmol) (Int. J. Peptide. Res., 36, 31 (1990)) in DMF (10 mL) was added dropwise to the cold amine solution. The solution was stirred at 0° for 30 min and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, dried (sodium sulfate) and concentrated to give a yellow-brown oil. The oil was purified by chromatography (silica gel, 3% isopropanol/CH2Cl2) to give the title compound (1.5 g, 36%). 1H NMR (400 MHz, CDCl3) δ8.5 (s, 1H), 8.2 (d, 1H), 7.7 (d, 1H), 4.05 (s, 2H), 2.5 (s, 3H), 1.6 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl[C:14](Cl)(Cl)[CH:15]([OH:17])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:28][OH:29].Cl>O>[OH:29][N:28]=[CH:14][C:15]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:17]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(NC(=O)C=NO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A slurry of 4-methoxy-2-nitro-phenylamine (5 g, 29.7 mmol), chloral hydrate (5.51 g, 33.3 mmol), sodium sulphate (21 g, 148.8 mmol), hydroxylamine hydrochloride (6.6 g, 95.2 mmol) and conc. HCl (5 mL) in water (150 mL) was heated for 2 h. After completion of the reaction, a solid separates out. The reaction mixture was then cooled to room temperature and the solids were filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as off white solid (5 g, 70.40%) which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:25](O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[CH3:25])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CCO
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde, MeMgBr was added (in THF at 0° C.) to give an ethanol derivative, which was oxidized to the title compound as in Example 15, Step 11.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: Nc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(-c2cn3cccc(Cl)c3n2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-2-pyridinamine (4.8 g, 37.4 mmol) and 2-bromo-1-(3-methoxyphenyl)ethanone (8.56 g, 37.4 mmol) in ethanol (30 mL) was added potassium carbonate (5.15 g, 37.4 mmol) and the resultant solution was heated at reflux for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant residue was taken up in dichloromethane, washed with water and then brine. The aqueous layer was extracted with dichloromethane and the combined organics dried over magnesium sulfate. Filtration and concentration followed by recrystallization of the residue from ethyl acetate-hexanes reulted in 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine (6.7 g, 70%) as a tan powder. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.89 (s, 1 H), 7.57–7.52 (m, 2 H), 7.33 (t, 1 H), 7.23 (d, 1 H), 6.89 (dd, 1 H), 6.71 (t, 1 H), 3.89 (s, 3 H); 13C NMR (CDCl3): δ 159.94, 146.31, 142.96, 134.61, 129.65, 124.30, 123.58, 123.26, 118.81, 114.33, 112.02, 111.44, 109.91, 55.39; MS m/z 259 (M+1); Anal. Calcd for C14H11ClN2O: C, 64.93; H, 4.29; N, 10.83. Found: C, 64.58; H, 4.51; N, 10.52.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:26])/[CH:21]=[CH:22]/[C:23](Cl)=[O:24].Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>C1COCC1>[OH:30][NH:29][C:20](=[O:26])[CH:21]=[CH:22][C:23]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH:11]=[CH:12]2)=[O:24]
Reactant: O=C(Cl)/C=C/C(=O)Cl
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=CC(=O)Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
A solution of 27 (0.20 g, 0.73 mmol) in THF (2 mL) was added dropwise to a solution of fumaryl chloride (0.08 mL, 0.73 mmole) in THF (1 mL). The mixture was stirred at room temperature for 10 min and was then dried under vacuum to provide a residue. The residue was then dissolved in THF (mL). In another vessel, to a suspension of hydroxylamine hydrochloride (0.26 g, 3.77 mmole) in THF (4 mL), a sat. NaHCO3 solution (3 ml) was added, and the reaction mixture was stirred at room temperature for 10 min. The contents of both vessels were combined and stirred at room temperature for 1 h. The mixture was partitioned between EtOAc (15 mL×3) and water. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (CH2Cl2:CH3OH=10:1:1% AcOH) to afford Compound 27 (0.12 g). 1H NMR (500 MHz, CD3OD): δ 7.70 (d, J=3.3 Hz, 1H), 6.86 (d, J=15.0 Hz, 1H), 7.10 (d, J=15.0 Hz, 1H), 7.46-7.51 (m, 3H), 7.58-7.61 (m, 1H), 7.65 (d, J=3.4 Hz, 1H), 7.90-7.97 (m, 4H). HRMS (EI) for C18H15N3O5S (M+): calcd, 385.0732. found, 385.0732.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:22]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][C:18]=3[C:17]([CH3:30])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:21]2[CH2:20][CH2:19][C:18]3[C:17]([CH3:30])=[N:16][N:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[C:23]=3[C:22]=2[CH:24]=1
Reactant: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCc3ccccc3)cc1)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(O)cc1)CC2
Reaction time: 2 h

Procedure:
1-(4-Benzyloxyphenyl)-8-methoxy-3-methyl-4,5-dihydro-1H-benzo[g]indazole (42 mg, 0.1 mmol) was dissolved in methanol/tetrahydrofuran (2/1, v/v, 1.5 mL) and a catalytic amount of 10% Pd/C (wet) was added. The flask was purged with nitrogen and hydrogen, then stirred under 1 atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite and washed with methanol, and the filtrate was concentrated. The reaction was assumed to be quantitative. LC-MS (C19H18N2O2 calculated 306) m/z 307 (M+H).
Reaction SMILES: Cl.[O:2]=[C:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[CH3:9])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Product: CC(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 7.5 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxopentanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 123, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxopentanoyl)pyrrolidine-2-carboxamide (2.2 mg, 7.5%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.88 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.45 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 2.60-2.69 (m, 3H), 2.57-2.59 (m, 2H), 2.44-2.53 (m, 2H), 2.45 (s, 3H), 1.92 (m, 2H). MS (EI) for C29H29FN2O4. found 489.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([O:12][CH3:13])[CH:5]=1.O.CC(=CC)C.[O-:21]Cl=O.[Na+]>C(O)(C)(C)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:21])=[O:11])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a stirred solution of 4-formyl-3-methoxy-benzoic acid methyl ester (5.0 g, 26 mmol) in tert-butyl alcohol (200 mL) was added NaH2PO4-2H2O (3.6 g, 26 mmol), water (50 mL), 2-methyl-2-butene (11 mL, 104 mmol), and finally NaClO2 (7.02 g, 78 mmol). The reaction was allowed to stir at room temperature for 4 hours. The solvent was then removed under reduced pressure. The crude reaction mixture was then dissolved in DCM (200 mL) and the product was extracted with 1N NaOH (200 mL). The aqueous layer was washed with DCM (200 mL) and then neutralized with 6N HCl (˜40 mL) and the product extracted with DCM (200 mL). The organic layer was then washed with water (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was sufficiently pure to use without further purification. The product, 2-methoxyterephthalic acid 4-methyl ester, was obtained in 47% yield (2.4 g, 12.3 mmol).
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl>>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Reaction time: 0.33 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.15 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. After filtration, the crude solid was dissolved in acetone (30 mL/g of bromophenyl pyrazole starting material) at reflux. TMT (0.22 equiv.) was added at 55° C., and the mixture was stirred for 20 min while its temperature was allowed to decrease to 30° C. The mixture was filtered twice through a Darco zeta pad. The filtrate was concentrated by partial removal of the organic solvents and recrystallized from acetone/water to afford 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 28 ppm of palladium.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:11]=1[F:12]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14](=[O:17])[CH:15]=[CH2:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S)=CC=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33](OO)=O)[CH:28]=1.[S:37]([O-])([O-:40])(=[O:39])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14](=[O:17])[CH2:15][CH2:16][S:37]([C:32]1[CH:31]=[CH:30][C:29]([CH3:33])=[CH:28][CH:27]=1)(=[O:40])=[O:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: Cc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)CCC(=O)CC2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
(±)-1-(t-Butoxycarbonyl)-2-(2-oxo-3-butenyl)pyrrolidine (206 mg (10.86 mmol), prepared as described in Reference example 1–2)) was dissolved in tetrahydrofuran (2 ml). To the solution was added 4-methylthiophenol (107 mg, 0.86 mmol), and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 ml). To the resulting mixture was added 70 wt % m-chloroperbenzoic acid (468 mg, 1.894 mmol) by portions under ice cooling, and the resulting mixture was stirred at room temperature for 2 hours. To the mixture were added an aqueous solution of 10% sodium thiosulfate and a saturated aqueous solution of sodium hydrogencarbonate in that order, and the resulting mixture was stirred and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure, to give the title compound (322 mg) as a colorless oil (yield 94%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][CH2:16][CH2:17][CH:18]=[C:19]([F:21])[F:20])(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][CH:8]=1)([OH:15])(=[O:14])=[O:13].[F:20][C:19]([F:21])=[CH:18][CH2:17][CH2:16][NH:1][C:2]([NH2:4])=[S:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: NC(=S)NCCC=C(F)F
Yield: 88.4 %

Procedure:
Thiourea (0.29 g) and 4,4-difluoro-3-butenyl 4-methyl-benzenesulfonate (see Example 3B) (1 g) were heated together under reflux in ethanol (20 cm3) for 24 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give an oil which slowly crystallised. Trituration with hexane gave (4,4-difluoro-3-butenyl)-thiourea tosylate salt (1.14 g). MH+ (FAB)=167; 1H NMR (DMSO): 2.48(3H,s); 2.46-2.58(2H,m); 3.42(2H,t); 4.66-4.84(1H,m) 7.32(2H,d); 7.68(2H,d); 9.10-9.40(3H, broad)
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:30])([C@H:27]([SH:29])[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH2:2][S:29][C@H:27]([CH3:28])[C@:20]([C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12])([OH:30])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:4])[NH2:5]
Reactant: NC(=O)CBr
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](SCC(N)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
58 mg (0.42 mmole) of 2-bromoacetamide and 48 mg (0.35 mmole) of potassium carbonate were added to a solution of 100 mg (0.35 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 3 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with benzene and washed with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The virtually pure product thus obtained was recrystallized from a mixture of acetone and hexane to afford 90 mg of the title compound, melting at 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH:9]([CH2:13][C:14]2[O:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:43]([CH2:46]C)CC)C.[OH2:48]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:23][C:46](=[O:48])[NH:43][CH:9]2[CH2:13][C:14]2[O:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Reactant: O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)o2)C(c2ccc(F)cc2)O1
Yield: 77 %

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionic acid (2.33 g, 7.01 mmol) in tetrahydrofuran (60 ml) were added diphenylphosphoryl azide (1.66 ml, 7.71 mmol) and triethylamine (1.47 ml, 10.5 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was allowed to stand at room temperature, water (50 ml) was added, and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(4-fluorophenyl)-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-2-one (1.78 mg, 77%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[N:9]1([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C1CNC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1c[nH]c(CN2CCC2)n1
Yield: 61.4 %

Procedure:
To a mixture of 2-imidazolecarboxaldehyde (3.0 g) and azetidine hydrochloride (3.21 g) in anhydrous tetrahydrofuran (180 ml) was added sodium triacetoxyborohydride (9.99 g) followed by glacial acetic acid (1.72 ml). The resultant mixture was stirred at room temperature for 22 h, after which the insoluble material was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified using silica SPE (eluting with DCM, methanol, methanol:20% aqueous ammonia) to give the title compound (2.63 g) as a beige solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22]O2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)[C:30](O)=[O:31].[CH3:35][C@H](OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.BrCCCBr.O1CCCC1CCN>>[CH3:35][C@H:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH:24]2[CH2:23][CH2:22][CH2:30][O:31]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Agent: BrCCCBr
Agent: NCCC1CCCO1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCNCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane, and [2-(tetrahydro-2-furanyl)ethyl]amine.