Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].N1([CH:9]2[NH:15][C:14](=[O:16])[C:13]3[S:17][CH:18]=[CH:19][C:12]=3[N:11]3[CH:20]=[CH:21][CH:22]=[C:10]23)CCCCC1>CO>[O:16]=[C:14]1[C:13]2[S:17][CH:18]=[CH:19][C:12]=2[N:11]2[CH:20]=[CH:21][CH:22]=[C:10]2[CH2:9][NH:15]1
Reactant: O=C1NC(N2CCCCC2)c2cccn2-c2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCc2cccn2-c2ccsc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
1 g (0.0028 mol) of sodium borohydride is added in small portions to a solution of 2 g (0.007 mol) of 6-piperidino-5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]thieno -[2,3-f][1,4]diazepine in 120 ml of methanol, and the reaction mixture is stirred at room temperature for 15 minutes and then heated to reflux for 30 minutes. The methanol is then removed under vacuum and the solid residue ground in 200 ml of water. The precipitate is drained, washed with water, dried and recrystallized. 1.2 g of 5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]-thieno[2,3-f][1,4]diazepine are obtained in the form of white crystals, melting point 191° C. (ethyl ether).
Reaction SMILES: [C:1]1([C:6]([O:8][C:9]2[C:10]([F:25])=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([CH3:18])=[C:13]([C:16]#[N:17])[C:14]=2[NH2:15])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([C:6]2[O:8][C:9]3[C:14](=[C:13]([C:16]#[N:17])[C:12]([CH3:18])=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:10]=3[F:25])[N:15]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1c(C#N)c(N)c(OC(=O)C2=CCCC2)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)c(F)c2oc(C3=CCCC3)nc2c1C#N
Temperature: 25 °C
Yield: 86.1 %

Procedure:
4-Amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl cyclopentenecarboxylate (I-213) (180 mg, 0.54 mmol) was dissolved in xylene (50 ml), pyridinium p-toluenesulfonate (50 mg) was added, followed by heating under reflux for 5 hours. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The resulting residue was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (4:1, v/v) to obtain the entitled compound (148 mg, 87%) as a white crystal.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[N:31]=[CH:30][C:14]2[NH:15][C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[Br:10][C:11]1[N:31]=[CH:30][C:14]2[N:15]([C:32](=[O:34])[CH3:33])[C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3cnc(Br)cc32)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2cnc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N,N-Diisopropylethylamine (0.018 mL, 0.102 mmol) was added to a solution of (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (0.013 g, 0.034 mmol) and acetyl chloride (3.6 μL, 0.051 mmol) in dichloromethane (2.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.010 g, 69%) as an off-white solid. MS (ESI, pos. ion) m/z 424, 426.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[C:20]=2Br)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:23][CH2:24][CH2:25][O:26][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc(OCCO)c(Br)c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)OCCO3)NC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
To a mixture of the alcohol from Step C (0.36 g, 0.79 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.064 mg, 1.59 mmol) and cuprous iodide (0.015 g, 0.79 mmol) under a nitrogen atmosphere with stirring. After 30 min the suspension was heated at 80° C. for 1 h, cooled and mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography on silica eluting with a gradient of 20% to 30% EtOAc/hexane gave an oil (0.056 g, 19%): LCMS (+APCI) 368 (M+H).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20](O)([CH:21](C)[CH2:22][CH:23]2[O:36][CH3:37])C(O)C(=O)N2C(CCCC2)C(=O)[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].[C:57](=[O:60])([O-])[O-:58].[K+].[K+]>CO>[CH2:1]([CH:4]([C:5](=[O:56])[CH2:6][CH2:7][CH:8]([CH3:55])[CH:9]([OH:10])[C:43]([CH3:54])=[CH:44][CH:45]1[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]1)[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]([OH:35])[CH:23]([O:36][CH3:37])[CH2:22][CH:21]([CH3:20])[C:57]([OH:58])=[O:60])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)CCC1=O
Agent: [K+]
Solvent: CO
Product: C=CCC(C=C(C)CC(C)CC(OC)C(O)C(CC(C)C(=O)O)OC)C(=O)CCC(C)C(O)C(C)=CC1CCC(O)C(OC)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 17-allyl-1,2-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-3,10,16-trione (the compound of Example 15, European Patent Application No 323042) (2.5 g) and potassium carbonate (1.14 g) in methanol (25 ml) was stirred at ambient temperature for 1.5 hours, and then filtered. To the filtrate were added water and diethyl ether, and the separated aqueous layer was acidified with 1N hydrochloric acid. The precipitate was extracted with diethyl ether and the extract was washed with brine, dried and then concentrated in vacuo to give the crude subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>O.CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCc1cccc(Cl)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
To a mixture of 2-chloro-6-methylpyridine (1.0 g, 7.84 mmol) and dichloromethane (20 mL) was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at 40° C. Water and sodium hydrogencarbonate were added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. Acetic anhydride (20 mL) was added to the resulting residue and stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (4 mL, 20.1 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 30 minutes. Water was added to this mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (200.0 mg, 18%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH2:25][CH2:26][CH3:27])=[CH:16][CH:17]=[CH:18][C:19]([CH3:24])=[CH:20][C:21]([O-:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([C:5]1[CH:6]=[C:7](/[C:15](/[CH2:25][CH2:26][CH3:27])=[CH:16]\[CH:17]=[CH:18]\[C:19](\[CH3:24])=[CH:20]\[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(=CC=CC(C)=CC(=O)[O-])c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Solvent: CO
Product: CCC/C(=C/C=C/C(C)=C/C(=O)O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Compound 28 was prepared in the same manner as 27 except that the cis isomer 26 was used instead of 25: TLC (10% MeOH-90% CHCl3) Rf 0.8; mp 166-169° C.; 1H-NMR (CDCl3)δ 0.89 (t, J=7 Hz, 3H, CH2CH3), 1.31 (s, 9H, CH3), 1.32 (s, 9H, CH3), 1.42 (m, 2H, CH2CH2CH3), 2.15 (s, 3H, CH3), 2.49 (t, J=7 Hz, 2H, CH2CH2CH3), 5.76 (s, 1H, =CH), 6.23 (d, J=11 Hz, 1H, =CH), 6.28 (d, J=15 Hz, 1H, =CH), 6.78 (dd, J=15 Hz, 1H, =CH), 7.04 (s, 2H, Ar--H), 7.35 (s, 1H, Ar--H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([NH2:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:24][CH2:22][CH3:23])=[O:14])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1CC[C@H](CC(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of trans-4-(2-ethoxy-2-oxoethyl)-cyclohexanecarboxylic acid (Intermediate 6; 800 mg; 3.74 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (4.7 mL; 9.35 mmol), followed by a drop of DMF. After 3 h, the reaction was concentrated in vacuo, redissolved in THF (4 mL) and added dropwise to a stirred solution of ethylamine (2.0 M; 1.87 mL; 3.74 mmol) in THF (4 mL) at 0° C. Triethylamine (521 mL; 3.74 mmol) was added and the reaction stirred at 0° C. for 1 h. The reaction was quenched with H2O (25 mL) and extracted with EtOAc (3×50 mL). The combined extracted were washed with H2O and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-75% EtOAc/hexanes gradient) to afford ethyl{trans-4-[(ethylamino)carbonyl]cyclohexyl}acetate as a white solid. LCMS=242.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 5.40 (s, 1 H), 4.14 (q, J=7.1 Hz, 2 H), 3.33-3.28 (m, 2 H), 2.21 (d, J=7.1 Hz, 2 H), 2.02 (tt, J=12.2, 3.4 Hz, 1 H), 1.94-1.78 (m, 5 H), 1.51 (qd, J=12.9, 3.2 Hz, 2 H), 1.27 (t, J=7.1 Hz, 3 H), 1.15 (t, J=7.3 Hz, 3 H), 1.07 (qd, J=12.8, 3.2 hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:34][CH:18]([C:19]1[S:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:3]([O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:14]=1[Cl:15])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-di-chlorophenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: [CH3:1][S:2](=[N:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])C(=O)SC.S(Cl)(Cl)(=O)=O.[Cl:23][CH2:24][Cl:25]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:7]=[SH:2]([CH3:1])=[C:24]([Cl:25])[Cl:23])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: CSC(=O)S(C)=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: C[SH](=NS(=O)(=O)c1ccc(Cl)cc1)=C(Cl)Cl
Temperature: 35 °C

Procedure:
The N-(4-chlorophenylsulphonyl)-iminodithiocarbonic acid-S,S-dimethyl ester (1000 g) obtained in the manner described is suspended in 1000 ml of dichloromethane, and 290 ml of sulphonyl chloride (3.6 moles) is added dropwise to the suspension, whereupon a yellow solution is obtained with generation of SO2. This solution is heated for about 2 hours at a temperature of 35° C. The solvent as well as the formed methanesulphonyl chloride and unreacted sulphonyl chloride is distilled off in a Rotovap, and the crystallised residue is taken up in hexane. After filtration with suction there is obtained N-(4-chlorophenysulphonyl)-S-methyl-iminothiocarbonic acid chloride: m.p. 86°-89° C.
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]>C(Cl)Cl.O.CCN(CC)CC>[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: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
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 Et3N (1.72 g) were added to a solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g) in dry CH2Cl2 (200 mL). The reaction mixture was stirred at 25° C. for 20 h. H2O (100 mL) was added to the reaction mixture and the mixture was extracted with CH2Cl2(2×50 mL). The combined extracts were washed with H2O (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed under reduced pressure to afford an yellow oil which was purified by column chromatography (SiO2, 70% EtOAc-hexane) to give 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (6.39 g, 85%): 1H-NMR (CDCl3, 300 MHz) δ1.4 (s, 9 H), 1.0-1.8 (m, 5 H), 2.6-2.8 (m, 2 H), 3.15-3.3 (m, 2 H), 4.0-4.3 (m, 4 H), 6.6-6.7 (m, 1H), 7.64 (s, 1 H), 7.60 (dd, 1 H, J=7.2, 7,2 Hz), 7.79 (d, 1 H, J=7,2 Hz), 8.0 (d, 1 H, J=7.2 Hz), 8.11 (s, 1 H); The purity was determined by RPLC/MS (97%); ESI/MS m/e 444.3 (M++H, C21H28F3N3O4).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:13]([CH2:15][OH:16])[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>CCCCCC>[C:32]([O:16][CH2:15][C:13]1[N:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[NH:11][C:12]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(CO)c(Sc2cccc(Cl)c2)[nH]1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)[nH]c1Sc1cccc(Cl)c1
Yield: 78.3 %

Procedure:
To a solution of 700 mg (1.8 mmol)of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methanol (46)in methylene chloride (14 ml), was added 1.29 g (12.8 mmol)of triethylamine, and then, 1.00 g (12.8 mmol)of acetyl chloride was added dropwise under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 15 minutes, and added to a cooled saturated aqueous sodium hydrogen carbonate solution to neutralize and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of methanol, to which was added 5 ml of 50% aqueous acetic acid, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2)to give 602 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methyl acetate as oil (yield 78%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[CH:3]=1.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:9][C:6]1[CH:5]=[C:4]([F:12])[CH:3]=[C:2]([Br:1])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25: 839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ 3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JHF =8.4).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14](=[O:15])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.[Zn].[Cu]>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([OH:15])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)CBr
Reactant: O=C1CCn2c1cc1c(Br)cc(F)cc12
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1(O)CCn2c1cc1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a suspension of the ketone of Step 6 (800 mg, 3 mmol) in THF (10 mL) was added methyl bromoacetate (2.3 g, 15 mmol) and 1 g of Zn-copper couple. The reaction mixture was put in a sonicator at r.t. until an exotherm was observed. The reaction flask was cooled in an ice bath to keep the internal temperature below 50° C. and the mixture was stirred at r.t. for 1 hour. The reaction mixture was poured into a 2:1 mixture of saturated aqueous NH4Cl/EtOAc (100 mL) and filtered on paper. The filtrate was extracted with EtOAc, the combined organic layers were washed with brine and water, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 35% EtOAc in Hexanes to provide 780 mg of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:33][C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)CN
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)c1ccc(O)nc1
Reaction time: 0.5 h

Procedure:
A solution of 6-hydroxynicotinic acid (1.39 g, 10.0 mmol), 1-hydroxy-7-azabenztriazole (1.50 g, 11.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11 g, 11.0 mmol) in dimethylformamide (25 mL) was stirred at room temperature for 20 minutes. A solution of 2,2-dimethylpropylamine (0.96 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 11.0 mmol) in a small amount of dimethylformamide was added. Stirring was continued for 0.5 hour at room temperature. Ethyl acetate was added and the reaction mixture was extracted twice with water. The solvent was evaporated in vacuo yielding the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[O:17][C:18]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=1)=[O:10]>C(O)C>[CH3:1][NH:2][C:3](=[O:4])[NH:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[O:17][C:18]([CH2:21][N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=1)=[O:10]
Reactant: CN(C)Cc1ccc(CSCCNC(=O)c2cccc(N)c2)o1
Reactant: CN=C=O
Solvent: CCO
Product: CNC(=O)Nc1cccc(C(=O)NCCSCc2ccc(CN(C)C)o2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.3 g of methyl isocyanate in 10 ml of absolute ethanol is added dropwise to a solution of 6 g of 3-amino-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide in 50 ml of absolute ethanol. Then the mixture is left to stand 30 minutes at room temperature and afterwards it is heated at 50° C. for 2 hours. The solvent is evaporated under reduced pressure, the residue is taken up with diluted hydrochloric acid, the aqueous solution is extracted twice with 100 ml of ethyl acetate and treated with concentrated sodium hydroxide to clearly basic pH. The mixture is extracted three times with 100 ml of ethyl acetate, the organic phase is washed with water, dried on anhydrous sodium sulfate and evaporated to dryness. Thus, the 3-(3-methylureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide is obtained as an oil which is dissolved in isopropanol and treated with a solution of 1.5 g of oxalic acid in isopropanol. A white solid is obtained which, after crystallization from 95% ethanol gives 4.5 g of 3-(3-methylureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide oxalate; m.p. 156°-158° C. Code number: SR 57934A.