Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH:7]([NH:20]C(=O)CC)[CH2:6]1.Cl>CO>[NH2:20][CH:7]1[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][OH:1])[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]1=2
Reactant: CCC(=O)NC1CC(CCCO)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: Cl
Solvent: CO
Product: NC1CC(CCCO)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Yield: 5.8 %

Procedure:
A mixture of compound from Step A (100 mg., 0.42 mM) CH3OH (25 ml.) and 12N HCl (3 ml.) was heated at reflux for 24 hours. The CH3OH was evaporated in vacuo. The aqueous phase was made basic with saturated sodium carbonate, evaporated to dryness and extracted with hot ethyl acetate which was evaporated to dryness to give 5 mg of title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13]>CO>[CH3:1][O:2][C@@H:3]1[C@@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C@H:7]([OH:10])[C@H:8]1[OH:9]
Reactant: COC1[C@@H](O)[C@@H](O)C(O)[C@H](O)[C@H]1O
Solvent: CO
Product: CO[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 47.4 %

Procedure:
3-O-methyl-D-chiro-inositol (D-pinitol) (283 mg, 1.457 mmol, 1 equiv) was dissolved in methanol (15 mL), then 1,2-cyclohexane diacetal (507 mg, 2.458 mmol, 1.7 equiv), trimethyl orthoformiate (200 mL, 1.752 mmol, 1.2 equiv) and 1-(S)-(+)-10-camphorsulfonic acid (24 mg, 0.102 mmol, 0.07 equiv) were added. The reaction mixture was heated at 70° C. for 24 h whereupon it was diluted with MeOH and quenched with solid NaHCO3. The residue was concentrated and purified by flash chromatography (Hex/EtOAc 1.15) to give 6 (222 mg, 0.664 mmol, 45%; 89% based on 134 mg of recovered D-pinitol). Rf (Hex/EtOAc 1:20): 0.22; [α]20D−22.9 (c=1.05, CHCl3); 1H NMR (CDCl3, 300 MHz): d=4.12 (Ys, 1H, H1), 4 10 (s, 2H, H4, H5), 4.07 (Ys, 1H, H6), 3.81 (dt, 1H, J2-3=9.0 Hz, J2-1=3.6 Hz, J2-OH=1.8 Hz, H2), 3.47 (t, 1H, J=9.0 Hz, H3), 3.23 (s, 3H, OCH3), 3.21 (s, 3H, OCH3), 2.76 (d, 1H, JOH-2=1.8 Hz, OH2), 2.60 (s, 1H, OH1), 2.56 (s, 1H, OH.6), 1.86-1.78 (m, 1H, CDA), 1.77-1.66 (m, 3H, CDA), 1.57-1.50 (m, 2H, CDA), 1.42-1.34 (m, 2H, CDA); 13C-NMR (CDCl3, 75 MHz); d=98.9 (C), 98.0 (C), 80.2 (C3), 71.5(C2), 70.8, 70.4, 70.3 (C1, C4, C6), 68.7 (C5), 61.1 (OCH3), 47.0(OCH3, CDA), 46.8 (OCH3, CDA), 27.1 (CH2), 27.0 (CH2), 21.5 (CH2), 21.4 (CH2); HRFABMS Calcd. for C15H26O8: 357.3571. found; 357.1528. MALDI-TOF Calcd. for C15H26O8+Na+: 357.4. found: 357.5. calcd. for C15H26O8+K+: 373.5. found: 374.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[CH3:29].[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[CH3:29]
Reactant: Cc1c(C#N)csc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C#N)csc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g (115 mmol) of triphenylphosphine were added at 5° C. to a solution of 16 g (104 mmol) of 5-hydroxymethyl-4-methylthiophene-3-carbonitrile in 300 ml of tetrahydrofuran. Then, a solution of 38 g (115 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator under a water pump vacuum and the residue was purified by column chromatography (eluant petroleum ether:dichloromethane 1:1). This gave 17 g (76%) of the title compound as yellow oil. 1H NMR (270 MHz, DMSO-d6): δ=2.25 (s, 3H), 5.0 (s, 2H), 8.5 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=O>CO.Cl>[CH3:20][C:18]1([CH2:17][C:16]([O:22][CH3:23])=[O:21])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 55 °C
Yield: 47.3 %

Procedure:
To a mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.11 g, 0.50 mmol) and methyl acetoacetate (0.54 mL, 5.0 mmol) in methanol (15 mL) was added 1 drop of concentrated hydrochloric acid, and the reaction was heated at 55° C. for 15 h and with reflux for 24 h. Then, the reaction mixture was cooled, and concentrated with NaHCO3 (0.5 g) and silica gel (5 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.075 g, 47%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[Li+:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Li+:17]
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccc(Cl)cc1
Yield: 46.4 %

Procedure:
The procedure of Example 1 was followed using methyl 4-chlorobenzoate (4.3 g, 25.2 mmol), lithium trimethylsilanolate (2.42 g, 25.2 mmol), and dry toluene (100 mL) and overnight heating at reflux. Lithium 4-chlorobenzoate (1.9 g, 46% yield) was isolated as a white solid: 1H NMR (D2O) δ 7.4 (ABq, Δν1-3 =31 Hz, J=9 Hz, Ar--H's, 2 H). This solid was contaminated with a small amount of lithium trimethylsilanolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24]>CC(C)=O>[CH2:24]([N:10]1[C:11](=[O:15])[N:12]([CH2:13][CH3:14])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: CCN1C(=O)N=NC1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(CC)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
To the solution of 3-(4-chlorophenyl)-4-ethyl-1,2,4-triazolin-5-one (2.23 g, 0.01 mole) in dry acetone (40 ml) was added, at room temperature, potassium carbonate (1.67 g, 0.012 mole) followed by propargyl bromide (1.8 g of 80% in toluene, 0.012 mole). The reaction mixture was then refluxed with stirring for 6 hr. The mixture was cooled down to room temperature and solvent was evaporated to give a residue. The product was purified by crystallization from hexane/ether, affording 1.8 g (69.2% yield) of 1-propargyl-3-(4-chlorophenyl)-4-ethyl-1,2,4-triazolin-5-one as a white solid. m.p.=115°-119° C. A proton NMR spectrum was consistent with the desired structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=O.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:26]=[C:17]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 60 %

Procedure:
5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (100 mg, 0.323 mmol) and o-phenylene diamine (38.5 mg, 0.356 mmol) were dissolved in dry THF (6 mL), and 2N HCl (2 drops) were added. The solution was heated at a gentle reflux for 30 min, and then 1N sodium bisulfite (2 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (100 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.86 (s, 1H), 8.79 (d, 1H, J=1.2 Hz), 7.83 (m, 1H), 7.50-7.41 (m, 3H), 7.25-7.22 (m, 2H), 5.69 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1>[O:29]=[C:13]1[C:9]2([CH2:12][CH2:11][CH2:10]2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:3][CH:4]=2)[C:15](=[S:16])[N:14]1[C:17]1[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cc1C(F)(F)F
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(Oc4ncccn4)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 50 mg, 0.12 mmol), 2-chloropyrimidine (17 mg, 0.15 mmol), and cesium carbonate (60 mg, 0.18 mmol) in anhydrous THF (1.2 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and water was added. The aqueous was extracted with EtOAc (3×), the organics combined and washed with brine, dried (MgSO4) and concentrated. Purification by column chromatography on silica gel eluting with 0 to 60% EtOAc/hexanes provided 30 mg of 5-(8-oxo-5-(4-(pyrimidin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.78 (d, 1H), 8.73 (d, 2H), 7.48 (dd, 4H), 7.35 (t, 1H), 2.72-2.61 (m, 2H), 2.54-2.42 (m, 2H), 2.10-1.93 (m, 1H), 1.69-1.52 (m, 1H). LCMS [M+1]+ 497.8.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[F:18][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
To solution of (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (4.33 g, 16.32 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (12.58 mL, 163 mmol) and the resulting mixture was stirred at rt for 5 h, then concentrated and sat. aqueous sodium bicarbonate (50 mL) was added followed by stirring for 20 min before extracting with diethyl ether (40 mL×3). The combined extracts were washed with brine and dried over sodium sulfate, filtered, and concentrated at rt (note: product is volatile) to afford 2.0 g (74%) of the title compound as a light tan oil that was used directly in the next transformation without any further purification. 1H NMR (400 MHz, MeOD) δ ppm 4.03 (1 H, dd, J=8.80, 6.82 Hz), 3.77 (3 H, s), 3.22-3.32 (1 H, m), 3.07-3.23 (1 H, m), 2.51-2.69 (1 H, m), 2.30-2.50 (1 H, m).
Reaction SMILES: [NH2:1][C:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:5]([C:2]1([NH:1][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:3]1)#[N:6]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: N#CC1(N)CC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC1(C#N)CC1
Yield: 73.8 %

Procedure:
General procedure F was used to 1.68 mmols of 1-amino-1-cyclopropanecarbonitrile to 2.184 mmols of oleoyl chloride. After standard purification techniques, 1.24 mmols (74%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 6.53 (s, 1H), 5.43-5.25 (m, 2H), 2.17 (t, J=7.6, 2H), 1.99 (dd, J=6.5, 12.5, 4H), 1.60 (d, J=7.2, 2H), 1.52 (dd, J=5.7, 8.3, 2H), 1.39-1.15 (m, 24H), 0.87 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 174.09, 130.00, 129.66, 120.14, 97.26, 35.97, 31.88, 29.74, 29.68, 29.51, 29.30, 29.23, 29.14, 29.09, 27.20, 27.14, 25.22, 22.66, 20.39, 16.74, 14.11.
Reaction SMILES: C(N(CC)CC)C.[N:8]#[C:9]Br.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CC(C)=O>[O:22]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:9]#[N:8]
Reactant: N#CBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OC#N
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
At −20° C., 20.0 g (0.198 mol) of triethylamine were added with stirring to 21.0 g (0.198 mol) of cyanogen bromide in 200 ml of acetone. After 5 min, 36.9 g (0.198 mol) of methyl 5-chloro-2-hydroxybenzoate were added, and the mixture was stirred at −20° C. for 30 min. The mixture was filtered, the filter was washed with 200 ml of acetone and the combined organic phases were concentrated under reduced pressure. This gave 34.4 g of the title compound as a yellow solid which was directly reacted further.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Yield: 24.4 %

Procedure:
Acetyl chloride (30 mg) was added at room temperature to a solution of (R)-3-(4-(azetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 482, step 1; 70 mg) and N,N-diisopropylethylamine (98 mg) in dichloromethane (4 mL), then after 2 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Flash chromatography (silica gel, 10 g, 2% to 5% methanol in dichlormethane) produced the title compound (19 mg). Colourless oil, MS (ESI+): m/z=413.0 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[C:3]([F:2])([F:17])[F:18])[CH2:8][CH2:9]2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)N1CCC(Oc2ccccc2C(F)(F)F)CC1

Procedure:
A solution of 4-(2-trifluoromethylphenoxy)piperidine hydrochloride (42 mg, 0.15 mmol), 3-chlorophenyl isocyanate (36 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) was stirred in dichloromethane (2 mL) at room temperature for overnight. The reaction mixture was diluted with dichloromethane and the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which was 98% pure by LCMS analysis (15.7 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[O:14]C(=O)[NH:12]2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[NH2:12][CH:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][CH:24]=1)[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:14]
Reactant: CC(C)(C)Oc1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (4RS,5SR)-4-(4-tert-butoxybenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (3.80 g, 10.6 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (3.96 ml, 31.7 mmol), and the mixture was stirred at 80° C. for 6 hrs. To the reaction solution was added water (20 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the objective substance (2.67 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8]
Reactant: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A stirred solution of methyl (3,5-dibromo-4-fluorophenyl)carbamate (0.82 g, 2.508 mmol) in DMF (20 mL) was treated with sodium bis(trimethylsilyl)amide (3.01 mL, 3.01 mmol), stirred at room temperature for 30 minutes, then 1-(chloromethyl)-4-methoxybenzene (0.410 mL, 3.01 mmol) was added, stirred at 70° C. for two hours. The reaction mixture was partitioned between NH4Cl solution and EtOAc. The organic layer was washed with NaHCO3 solution (2×), then brine, then dried over MgSO4, filtered and evaporated to dryness to give 1.40 g colorless film, which was purified by column chromatography on silica (120 g silica, gradient from 100% hexanes to 20% EtOAc in hexanes) to give methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (1.01 g)
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12](O)=[O:13])=[N:6][S:7][N:8]=1)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1>>[CH:1]([C:4]1[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])=[N:6][S:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3nsnc3C(C)C)c2)nc1
Reactant: Cc1cnc(CN)cn1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3nsnc3C(C)C)c2)nc1

Procedure:
Following the procedure of step 4 of Example 1, 3-(4-isopropyl-[1,2,5]thiadiazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine to afford 3-(4-isopropyl-[1,2,5]thiadiazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=445.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([N:6]=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:10]3[C:5]([N:6]=[N:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)=[N:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: Brc1nnc2nnc3ccccc3n12
Solvent: CCO
Solvent: O
Product: CN1CCN(c2nnc3nnc4ccccc4n23)CC1
Yield: 70 %

Procedure:
A mixture of 12.0 g (0.048 mole) of 1-bromo-s-triazolo[3,4-c]benzo-as-triazine, 40 ml of N-methyl-piperazine and 80 ml of ethanol is refluxed for 2 hours. The solution is poured into water and the product is extracted mit methylene chloride. The solvent is evaporated from the extract and the residue is recrystallized from benzene. 9.7 g (70%) of 1-(N-methyl-piperazino)-s-triazolo[3,4-c]benzo-as-triazine are obtained; m.p.: 162°-163° C. This product is added to a suspension of 12 g (0.068 moles) of sodium dithionite in 100 ml of water, and reduced into the respective dihydro compound under argon atmosphere. The separated precipitate is filtered off, dried, admixed with 50 ml of propionic anhydride, and the mixture is heated at 120° to 125° C. for 2 hours. The reaction mixture is cooled and the separated product is filtered off. 12.3 g (67.0%) of the title compound are obtained; m.p.: 173°-175° C.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][CH:6]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[F:22])[C:9]1=[O:23])[CH3:7]>C(Cl)Cl>[CH3:7][CH:6]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[F:22])[C:9]1=[O:23])[CH3:5]
Reactant: COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
A 1M methylene chloride solution of boron tribromide (41.6 ml, 0.0416 mole) was cooled to -20° C. While this temperature was maintained, a solution of 5.55 g (0.0208 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-methoxy-phenyl)imidazolidin-2,4-dione in 25 mL of methylene chloride was added to the reaction during an eight minute period. The reaction mixture was allowed to warm to room temperature, where it was stirred for approximately 17 hours. At the end of this time the reaction was poured over ice, and the resulting two-phase mixture was filtered. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving a black solid as a residue. This solid was recrystallized from ethyl acetate/petroleum ether, to yield 3.25 g of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxyphenyl)imidazolidin-2,4-dione as a tan solid, m.p. 190°-192° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13](OCC)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1csc(-c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1csc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
Reduction of the latter ester to the title compound is effected as follows: The ester (159 g) is dissolved in dry tetrahydrofuran (250 ml) and added dropwise during 30 min to a stirred mixture of lithium aluminum hydride (50 g) in tetrahydrofuran. The mixture is stirred for one hour, cooled and water (150 ml) is slowly added. The mixture is dried over magnesium sulfate and evaporated to give the title compound as a yellow oil, γmaxCHCl3 3610, 3420 and 1520 cm- 1.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>CN(C)C=O>[N:26]([C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)=[CH:21][CH:22]=1)=[C:1]=[S:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of thiocarbonyldiimidazole (4.46 g, 25.0 mmol) (Aldrich) and N,N-dimethylformamide (20 mL) was cooled to about −15° C. and a solution of 4-(4-methyl-1-piperazinyl)benzenamine (prepared according to the procedure of Chong, W. K. et al. WO9921845; 4.78 g, 25.00 mmol) was added over a period of 30 min. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was cooled to 0° C. and ice-water was added. After 30 min, the mixture was extracted with ether (3×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-methylpiperazine (4.84 g, 83%) as a pale purple solid.