Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10](=[S:12])=[S:11].Br[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([S:12][CH:14]([C:15]#[N:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:11])=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: N#CC(Br)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N#CC(SC(=S)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 10 ml 4-fluorophenyl magnesium bromide (1.0M solution in ethyl ether) and diluted to 20 ml with anhydrous THF. 0.76 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 2 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 2 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (10:3 mixture of hexane and ethyl ether), pure α-cyanobenzyl 4-fluorodithiobenzoate was obtained as a red odorless solid (62% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[N:17]=[C:13]3[NH:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:5][CH:4]=1)#[N:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])[N:17]=[C:13]3[N:12]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:47])([F:46])[F:35])[CH:42]=3)[C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4,7-dihydro[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (50 mg, 0.11 mmol), 3-(trifluoromethyl)phenylboronic acid (63 mg, 0.33 mmol, 3 eq.), anhydrous copper(II) acetate (60 mg, 0.33 mmol, 3 eq.) and molecular sieve (50 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (2.5 ml), pyridine (71 μl, 0.88 mmol) and triethylamine (46 μl, 0.33 mmol, 3 eq.) were added. After 12 h of stirring, more 3-(trifluoromethyl)phenylboronic acid (21 mg, 0.11 mmol, 1 eq.), anhydrous copper(II) acetate (20 mg, 0.11 mmol, 1 eq.) and pyridine (36 μl, 0.44 mmol) were added. After a further 24 h of stirring, the mixture was filtered through kieselguhr, the residue was washed with dichloromethane and methanol and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23.3 mg, 35% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=2[O:19]1>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22](/[CH:23]=[C:4](/[C:5](=[O:16])[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH3:15])[CH:7]=3)\[C:3]([O:2][CH3:1])=[O:17])=[CH:21][C:20]=2[O:19]1
Reactant: CCCOc1cccc(C(=O)CC(=O)OC)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCCOc1cccc(C(=O)/C(=C/c2ccc3c(c2)OCO3)C(=O)OC)c1
Yield: 478.3 %

Procedure:
To a solution of methyl-3-(Prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 mL) was added 3,4-methylenedioxybenzaldehyde (6.36 g, 4.2 mmol) followed by piperidine (0.42 mL, 0.42 mmol) and glacial acetic acid (8 drops approx.). The mixture was refluxed for 2 h. and the volatiles removed in vacuo to give methyl (Z)-3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)benzoyl]propenoate (7.4 g, 48%) as an off white solid after trituration with methanol (m. p. 122°-123° C.). Anal. Calc. for C21H20O6 : C, 68.47; H, 5.47. Found: C, 68.81; H, 5.49.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:56]([C:57]([N:10]3[CH2:11][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]([CH2:12][OH:13])[CH2:9]3)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:50][CH:51]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1624.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(#N)C>[CH2:16]([O:15][C:13](=[O:14])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC#N
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 100 %

Procedure:
A suspension of MgO (2.0 g), 2-chloro-4-nitroaniline (3.768 g, 21.83 mmol) and ethyl chloroformate (5 mL) in acetonitrile (25 mL) was heated to reflux temperature for 4 hours followed by addition of more ethyl chloroformate (4 mL). The heating was continued until full conversion (20 hours) then the reaction mixture was filtered via a plug of SiO2 (5 g) with ethyl acetate as an eluent. Evaporation in vacuo (50° C.) gave 5.8 g (100% yield) of crude title compound which was used in the next step without further purification. LC/MS (m/z) 245 ([M+H]+); RT=2.95, (UV, ELSD) 96%, 98.5%. 1H NMR (DMSO-d6): 1.27 (t, 3H), 4.19 (q, 2H), 8.06 (d, 1H), 8.19 (dd, 1H), 8.30 (d, 1H), 9.49 (s, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:29]([NH2:31])=[O:30])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[C:4]([CH3:34])[CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:5]5[CH:6]=[N:7][C:2]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[CH:3][C:4]=5[CH3:34])=[O:9])[CH:33]=[CH:32][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:29]([NH2:31])=[O:30])=[N:19]2)=[CH:23][CH:24]=1
Reactant: Cc1cc(Cl)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(N2CCOCC2)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 27 h

Procedure:
The title compound of Example 246 (1.47 mmoles) and morpholine (23.1 mmoles) were dissolved in 10 mL of N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 27 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 301° C. (decomp.) 1H NMR (d6-DMSO, 400 MHz): δ 2.22 (s, 3H); 2.80-2.94 (m, 4H); 3.46 (t, 4H, J=4.8 Hz); 3.62 (t, 4H, J=4.8 Hz); 6.67 (s, 1H); 7.22-7.27 (m, 3H); 7.31-7.38 (m, 2H); 7.42 (dd, 1H, J=1.9 Hz, 8.2 Hz); 7.49-7.57 (m, 3H); 8.11 (s, 1H); 9.92 (s, 1H). 13C NMR (d6-DMSO, 100 MHz): δ 20.35, 20.38, 29.63, 45.55, 66.54, 108.46, 114.91, 117.02, 117.25, 119.91, 121.23, 122.78, 126.42, 128.64, 128.73, 129.36, 132.60, 136.82, 136.85, 138.38, 139.82, 143.15, 147.70, 148.03, 160.04, 161.39, 163.84, 164.47, 166.18. M+1=527
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][N:3]=1.Cl[C:11]1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1cnc(Cl)nc1C

Procedure:
The title compound was prepared in a manner analogous to Intermediate 55, substituting 2,4-dichloro-5-methylpyrimidine for 2,4-dichloro-5-fluoropyrimidine. MS (ESI): mass calculated for C6H7ClN2, 142.03, m/z found 143.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 8.32-8.25 (m, 1H), 2.52-2.46 (m, 3H), 2.28-2.22 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[C:13]([CH:15]=[C:16]([O-])[CH3:17])#[N:14].[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=1.C(O)(=O)C>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:22]3[C:23](=[O:27])[NH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:16]([CH3:17])=[C:15]2[C:13]#[N:14])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: CC([O-])=CC#N
Reactant: Nc1cc[nH]c(=O)c1
Reactant: COc1cc(C#N)ccc1C=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2cc[nH]c(=O)c21

Procedure:
1.05 g (6.51 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 684 mg (6.51 mmol) of sodium 1-cyanoprop-1-en-2-olate, 789 mg (7.16 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 600 μl (9.77 mmol) of acetic acid in 30 ml of isopropanol and heated under reflux under argon for 12 h. Cooling is followed by filtration, and the remaining solid is washed with diethyl ether (40 ml). 1.96 g (94% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]4[CH2:26][CH:25]4[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCOC(C)=O.CCCCCC>CO>[OH:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]4[CH2:26][CH:25]4[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC1CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C1CC1CCC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of methyl 2-(2-(1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (61A; 8.8 g, 21.2 mmol), and PPTS (1.07 g, 4.25 mmol) in MeOH (50 mL) was stirred at 50° C. for 3 h, then was cooled to rt and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient with 0% to 30% EtOAc/hexane over 20 min to give methyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (racemate; 7.0 g, 21.2 mmol, 100% yield) as a white solid. LCMS [M+H]+=331.1; 1H NMR (CDCl3) δ: 7.18 (t, J=7.9 Hz, 1H), 6.99-6.86 (m, 2H), 6.69 (ddd, J=8.0, 2.6, 1.0 Hz, 1H), 5.32 (s, 1H), 3.82 (d, J=1.1 Hz, 2H), 3.69 (s, 3H), 2.07-1.95 (m, 4H), 1.71-1.57 (m, 4H), 1.45-1.14 (m, 7H), 0.73 (ddd, J=8.1, 6.3, 4.2 Hz, 1H). This racemate was separated by chiral preparative HPLC (Instrument=Berger Multigram II SFC; Column: CHIRALPAK® AD-H, 30×250 mm, 5μ; Mobile Phase: 20% MeOH/80% CO2; Flow Conditions: 85 mL/min, 150 Bar, 40° C.; Detector Wavelength: 220 nm; Injection Details: 1.0 mL of ˜150 mg/mL) to give Example 65A (2.35 g, 7.11 mmol, 45% yield; [α]=+60.6° (1.8% in DCM) @589 nm) and Example 65B (2.34 g, 7.08 mmol, 45% yield; [α]=−72.2° (1.0% in DCM) @589 nm) as oils.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C(#N)C.FC(F)(F)C(O)=[O:18].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>O>[OH:18][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)CO)cc1
Yield: 54.2 %

Procedure:
4-Methoxyacetophenone (10 g; 66.59 mmol) was added to a solution of acetonitrile (350 ml), water (70 ml) and trifluoroacetic acid (TFA) (10.26 ml; 133.20 mmol). Then (bis(trifluoroacetoxy)iodo)benzene was added, and the reaction mixture was heated under reflux for 3 h. The acetonitrile was then stripped off in a rotary evaporator, and the reaction mixture was partitioned in NaHCO3 solution/CH2Cl2. After extraction with CH2Cl2 (2×), the combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by column chromatography (CH2Cl2/MeOH 50:1) resulted in 2-hydroxy-1-(4-methoxyphenyl)ethanone (6.0 g; 36.1 mmol). MS: 167.15 (M+H); Rt: 0.83 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:20][C:21](OC(C)=O)=[O:22]>C(Cl)Cl>[C:8]([O:7][C:6](=[O:12])[NH:5][CH:3]1[CH2:4][N:1]([C:21](=[O:22])[CH3:20])[CH2:2]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (100 g, 0.58 mol) and Et3N (88 g, 0.87 mol) in DCM (1500 mL) was added Ac2O (59.6 g, 0.88 mol) dropwise at 0° C. The mixture was then stirred at 0° C. for 2 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of water (1000 mL) and then stirred at 20° C. for 30 min. The organic phase was separated, dried (Na2SO4) and concentrated to give the crude product. Seven batches were run in parallel and produced a combined crude product weight of 530 g. This crude was used in next step without the further purification. LCMS (m/z): 215.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[C:10]1([S:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si](C)(C)C.Br>O1CCCC1>[Br-:1].[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S+:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(Br)cc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In a 4-methylphenyl Grignard reagent of 1.32 L (1.88 mol, 1.42 mol/L, 2.5 equiv.) prepared by a common method from 4-bromotoluene and magnesium as raw materials using tetrahydrofuran (THF) as a solvent was added a solution dissolving diphenyl sulfoxide of 151.71 g (0.75 mol, 1 equiv.) and chlorotrimethylsilane (TMSCl) of 407.25 g (3.75 mol, 5 equiv.) in THF of 0.6 L at −5° C. to room temperature, followed by reacting under stirring for 30 minutes. After termination of the reaction, the resultant reaction mixture was poured into 12% hydrobromic acid of 1.1 L and extracted two times with dichloromethane of 1.8 L. The obtained product was washed with water and then concentrated to dryness and crystallized in acetone of 1.8 L to obtain the product of 203.7 g as a white crystal (yield: 76%). Property data thereof are shown in Table 1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45].N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (250 mg, 1.242 mmol) was added triphenylphosphine (326 mg, 1.242 mmol) and 2-hydroxyisoindoline-1,3-dione (203 mg, 1.242 mmol). After stirring at rt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (251 mg, 1.242 mmol) was added. After stirring at 30° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give the title compound as a colorless oil (252 mg, 59%). LCMS (method B): [MNa]+=369, tR=2.59 min.
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:11](=[O:13])[CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: CSc1nccc(C)n1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Product: COc1cc(C)cc(C(=O)Cc2ccnc(SC)n2)c1

Procedure:
For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 7, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 4-methyl-2-(methylthio)-pyrimidine, represented by Formula 10, at room temperature (e.g., 20° C.-30° C.) in the presence of lithium hexamethyldisilazide (LHMDS) in tetrahydrofuran to afford 1-(3-methoxy-5-methylphenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone. The compound of Formula 11 is converted into a pyrazole derivative through a two step successive process. In this regard, the compound of Formula 11 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 3-(3-methoxy-5-methylphenyl)-4-(2-methylthiopyrimidine-4-yl]-1H-pyrazol, represented by Formula 12. Thereafter, the compound of Formula 12 is converted into a cyano compound of Formula 13 by heating with iodoacetonitrile in DMF, subsequently by the oxidation of the sulfide with meta-chloroperbenzoic acid to a sulfone, [4-(2-methanesulfonylpyrimidin-4-yl)-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile, represented by Formula 14. The sulfone compound of Formula 14 is then subjected to nucleophilic substitution with 3-hydroxyazetidine hydrochloride, and then to demethylation with boron tribromide into [4-[2-(3-hydroxyazetindin-1-yl)-pyrimidin-4-yl]-3-(3-hydroxy-4-methylphenyl)-pyrazol-1-yl]acetonitrile, represented by Formula 16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)OC(C)(C)C)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylate (4.00 g, 8.53 mmol) in CH2Cl2 (60 ml) was added excess TFA (8.40 ml, 0.111 mol). The solution was reacted at room temperature for 16 hours and subsequently concentrated in vacuo. Water was added and the formed precipitate was collected by filtration and subsequently dried to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid in 98% yield, mp˜100° C. (decomposition); 1H-NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.60 (br s, 1H), 7.08 (br d, J˜8 Hz, 2H), 7.26 (dd, J=8 and 2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.35 (d, J=2 Hz, 1H), 7.37 (br d, J˜8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:15]([C:11]1[S:10][C:9]([N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]2=[O:18])=[N:13][C:12]=1[CH3:14])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccn(-c2nc(C)c(C(=O)O)s2)c(=O)c1
Reactant: NCc1ccccc1
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)c(=O)c1
Yield: 17 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 17% yield: mp 205-208° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=6.0 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 7.35-7.17 (m, 5H), 6.33 (dd, J=8.1, 2.7 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.6, 161.9, 161.6, 153.9, 150.3, 139.9, 132.0, 128.7, 127.2, 123.7, 104.2, 86.5, 56.8, 43.1, 17.5; MS (ES+) m/z 356.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(Br)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethyl benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:9]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1

Procedure:
By the method of preparation 1, 3-bromophenol (5.0 g, 28.90 mmol) in dimethylformamide (20 mL) was treated with t-butyldimethylsilyl chloride (4.4 g, 28.9 mmol) and imidazole (3.9 g, 57.9 mmol) to provide, after chromatography (silica gel, hexanes), the desired product as a clear oil: 1H NMR d 0.22 (s, 6H), 1.00 (s, 9H), 6.78 (m, 1H), 7.02 (s, 1H), 7.10 (d, J=5.1 Hz, 2H); MS (FD) m/e 288 (M+); Anal. calc'd. for C12H19BrOSi: C, 50.17; H, 6.67. Found: C, 50.07; H, 6.45.