Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2ccc(C=O)c(F)c2)cc1

Procedure:
Analogously to Example (40a) 2,4-difluorobenzaldehyde and 4-methoxyphenol were used as starting material.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:23][CH2:22]1)=[O:6].[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.CCOCC>[C:34]([N:4]([CH3:3])[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:25][CH2:26]1)=[O:6])(=[O:36])[CH3:35]
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N(C)C(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
0.1 g of sodium hydride (60% oil dispersion) is added to a solution of one g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide in 30 ml of dimethylformamide, and a solution of 0.19 g of acetyl chloride in 5 ml of ether is added thereto. After the mixture is stirred at 50° C. for 20 hours, the mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:n-hexane=4:1). 0.32 g of N-acetyl-N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained as an oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH2+:22][CH2:21][CH2:20]1)=[O:17].C(Cl)(Cl)Cl.C(O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl

Procedure:
4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86, 6.07 g) was suspended in water (100 ml). To this was added 100 ml of CHCl3:isopropanol (3:1) and sat. Na2CO3 (50 ml). The organic portion was separated and the aqueous portion was washed with 100 ml portions of CHCl3:isopropanol (3:1) five times. The organic portions were combined, dried with MgSO4 and concentrated to a yellow solid (2.73 g, 64%).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19]>ClCCCl>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[O:12])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(=O)c1cccc2ccccc12

Procedure:
1. To a solution of naphthalene-1-carbonyl chloride (3.43 g) and AlCl3 (2.40 g) in 1,2-dichloroethane (7 ml) was added at 0° C. a solution of 1H-indole-2-carboxylic acid ethyl ester (1.70 g) in 1,2-dichloroethane (7 ml) and the mixture was heated at reflux temperature for 2 h. The mixture was partitioned between ice cold water and AcOEt, the organic layer was washed with aqueous Na2CO3, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, 5:1) to give 3-(naphthalene-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester as pale yellow solid. MS: 344.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
4-Fluorobenzoic acid methyl ester (200 mmol), 1-benzyl-piperazine (300 mmol), and potassium carbonate (300 mmol) are suspended in acetonitrile (400 ml) and stirred under reflux for 6 days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with diethylether. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatographic on silica gel with (CH2Cl2 first, then CH2Cl2/MeOH=15:1) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 105-107° C. is obtained.
Reaction SMILES: [C:1]([CH2:3][CH:4](OS(C)(=O)=O)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2].[NH:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)OS(C)(=O)=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 100.8 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[(methylsulfonyl)oxy]propyl}-1,4-diazepane-1-carboxylate (4.00 g, 11.1 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.50 g, 11.1 mmol) in DMF (30 mL) was added potassium carbonate (4.6 g, 33 mmol). The resulting mixture was stirred at room temperature for 66 hours. The reaction solution was diluted with ethyl acetate (˜300 mL) then washed with water twice and brine. The organic solutions were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0% to 10% methanol/DCM) to give the desired product as clear oil (6.5 g, 100%). LCMS calculated for C29H45N8O3Si(M+H)+: m/z=581.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[N:9]([CH2:34][CH2:33][CH2:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:8]=1
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nn(CCCOC3CCCCO3)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.24 g of 3-bromopropyl 2-tetrahydropyranyl ether and 0.24 g of potassium carbonate. The obtained mixture was stirred at 50° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to give 0.20 g of the title compound as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH:21]=[CH:20]3)[CH:10]=1.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:20]3)[CH:10]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3c(ccn3CC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a solution of ethyl {5-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-1H-indol-1-yl}acetate (0.27 g, 0.65 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL) was added 85% aqueous solution (5 mL) of potassium hydroxide (0.13 g, 1.97 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was made weak acidic with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2-2:1) to give the title compound (0.19 g, yield 76%) as a pale-yellow amorphous solid.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:5]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH:4]=[O:3]
Reactant: BrBr
Reactant: COC(=O)c1ccc(CCC=CO[Si](C)(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CCC(Br)C=O)cc1
Yield: 100.8 %

Procedure:
To 4.46 g (16 mmol) of methyl 4-(4-trimethylsilyloxy-3-butenyl)benzoate, prepared in Preparation 1, in 16 ml carbon tetrachloride at -20° C. was slowly added 2.56 g (16 mmol) of bromine in 16 ml carbon tetrachloride over 4 hours. The mixture was allowed to come to room temperature then decanted from a small amount of insoluble material. The solvent was removed by vacuum rotary evaporation to give 4.60 g of 2-bromo-4-(4-carbomethoxyphenyl)butanal. Chromatography purification (silica; hexane--ethyl acetate 7:3) of the above product gave 4.0 g in a yield of 87.8 percent. 1H NMR (CDCl3) δ 2.24 (m, 1H), 2.36 (m, 1H), 2.81 (m, 1H), 2.90 (m, 1H), 3.90 (s, 3H), 4.16 (m, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.97 (d, J=8.2 Hz, 2H), 9.46 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3) δ 32.5, 32.7, 51.7, 54.3, 128.3, 128.4, 129.8, 145.0, 166.6, 192.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]([NH2:10])[C:7]([OH:9])=O)=[O:4].Cl.[CH3:12]CN(CC)CC.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:28][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:10][CH:6]([C:7](=[O:9])[CH3:12])[CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:26])=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C[C@H](N)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of L-aspartic acid β-methyl ester hydrochloride (250 g, 1.36 mol) in chilled (<5° C.) CH2Cl2 (4 L) was added Et3N (440 g, 4.35 mol) in a steady flow followed by a slow addition of me3SiCl (324 g, 2.99 mol). The mixture was warmed to 25° C. and stirred for one hour, cooled again (<10° C.), and p-toluoyl chloride (205 g, 1.36 mol) was added dropwise. The mixture was allowed to warm to ambient slowly with stirring for 16 hours. The reaction mixture was then diluted with CH2Cl2 (500 mL) and washed with 1N HCl (500 mL), brine (500 mL), and dried over Na2SO4. The resultant amide product (310 g, 91%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (1.25 L) and DMAP (5 g) was added. Acetic anhydride (840 mL) was added slowly and then the reaction was heated at 90° C. for 2 hours. The cooled solution was poured into 7 L ice water and extracted with 6 L EtOAc. The organic layer was washed with 2N HCl (3×1 L) and 1N NaOH (1 L), dried over MgSO4 and concentrated to afford the title compound as a white solid (301 g, 93%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](B(O)O)[CH:43]=2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:42]4[CH:43]=[C:44]5[C:39]([CH:38]=[N:37][N:36]5[CH3:35])=[CH:40][CH:41]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ncc2ccc(B(O)O)cc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 110 °C

Procedure:
The reaction mixture of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (20 mg, 0.039 mmol), 1-methyl-1H-indazole-6-boronic acid (10.3 mg, 0.058 mmol), 2N K2CO3 (100 μL, 0.19 mmol), Pd(PPh3)4 (4.3 mg, 0.004 mmol) in dioxane (1.5 mL) in sealed tube was heated at 110° C. for 2 h. After the starting material consumed, the reaction was cooled down, to the mixture was added MeOH, excess NaOH, the reaction mixture was heated at 45° C. overnight. Then the reaction mixture was neutralized by acetic acid, concentrated down, then treated by MeOH, and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C33H29ClN4O3S: 597.2 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.78 (d, J=2.6 Hz, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 8.03-7.82 (m, 4H), 7.71-7.69 (m, 1H), 7.61-7.60 (m, 3H), 5.28 (s, 1H), 4.16 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([C:6]([O:8]C)=O)=[C:4]([I:13])[CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:47][C:48]1([F:61])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:59][CH2:58][CH:57]([NH2:60])[CH2:56][CH2:55]2)[CH2:50][CH2:49]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:61][C:48]1([F:47])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:55][CH2:56][CH:57]([N:60]3[CH2:12][C:10]4[C:5](=[C:4]([I:13])[CH:3]=[C:2]([Cl:1])[CH:11]=4)[C:6]3=[O:8])[CH2:58][CH2:59]2)[CH2:50][CH2:49]1
Reactant: COC(=O)c1c(C)cc(Cl)cc1I
Reactant: NC1CCN(C2CCC(F)(F)CC2)CC1
Agent: COC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2c(I)cc(Cl)cc2CN1C1CCN(C2CCC(F)(F)CC2)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of methyl 4-chloro-2-iodo-6-methylbenzoate (175 mg, 0.56 mmol) in methyl pivalate (1 mL), N-bromosuccinimide (120 mg, 0.67 mmol) and benzoylperoxide (14 mg, 0.06 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Additional N-bromosuccinimide (60 mg) and benzoylperoxide (7 mg) were added and stirring continued for 1 hour. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (2 mL). Triethylamine (0.28 mL, 2 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (110 mg, 0.5 mmol) were added and the reaction mixture was stirred at 90° C. for 4 hours. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:97/3) afforded title compound (116 mg, 45% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=[O:22]>O>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[O:22][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Oc1ccc(C2CO2)cc1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
30 g of 4-acetoxy styrene and 1 L of chloroform were added into a 2 L reactor, and was stirred and cooled in iced water. 47 g of 3-chloroperoxybenzoicacid were added into the cooled solution, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, the 3-chlorobenzoicacid (by-product) was removed by filtering the product, and then the residual 3-chlorobenzoicacid was removed by washing 2 times with saturated sodium sulfite aqueous solution, 1 time with saturated sodium bicarbonate aqueous solution, 1 time with saturated sodium chloride aqueous solution, and 1 time with distilled water. Next, the product was dried with magnesium sulfate, and chloroform was removed under reduced pressure, and then the product was vacuum dried for 1 day to obtain 27.6 g of the pure 4-acetoxy styreneoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In dichloromethane (1.5 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (60 mg), followed by addition of triethylamine (33 ml) and acetyl chloride (13 ml) under ice-cooling. The mixture was then stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:2) and the desired fraction was concentrated to give (2R,3R)-3-acetylthio-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 45:59 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C:3]([O:2][CH3:1])([CH3:4])[CH3:5])=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: COC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(C)(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 4-(2-methoxypropan-2-yl)benzoic acid (0.09 g, 0.46 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methoxypropan-2-yl)benzamide (0.09 g, 61%) as a white solid. LRMS (M+H+) m/z: calcd for 328.18. found 328. HPLC Purity (214 nm) 99.8%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.86 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 2.97 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.CO>ClCCl>[Br:1][C:2]1[C:3]([CH2:10][O:11][CH2:21][O:22][CH3:23])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COc1ccc(Br)c(CO)n1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1nc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of (3-bromo-6-methoxypyridin-2-yl)methanol (10.6 g, 48.6 mmol) synthesized by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) in dichloromethane (150 mL) was successively added dropwise with N,N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g, 165 mmol) under ice cooling. The mixture was warmed to room temperature, stirred for 16 hours, and then added with methanol (30 mL), and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1→20:1) to obtain 3-bromo-6-methoxy-2-[(methoxymethoxy)methyl]pyridine (12.1 g, 95%) as pale yellow oil.