Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[C:7](C(F)(F)F)[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28]C3CC3)=[O:27])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O[O:39][S:40]([O-:42])=O.[K+].[CH3:44]O.O>>[CH3:35][C:34]1[CH:33]=[CH:32][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][C:23]=1[C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:4]1[CH:5]=[CH:6][C:7]([S:40]([CH3:44])(=[O:42])=[O:39])=[CH:8][C:3]=1[CH3:2])=[N:14][N:15]=[CH:16]2
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccc(C(F)(F)F)cc3C(F)(F)F)nncc2c1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(-c3ccc(S(C)(=O)=O)cc3C)nncc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-methyl-3-(1-(2-methyl-4-(methylthio)phenyl)phthalazin-6-yl)benzamide (170 mg, 0.43 mmol, Method D) in 2 mL of 10/1 methanol/H2O at 0° C. was treated with oxone (262 mg, 0.43 mmol). The mixture stirred at 0° C. for 1 h and then warmed up to RT for 1 h. The reaction was quenched with 20 mL sodium sulfite (sat.) and extracted with 10% MeOH in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by HPLC to give 4-methyl-3-(1-(2-methyl-4-(methylsulfonyl)phenyl)phthalazin-6-yl)benzamide as a white solid. Found MS (ES+)=432.1 (M+H+).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][OH:25])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[OH:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][OH:25])[C:15]1[CH:22]=[CH:21][C:18]([C:19]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Reactant: NC(=O)c1ccccc1N
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: O=c1[nH]c(-c2ccc(N(CCO)CCO)cc2)nc2ccccc12
Yield: 42 %

Procedure:
2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (150 mg, 42%) was isolated as a brown solid. Selected data: MS (m/z): 326.03; MP 228-230° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=2)[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: CCCCCCCCCc1ccc(B(O)O)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCCc1ccc(-c2cccc(F)n2)cc1
Yield: 90.7 %

Procedure:
A solution of 232 mmol of 2-bromo-6-fluoropyridine in 400 ml of toluene is admixed with 290 mmol of 4-nonylphenylboronic acid, 200 ml of ethanol, a solution of 464 mmol of sodium carbonate in 200 ml of water and 2.3 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 3.5 h. After cooling, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried with magnesium sulfate. The solvents are removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane/dichloro-methane 1:1 as eluent and recrystallization from acetonitrile/acetone 5:1, giving 63 g (91%) of 2-fluoro-6-(4-nonylphenyl)pyridine.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:1]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C2OCCO2)cc1
Yield: 68.5 %

Procedure:
To 134 g of terephthalaldehyde and 62 g of ethylene glycol, was added 400 mL of toluene, and then was added thereto 2 g of p-toluenesulfonic acid, to conduct dehydration reaction under azeotropic conditions. After the time when the reaction of water stopped in the reaction, the reaction liquid was heated under reflux for another 2 hours, followed by cooling. The resultant reaction liquid was poured into an aqueous sodium bicarbonate solution. The organic phase was concentrated, and then purified by silica gel column chromatography (yield amount 122 g, and yield 68.5%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:12]([Br:23])=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:12]([Br:23])=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)[O:10][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(Br)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate (330 mg, 0.87 mmol) in t-butylacetate (10 mL) was added perchloric acid (0.3 mL, 3.5 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C22H31BrNO3: 436.1; Found: 436.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32](O)=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]([NH:37][CH3:36])=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CN
Product: CNC(=O)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid following a procedure analogous to that described in Example 76 using methylamine in place of ammonia. LC-MS Method 3 tR=1.249 min, m/z=497.2; 1H NMR (CD3OD) 1.51 (m, 3H), 1.97 (s, 1H), 2.07-2.31 (m, 6H), 2.64-2.74 (s, 3H), 2.94 (d, 1H), 5.62 (m, 1H), 6.13 (s, 1H), 6.79-6.89 (m, 2H), 6.97 (m, 4H), 7.15 (s, 2H), 7.23 (m, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=CC=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16]([O-])(=O)[CH3:17].[NH4+:20].[Na].Cl>CO>[N:1]1([CH:6]([C:7]2[CH:8]=[CH:10][CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:16][NH2:20])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCn1ccnc1)c1ccccc1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NCCC(c1ccccc1)n1ccnc1
Reaction time: 144 h

Procedure:
A solution of 6.0 g. of 3-(1H-imidazol-1-yl)propiophenone in 100 ml. of methanol was stirred as 23.1 g. of ammonium acetate, and then 1.35 g. of sodium cyanoborohydrate was added. After 6 days at room temperature, 60 ml. of concentrated hydrochloric acid was added and the solvent was distilled off. The residue was treated with 65 ml. of 10N sodium hydroxide, 25 g. of sodium chloride and 200 ml. of methylene chloride and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to obtain the desired product as a viscous oil, 5.4 g. When this was reacted with 4-chlorobenzoyl chloride and 4-bromobenzoyl chloride by the procedure of Example 27, the compounds set forth in Table XIX were obtained.
Reaction SMILES: [CH:1]1([C:6]([OH:30])([CH2:20][C:21]2[O:22]C(C)(C)[O:24][C:25](=O)[CH:26]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[C:11]([F:19])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CCC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[C:11]([F:19])[CH:10]=3)[CH2:20][C:21](=[O:22])[CH2:26][C:25](=[O:24])[O:30]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C#N)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Product: CC(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The title compound was prepared analogously to example A(237) substituting 2{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-propionitrile from step 2 below in place of 1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile. 1H NMR (400 MHz, CDCl3) δ: 1.33–1.50 (m, 3H), 1.56 (d, J=7.33 Hz, 3H), 1.62–1.75 (m, 5H), 1.85–1.93 (m, 2H), 2.15–2.26 (m, 1H), 2.58–2.68 (m, 3H), 2.72 (d, J=6.57 Hz, 2H), 3.38 (d, J=3.54 Hz, 2H), 4.09 (q, J=7.33 Hz, 1H), 6.84 (d, J=11.12 Hz, 1H), 6.93 (d, J=7.83 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:11]=[C:12]([C:18]2[N:19]=[CH:20][N:21]([C:23]([N:25]([CH3:32])[CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:24])[CH:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].Cl[CH2:34][CH2:35][C:36]#[N:37]>ClCCl.C(O)(C)C>[C:36]([CH2:35][CH2:34][N:29]1[CH2:30][CH2:31][CH:26]([N:25]([CH3:32])[C:23]([N:21]2[CH:22]=[C:18]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([F:9])[CH:11]=3)[N:19]=[CH:20]2)=[O:24])[CH2:27][CH2:28]1)#[N:37]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCNCC3)cn2)cc1F
Reactant: N#CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(CCC#N)CC3)cn2)cc1F
Temperature: 25 °C
Yield: 68 %

Procedure:
Triethylamine (0.159 mL, 1.139 mmol) was added to a stirred suspension of 4-(3-fluoro-4-methoxyphenyl)-N-methyl-N-(piperidin-4-yl)-1H-imidazole-1-carboxamide hydrochloride (0.200 g, 0.542 mmol) and 3-chloropropanenitrile (0.058 g, 0.651 mmol) at room temperature. The clear solution was allowed to stir at reflux for 2 h, during which time a white suspension formed. The mixture was allowed to cool to room temperature, diluted with a mixture of dichloromethane/isopropanol (7:3) and then washed with water. The organic layer was dried (MgSO4), filtered and evaporated to give a colourless solid that was triturated with ethanol to give the product (142 mg, 64%).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH3:31])[CH:18]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>CS(C)=O.COC(C)(C)C.CCCCCC>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH3:31])[CH:18]=4)=[N:14][CH:15]=[C:10]3[CH:9]=[N:8][C:7]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C2CCCC2)C(=O)NC3)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cnc(=O)n(C4CCCC4)c3n2)cc1C
Yield: 24.3 %

Procedure:
Prepared from 70 mg (0.16 mmol) of 1-cyclopentyl-7-{3-methyl-4-[2-(diethylamino)ethoxy]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 72 mg (0.58 mmol) of potassium tert-butoxide in 3.0 mL of DMSO. The crude semi-solid residue is dissolved in a mixture of tert-butyl methyl ether and hexane. The solution is allowed to evaporate slowly to less than 1 mL, then diluted with 2 mL of 1:3 diethyl ether/hexane. The precipitated solids are collected and dried to give 17 mg (24%) of the title compound: mp>95° C. (dec).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:13]([N:20]1[CH2:25][C@H:24]([CH2:26][CH3:27])[NH:23][CH2:22][C@H:21]1[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:22][C@@H:21]([CH3:28])[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][C@@H:24]1[CH2:26][CH3:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Benzyl bromoacetate (2.6 mL, 16 mmol) was added to a solution of (2R,5S)-1-benzyl-5-ethyl-2-methyl-piperazine (3.5 g, 16 mmol) in acetonitrile (20 mL) containing K2CO3 (2.4 g, 17.6 mmol). The reaction mixture was stirred at ambient temperature overnight. The suspension was diluted with CHCl3 and the solid was filtered off. Filtrate was evaporated in vacuo and the residue was purified by SiO2 chromatography (EtOAc:petrol 4:6) to give ((2S,5R)-4-benzyl-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid benzyl ester (3.4 g) as a pale yellow oil. 1H NMR (CDCl3): 7.46-7.14 (10H, m), 5.18 (2H, d), 4.10 (1H, d), 3.49 (1H, d), 3.32 (1H, d), 3.17 (1H, d), 2.91-2.79 (1H, m), 2.73 (1H, dd), 2.60-2.42 (3H, m), 2.01-1.79 (1H, m), 1.60-1.44 (1H, m), 1.41-1.23 (1H, m), 1.14 (3H, d), 0.77 (3H, t).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]([O:19][CH3:30])([C:15]([F:18])([F:17])[F:16])/[CH:13]=[CH:12]/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0° C. The reaction was allowed to stir at 0° C. for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aq NH4Cl solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).
Reaction SMILES: [Cl-:1].[Ce+3].[Cl-].[Cl-].[I-].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[ClH:1].[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]([CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)([OH:36])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1ccc(N2CCOCC2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Cl-]
Agent: [Ce+3]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CC1(O)CCN(Cc2ccccc2)CC1)c1ccc(N2CCOCC2)cc1
Reaction time: 2 h
Yield: 40 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. Dissolving 1.07 g (4.0 mmol) of 2-bromo-1-(4-morpholinophenyl)ethanone and 0.76 g (4.0 mmol) of N-benzyl-4-piperidone into 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension and reacting at room temperature for 2 hours. Operating according to the post-treatment procedure in General Method three to obtain 0.69 g of a white crystal, with yield of 34.3%.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28]O)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:2][S:1]4=[O:3])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: OCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1OCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sulfonyl chloride (0.63 g, 5.3 mmol) in THF (2 ml) is added within 5 minutes to a solution of 2-{4-(2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-ethanol (1.50 g, 4.4 mmol) and triethylamine (3.0 ml, 22 mmol) in absolute THF (20 ml) at +5° C. After stirring the resulting suspension for four hours at room temperature it is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 202–203° C.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:9]([C:15]#[N:16])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[Cl:14][C:12]1[CH:13]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:9]([C:15]#[N:16])=[N:10][CH:11]=1
Reactant: N#Cc1ncc(Cl)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A pressure vessel was charged with TEA (7.65 mL, 55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I) iodide (0.263 g, 1.380 mmol), palladium (0) tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol), 3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and DMF (50 ml). The vessel was flushed with argon, sealed, stirred at ambient temperature for 15 minutes, and then heated at 50° C. for 4 hours. The solution was diluted with water and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by silica-gel chromatography, eluting 0-50% ethyl acetate in hexane, to afford the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH3:10])[CH3:2].[OH:18]O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH3:10])[CH3:2]
Reactant: OO
Reactant: CCCCCCSC1(CC)CCCCC1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCCS(=O)C1(CC)CCCCC1CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of n-hexyl 1,2-diethylcyclohexyl sulphide (6.5 g., 25 mmoles), glacial acetic acid (50 ml.) and hydrogen peroxide (2.7 ml. of 100 vols.) was stirred at room temperature for 20 hours. The mixture was poured into an excess of 2N sodium hydroxide and extracted with methylene chloride. The extract was washed with water and dried (MgSO4). The solvent was removed and the residual oil (6 g.) was eluted with chloroform from a silica column (Merck Kieselgel 7734). n-Hexyl 1,2-diethylcyclohexyl sulphoxide was obtained as a viscous liquid (Found: S= 11.7%. C16H32OS requires S= 11.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[C:30](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(O)cc2)C1c1ccccc1Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(2-chlorophenyl)-3-(4-hydroxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (4.33 g), potassium carbonate (2.76 g), methyl iodide (5.68 g), and N,N-dimethylformamide (DMF) (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was crystallized from ether to give 4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 176°-178°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCNC(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was cooled to 0° C. and treated with 0.378 g of N-tert.-butoxycarbonyl-β-alanine and 0.383 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed in succession with water, 5% citric acid solution and water, dried over anhydrous magnesium sulphate and evaporated. Chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution followed by evaporation gave 0.48 g of (E)-2′-(N-tert.-butoxycarbonyl-β-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.