Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][C:26]3=[O:27])[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.[O:38]([C:40]#[N:41])[Na].C1(C)C=CC=CC=1>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:40]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][C:26]3=[O:27])[CH2:23][CH2:24]2)=[O:18])=[CH:36][CH:37]=1)(=[O:38])[NH2:41]
Reactant: O=C(c1ccc(OCCCO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: N#CO[Na]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Trifluoroacetic acid (0.21 ml) is added dropwise with stirring to a mixture of 1-{1-[4-(3-hydroxypropoxy)-benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.51 g), NaOCN (0.16 g), toluene (5 ml) and chloroform (5 ml) at room temperature. After adding, the mixture is stirred at room temperature overnight. Ethyl acetate is added to the reaction mixture and the mixture-is washed with saturated aqueous sodium hydrogen carbonate solution, water and saline solution successively and then dried with sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1) to give 1-{1-[4-(3-carbamoyloxypropoxy)benzoyl-4-piperidinyl}-3,4-dihydrocarbostyril (0.15 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([O:17][CH2:18][CH3:19])(=O)C>>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:4]2[CH:3]=[CH:19][C:18]([O:17][CH3:14])=[C:6]([O:8][CH3:9])[CH:5]=2)=[CH:3][C:4]=1[O:12][CH3:13])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C

Procedure:
A solution of 9.3 mL of 4-bromoveratrole in 200 mL of THF was cooled to -78° C. and 73 mL of 1.51M n-butyl lithium was added dropwise. The reaction mixture was stirred for 3 hours at -78° C. and a solution of freshly fused zinc chloride in 100 mL of THF was added. After 1 hour, this solution was added to a second solution formed by treatment of a suspension of 1.7 g of bis(triphenylphosphine)palladium dichloride in 300 mL of THF with 4.9 mL of a 1M solution of diisobutylaluminum hydride in hexane followed by addition of 16.2 g of methyl 4-bromo-2-methoxybenzoate using a double tipped syringe needle. The reaction mixture was allowed to stir at room temperature over night and was diluted with ethyl acetate. The organic solution was washed with 1M HCl, water, and brine, dried, and evaporated to a dark oil which was purified by preparative hplc eluting with 3:1 hexane:ethyl acetate and crystallized from ethyl acetate-hexane to give 8.4 g 3,3',4'-trimethoxy[1,1'-biphenyl]-4-carboxylic acid methyl ester. mp 96°-97.5° C.
Reaction SMILES: C(N(CC)CC)C.Br.Br[CH:10]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1)[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=O.[NH2:35][C:36]([NH2:38])=[S:37]>C(#N)C>[CH3:20][C:15]1[CH:14]=[C:13]([C:11]2[N:35]=[C:36]([NH2:38])[S:37][C:10]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(C(=O)C(Br)c2ccnc(OCc3ccccc3)c2)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added dropwise to a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone hydrobromide (4.8 g, 9.8 mmol) and thiourea (0.77 g, 11 mmol) in acetonitrile (40 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. The resulting crude crystals were recrystallized from ethyl acetate to obtain 2.0 g (5.2 mmol, yield 53%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]([CH3:20])[CH:12]=1)=[C:5]2[CH3:21].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:19][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:21])=[CH:3][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:10][CH:9]=3)=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)cc(-c2[nH]c3ccc(N)cc3c2C)cc1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(C)cc(-c2[nH]c3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.85 g of 5-amino-2-(4-methoxy-3,5-dimethylphenyl)-3-methylindole was dissolved in 20 ml of pyridine, and 1.51 g of p-toluenesulfonyl chloride was added. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% hydrochloric acid and water, and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 2-(4-methoxy-3,5-dimethylphenyl)-3-methyl-5-p-toluenesulfonylaminoindole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CCN1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 22.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 1-ethyl-1,4-diazepane (0.120 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The mixture was diluted with a saturated solution of sodium hydrogencarbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-30%) in dichloromethane furnished 0.030 g (21%) of the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[I:14]Cl>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: ClI
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(N)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of methyl 4-amino-2-methoxybenzoate (13 g, 0.07 mol) in acetic acid (300 mL) was added dropwise a solution of iodine monochloride (11.5 g, 0.07 mol) in acetic acid (50 mL). The mixture was stirred for 1.5 hours at room temperature. The precipitate was filtered and washed with ether. Then was dissolved with bicarbonate 4% and extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was removed under reduced pressure giving the title compound as a white solid (88%), which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C@H:12]([CH2:17][C:18]#[CH:19])[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C@H:12]([CH2:17][C:18]#[CH:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: C#CC[C@@H](N)C(=O)OC
Reactant: O=[N+]([O-])c1ncccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CC[C@@H](Nc1cccnc1[N+](=O)[O-])C(=O)OC

Procedure:
To a mixture of 3-fluoro-2-nitropyridine (860 mg, 6.05 mmol) and (R)-methyl 2-aminopent-4-ynoate (1.924 g, 15.131 mmol) in DMF was added triethylamine (2.55 ml, 18.16 mmol) and the resulting solution was stirred over the weekend. The reaction mixture was quenched with sat. NaHCO3, extracted with EtOAc/hexane=2:1, washed with brine, dried over Na2SO4 and the solvent was evaporated. Flash chromatography (SiO2, DCM to DCM/EtOAc=3:1 to 2:1) afforded the title compound as a pale yellow solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])[CH2:25][CH2:24]3)[NH:13][C:12]2=1.IC>CN(C)C=O>[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:24][CH2:25][C@H:26]([N:29]4[C:30](=[O:39])[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]4=[O:38])[CH2:27][CH2:28]3)[N:13]([CH3:1])[C:12]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Cesium carbonate (119 mg, 0.36 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (190 mg, 0.36 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by iodomethane (23 μL, 0.36 mmol, 1.0 eq). After 5 hours stirring at room temperature, one additional equivalent of iodomethane is added to the reaction mixture and, after 2 hours stirring, solvent is removed to give a residue that is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford 2-[trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as an orange solid (113 mg, 54% yield).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>C1COCC1>[CH:34]1([S:37]([N:12]2[C:4]3=[N:5][C:6]4[C:7](=[N:8][O:9][C:10]=4[CH3:11])[C:2]([F:1])=[C:3]3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:39])=[O:38])[CH2:36][CH2:35]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1onc2c(F)c3c(nc12)[nH]c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc2c(F)c3c(nc12)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-fluoro-7-(2-fluoro-4-iodophenyl)-3-methyl-5H-imidazo[4,5-b]isoxazolo[3,4-e]pyridin-6(7H)-one (143 mg, 0.33 mmol) in THF (10 ml) at −78° C. is added LiHMDS (0.38 ml, 1 M in THF, 0.38 mmol). The reaction mixture is stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (69 mg, 0.50 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×20 ml). The combined organic solution is washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([C:15](=[S:16])[NH2:17])[NH2:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: NC(=S)N(N)C(=O)Cc1cc(F)cc(F)c1
Reaction time: 18 h
Yield: 46.9 %

Procedure:
2.5 g of 3,5-difluorophenylacetic acid (14.52 mmol, 1 eq.) are placed in 70 mL of dichloromethane with stirring. 1.46 g of thiosemicarbazide (15.98 mmol, 1.1 eq.), 2.22 g of hydroxybenzotriazole (14.52 mmol, 1 eq.) and 2.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.52 mmol, 1 eq.) are successively added with continued stirring at room temperature. After 18 hours at room temperature, the dichloromethane is evaporated off. The residue is taken up in ethyl acetate and 1N hydrochloric acid. The precipitate is filtered off and dried to give 1.67 g of [(3,5-difluorophenyl)acetyl]hydrazinecarbothioamide.
Reaction SMILES: COC1C=C(C)C(S(N2CCCCC2COCC(O)=O)(=O)=O)=C(C)C=1.N1(CC2C=C(C=CC=2)C#N)CCNCC1.C(=O)([O-])O.[Na+].[CH3:46][O:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51]([S:55]([N:58]2[CH2:63][CH2:62][CH2:61][CH2:60][CH:59]2[CH2:64][O:65][CH2:66][C:67]([N:69]2[CH2:74][CH2:73][N:72]([CH2:75][C:76]3[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=3)[C:79]#[N:80])[CH2:71][CH2:70]2)=[O:68])(=[O:57])=[O:56])=[C:50]([CH3:84])[CH:49]=1.[Cl:85][Si](C)(C)C>ClCCl.C(C(C)=O)C.C(OCC)C>[ClH:85].[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH3:84])[C:51]([S:55]([N:58]2[CH2:63][CH2:62][CH2:61][CH2:60][CH:59]2[CH2:64][O:65][CH2:66][C:67]([N:69]2[CH2:74][CH2:73][N:72]([CH2:75][C:76]3[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=3)[C:79]#[N:80])[CH2:71][CH2:70]2)=[O:68])(=[O:56])=[O:57])=[C:52]([CH3:54])[CH:53]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(Cc3cccc(C#N)c3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Agent: N#Cc1cccc(CN2CCNCC2)c1
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 3-(piperazin-1-ylmethyl)benzonitrile (81 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/hexane (20:1). 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-yl)methyl)benzonitrile (100 mg, 0.180 mmol) was dissolved in methyl ethyl ketone (3 ml), and chlorotrimethylsilane (27 μl, 0.216 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.255 g, 0.97 mmol) and N-methyl-benzylamine (0.25 mL, 1.9 mmol) gives the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]2[CH:9]([O:16]2)[CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1C=CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2OC2C1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methanesulfony-1,2,3,4-tetrahydropyridine (2.18 g, 13.52 mmol, Example 302) in methylene chloride (30 mL) at 0° C., meta-chloroperoxybenzoic acid (3.94 g, 77%, 17.5 mmol, Aldrich) in 20 mL of methylene chloride was added and the mixture was stirred for 30 minutes. An additional 600 mg of meta-chloroperoxybenzoic acid was added and the mixture was stirred for 6 hours. The reaction was quenched with 30% sodium thiosulfate solution and the mixture was extracted with methylene chloride. The extracts were combined, washed with 5% sodium carbonate and dried with MgSO4. The solvent was removed to give the desired product as a white solid. 2.40 g, 100%. The compound was used directly for the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].F[C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:9]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
After cooling a suspension of sodium hydride (1.64 g, 60% suspension in mineral oil, 37.5 mmol) in N,N-dimethylformamide (50 mL) to 0° C., 2-methyl-1-propanol (3.47 mL, 37.5 mmol) was added stepwise. And the reaction mixture was stirred at 25° C. for 20 minutes. Again, the reaction mixture was cooled to 0° C., 2-fluoro-5-bromobenzonitrile (5.00 g, 25.0 mmol) was added stepwise to the reaction mixture and the mixture was stirred at 25° C. for 15 hours. After the completion of the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with saturated brine (2×50 mL), and dried over sodium sulfate anhydrous. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the resulting crude compound was purified on silica-gel chromatography (hexane/ethyl acetate=9/1) to obtain the titled compound (6.04 g). Yield: 95%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][C:12]([Br:24])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (compound of Example 181(2); 0.20 g, 0.50 mmol) was dissolved in acetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound as a crude product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([NH2:23])[CH:22]=1>CCOCC>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:21]([NH:23][C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:22]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Solvent: CCOCC
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C(F)(F)F)ccc23)c1

Procedure:
The product from Example 7d (65 mg, 0.28 mmol) and the product from Example 1f (61.5 mg, 0.28 mmol) was reacted 28 h following the procedure from Example 1g giving the title compound as a hydrochloride salt after trituration with ether giving (131 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.43 (d, J=6.99 Hz, 1H) 7.23 (m, 4H) 7.35 (m, 4H) 8.39 (d, J=8.82 Hz, 1H) 8.55 (d, J=6.99 Hz, 1H) 9.48 (d, J=8.46 Hz, 1H) 11.55 (brs, 1H); MS (ESI+) m/z 412 (M−Cl)+; (ESI−) m/z 410 (M−HCl)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C

Procedure:
2-(4-Bromophenoxy)-5-(trifluoromethyl)pyridine (2) was prepared by heating a mixture of 4-bromophenol (1.0 eq, Aldrich), 2-chloro-5-(trifluoromethyl)pyridine (0.9 eq, Aldrich), and K2CO3 (2 eq) in 25 mL of CH3CN at 80° C. under argon for 14 hours. After cooling to room temperature, water (30 mL) was added, extracted with EtOAc (2×100 mL), concentrated and purified by column (silica gel, Hexanes, then Hexanes/EtOAc 10/1) to give compound 2: 1H-NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.94 (ddd, 1H, 0.6, 2.6 & 8.6 Hz), 7.56 (d, 2H, 8.9 Hz), 7.05-7.08 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)c1cccc(O)c1
Reactant: BrCC1CCCCC1
Product: CC(=O)c1cccc(OCC2CCCCC2)c1

Procedure:
Alkylation of 3′-hydroxy-acetophenone by bromomethylcyclohexane (2) was performed following the method given in Example 1. The product was purified by flash chromatography (5 to 30% EtOAc/hexane gradient) to give 1-(3-(cyclohexylmethoxy)phenyl)ethanone (103) as a colorless oil. Yield (3.17 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dt, J=1.4, 6.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.16 (ddd, J=1.0, 2.7, 8.2 Hz, 1H), 3.80 (d, J=6.3 Hz, 2H), 2.54 (s, 3H), 1.60-1.80 (m, 6H), 1.10-1.30 (m, 3H), 0.90-1.10 (m, 2H).