Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Cl[CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[S:40]1[CH:41]=[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: ClCc1csc2ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 15 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, and then a solution of 132 mg (0.72 mmol, 1.1 equiv) of 3-chloromethylbenzo[b]thiophene (Wolf, G.; Zymalkowski, F. Arch. Pharm. 1976, 279) in 1 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 5/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 222 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.79 (m, 2H), 7.44-6.93 (m, 15H), 6.88 (dd, 1H, J=1.5, 8.1), 5.03 (m, 1H), 4.42 (d, 1H, J=16.6), 4.09 (d, 1H, J=16.6), 3.85 (s, 3H), 3.80 (t, 1H, J=6.6), 3.61 (m, 2H), 1.10 (t, 6H, J=6.8); low resolution MS (FAB)m/e 604 (MH+), 439.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:27]([O:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COCc4ccccc4)CC3)nc12
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere [1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methanol (compound 150)(0.033 g, 0.06 mmol) was dissolved in DMF (0.5 mL). NaH (0.014 g, 0.36 mmol) was added and the suspension was heated at 65° C. for 1 h after which benzyl bromide (0.071 mL, 0.6 mmol) was added. The reaction mixture was stirred at 65° C. for 30 min after which is was cooled to rt. Aq. NaHCO3 and H2O was added. The aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14]>O.C(O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([S:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[C:13]([OH:15])=[O:14])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)C(Br)CCCCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(SC(CCCCCc2ccc(Cl)cc2)C(=O)O)cc1
Reaction time: 8 h

Procedure:
A solution of 2.12 g (53 mmol) of caustic soda in 5 ml of water is added under nitrogen, at 0° C., to a solution of 3.27 g (26.3 mmol) of p-thiocresol in 50 ml of ethanol. Then a solution of 8.4 g (26.3 mmol) of 2-bromo-7-(4-chlorophenyl)heptanoic acid in 5 ml of ethanol is added and the cooling bath is removed. Then stirring is continued for 6 at room temperature; the mixture is let stand overnight and concentrated by evaporation. The residue is taken up in water, washed with ether and acidified with hydrochloric acid. The precipitated oil is extracted with methylene chloride. The extracts are dried and concentrated. The concentrate is chromatographed with a mixture of toluene and dioxane (5:1) on silica gel. Yield: 6.6 g (69% of theory) of 7-(4-chlorophenyl)-2-(4-methylphenylthio)heptanoic acid, M.P. 58°-61° C.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]2[CH2:8][C@H:4]([CH:5]=[CH:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:16][Si:17]([CH:20]=[N+]=[N-])([CH3:19])[CH3:18]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:11][C:9]([N:3]1[C:2](=[O:1])[C@H:7]2[CH2:8][C@@H:4]1[C@H:5]1[C@@H:6]2[CH:16]1[Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C=C[C@H]1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@@H]1C([Si](C)(C)C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a solution of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1.3 g, 6.2 mmol) and palladium(II) acetate (0.070 g, 0.31 mmol) in Et2O (62 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 3.00 mL, 11.5 mmol) drop-wise at ambient temperature over about 1 h. The mixture was stirred at ambient temperature for about 18 h and filtered through Celite®. The Celite® pad was washed with Et2O (50 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc/heptane to afford (1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid tert-butyl ester (1.7 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 4.37 (s, 1H), 2.70 (s, 1H), 1.45 (m, 10H), 1.23 (t, 1H), 0.76 (t, 1H), 0.10 (s, 2H), −0.03 (s, 9H).
Reaction SMILES: [NH:1]=[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:13]2.[BH4-].[Na+].CC(C)=O>CO>[NH2:1][CH:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[CH:13]2
Reactant: Cc1cccc(C(=N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cccc(C(N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) solution of 6-(2-(imino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine (0.058 g, 0.137 mmol) in MeOH (5.0 mL) was added sodium borohydride, 99% (0.033 mL, 0.925 mmol). The mixture was then warmed to RT and stirred for 1 h. The excess NaBH4 was then treated with acetone. The resulted solution was concentrated and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford 6-(2-(amino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 425 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:19].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:19])=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccccc1-c1c(Cl)ccc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Yield: 85.5 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.II.[Mg].C(O[Si:16]([O:19][CH2:20][CH2:21][CH3:22])([CH3:18])[CH3:17])CC>O1CCCC1>[CH2:20]([O:19][Si:16]([CH3:17])([CH3:18])[C:2]1[CH:7]=[CH:6][C:5]([Si:16]([O:19][CH2:20][CH2:21][CH3:22])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[CH2:21][CH3:22]
Reactant: Clc1ccc(Cl)cc1
Reactant: CCCO[Si](C)(C)OCCC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCO[Si](C)(C)c1ccc([Si](C)(C)OCCC)cc1
Temperature: 132 °C
Yield: 81.5 %

Procedure:
Magnesium turnings (478 g, 19.7 m) in a 12 l, flask were dried as described in Example II. The reactant stock solution was prepared by dissolving 1400 g (9.7m) of para-dichlorobenzene in 3700 g (21m) of di-n-propoxydimethylsilane and 515 g (7.2 m) of tetrahydrofuran. Fresh cuprous chloride (10.0 g, 0.10 m), a crystal of iodine, and 300 ml of the stock solution were added to the magnesium turnings. The vessel was heated to 132° C to initiate the reaction. The remaining stock solution was added over a 3 hour period and the system was refluxed at 137°-144° C for a total of 123/4 hours. The crude product was decanted away from the salt. The salt cake was washed with dry toluene and the washings and crude were combined and flash distilled. A crude product, 2563 g (83.9% yield) was obtained; subsequent fractionation gave 2412 g (79% recovered yield) of 1,4-bis(n-propoxydimethylsilyl)benzene, b.p. 140°-142° C/5 mm vacuum.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([S:29]([NH:32][CH:33]2[CH2:37][CH2:36][O:35][NH:34]2)(=[O:31])=[O:30])[C:23]=1[OH:38])=[S:20].[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].N1C=CN=C1>>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([S:29]([NH:32][CH:33]2[CH2:37][CH2:36][O:35][NH:34]2)(=[O:31])=[O:30])[C:23]=1[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(NC1CCON1)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1c(NC(=S)Nc2ccccc2Br)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 45.4 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 1, N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]thiourea (627 mg, 1.24 mmol), tert-butyldimethylsilyl chloride (934 mg, 6.2 mmol) and imidazole (169 mg, 2.48 mmol) were reacted to form the desired product (350 mg, 45%). EI-MS m/z 622 (M+) .
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C(N([CH2:15][CH3:16])CC)C.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18].O>C(OC(C)COC)(=O)C.CC(C)=O>[CH:16]1([CH2:18][CH2:17][O:20][CH:21]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[CH3:22])[CH2:15][CH2:4][CH2:3][CH2:2][CH2:9]1.[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Agent: C=Cc1ccc(O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: COCC(C)OC(C)=O
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
In 320 g of propylene glycol monomethyl ether acetate (PGMEA) was dissolved by heating 70 g of p-hydroxystyrene (VP-8000, manufactured by Nippon Soda Co., Ltd.), and after dehydrating by vacuum distillation the solution was cooled to 20° C. To the solution were added 0.35 g of pyridinium-p-toluenesulfonate and 22.4 g of cyclohexane ethanol. Then, after slowly adding 17.5 g of tert-butyl vinyl ether to the solution, the reaction was carried out at 20° C. for 5 hours. To the reaction liquid were added 0.28 g of triethylamine and 320 ml of ethyl acetate and the mixture was washed three times with 150 ml of distilled water. The solvent was distilled off and the residue was concentrated. The oil obtained was dissolved in 100 ml of acetone and 2 liters of distilled water was slowly added to the solution. A powder deposited was collected by filtration and dried to obtained 54 g of the desired product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.084 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as an off-white solid (0.054 g, 10%). MS (ISP) 514.2 [(M+H)+]; mp 239° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl>CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:1][CH2:2][CH2:9][CH3:8])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C=O)c1
Agent: Cl
Solvent: CCOCC
Product: CCCCC(O)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Thereafter, the mixture is heated under reflux for 1 hour and then cooled to 0° C. 60 g of 3-methylbenzaldehyde, dissolved in 250 ml of absolute ether, are added dropwise at 0° C. The reaction solution is left to stand overnight and is then poured onto 1 l of ice-water. The reaction mixture is acidified with 2N hydrochloric acid. The organic phase is separated off, the aqueous phase is extracted twice with 300 ml of ethyl acetate each time and the combined organic phases are washed twice with 200 ml of water each time, dried over MgSO4 and evaporated on a rotary evaporator in vacuo. The residue is distilled at 64°-66° C./0.02 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[C:11]([O:18][CH3:19])[CH:10]=1.C(N(CC)CC)C>ClCCl>[C:2]1([NH:1][C:15](=[O:16])[C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[O:18][CH3:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Aniline(1.24 mL, 13.62 mmol) was added slowly to a mixture of 4-bromo-2-methoxy-1-benzenecarbonyl chloride (3.24 g, 12.98 mmol) and triethyl amine (2.7 mL, 19.48 mmol) in dichloromethane (130 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromo-2-methoxybenzamide (2.92 g, 74%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 7.09 (s, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 7.39 (s, 1H), 7.55 (d, J=8.15 Hz, 1H), 7.71 (m, 2H), 10.10 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH:3]1[S:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4]1.[OH-].[Na+].[CH3:12][NH2:13]>>[S:4]1[CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:3]1[CH2:2][NH:13][CH3:12]
Reactant: ClCC1SCCCCS1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNCC1SCCCCS1
Reaction time: 18 h

Procedure:
A 40% by weight aqueous solution of methylamine (100 ml) and 2-chloromethyl-1,3-dithiepane (50 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture is stirred for a period of about 18 hours. After this time sodium hydroxide (18 grams) is added with stirring over a period of about 3 hours. Stirring is then continued for an additional period of about 16 hours. The organic phase of the reaction mixture is then separated, is washed with aqueous potasssium carbonate and dried over anhydrous magnesium sulfate. The dried product is then distilled under reduced pressure to yield the desired product N-(1,3-dithiepan-2-ylmethyl)-N-methylamine.
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:15][CH2:16][C@@H:17]([NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[NH2:14][C:3]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([NH:24][C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:15])=[O:41])=[CH:27][CH:28]=2)=[N:7][C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N[C@H](CO)c3ccccc3)cc2)OC1(C)C
Reactant: Nc1ncc(C2CCOCC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)cc1
Temperature: 120 °C

Procedure:
To a solution of 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (154 mg, 0.418 mmol), (S)—N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (90 mg, 0.349 mmol), and PdCl2(dppf) (25.5 mg, 0.035 mmol) was added dioxane (2.3 mL) and 2 M Na2CO3 solution (1.163 mL). The reaction mixture was heated at the microwave synthesizer (120° C., 10 min). The reaction mixture was worked up with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by prep HPLC. The pure fractions were combined, free-based with sodium carbonate solution, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered off, and dried in vacuo. The pure solid was dissolved in MeCN/water (1:1, 6 mL) and lyophilized yielding (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-hydroxy-1-phenylethyl)benzamide as free base (46%). LCMS (m/z): 419.2 (MH+), 0.58 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, J=12 Hz, 1H), 7.99 (d, J=8 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J=12 Hz, 2H), 7.37 (d, J=8 Hz, 2H), 7.29 (m, 2H), 7.22 (m, 1H), 5.99 (bs, 1H), 5.07 (m, 1H), 3.91 (m, 2H), 3.67 (m, 2H), 3.41 (m, 2H), 2.82 (m, 1H), 1.72 (m, 4H).
Reaction SMILES: CI.[F:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[C:8]([F:10])[CH:9]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC#N>[F:3][C:4]1[CH:5]=[C:6]([S:11][CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(F)cc(S)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSc1cc(F)cc(F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methyl iodide (2.91 g, 20.5 mmol) was added dropwise to a stirred mixture of 3,5-difluorobenzenethiol (2.00 g, 13.7 mmol) and potassium carbonate (5.67 g, 41.0 mmol) in dry MeCN (24 mL) at room temperature. The reaction mixture was stirred at 80° C. for 2 h. After cooling, the mixture was filtered under vacuum, washed with MeCN and concentrated under reduced pressure to give the sub-title compound, which was used directly in the next step without further purification (1.74 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[C:25]([F:28])([F:27])[F:26])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:35][S:36][CH3:37])=[O:34].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:35](\[S:33]([CH3:32])=[O:34])/[S:36][CH3:37])=[CH:19][C:18]=3[C:25]([F:26])([F:28])[F:27])=[CH:12][CH:11]=2)=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1)S(C)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of N-(4-chlorophenethyl)-4-(4-formyl-2-(trifluoromethyl)phenoxy)benzamide (0.225 g, 0.502 mmol) in THF (5 ml) was added methylsulfinyl(methylthio)methane (0.125 g, 1.00 mmol) followed by benzyltrimethylammonium hydroxide (0.114 ml, 0.251 mmol) and the reaction was stirred at 70° C. for 1 hour. The reaction was cooled, loaded onto a silica gel samplet and the product was eluted using a gradient of 0.5% methanol/dichloromethane to 15% methanol/dichloromethane. Isolated (Z)—N-(4-chlorophenethyl)-4-(4-(2-(methylsulfinyl)-2-(methylthio)vinyl)-2-(trifluoromethyl)phenoxy)benzamide (0.220 g, 79.0% yield) which by TLC appeared to be a 4:1 mixture of olefin isomers. The crude material was used directly in the next step.