Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: CNCCc1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)CCc3ccccc3)c2)C[C@H]1C

Procedure:
N-Methylphenethylamine was coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenethylbenzamide as a light yellow powder. NMR (300 MHz, DMSO-d6, 80° C.): δ 0.91 (d, J=5.5 Hz, 3H); 1.08 (d, J=6.3 Hz, 3H); 1.87 (dd, J1 =7.1 Hz, J2 =11.2 Hz, 1H); 2.09 (dd, J1 =7.1 Hz, J2 =11.0 Hz, 1H); 2.58 (d, J=11.3 Hz, 1H); 2.67 (m, 1H); 2.76 (dd, J1 =6.2 Hz, J2 =13.2 Hz, 1H); 2.77-2.87 (m, 4H); 2.89 (s, 3H); 3.18 (dd, J1 =5.5 Hz, J2 =14.2 Hz, 1H); 3.55 (br s, 2H); 4.97 (s, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.74-5.89 (m, 1H); 6.65-6.73 (m, 3H); 7.07-7.41 (m, 9H); 7.43 (d, J=7.9 Hz, 1H); 9.07 (s, 1H). Mass spectrum (CI--CH4) m/e: 498 (M+1, 88%), 344 (22%), 153 (100%). [α]D20 =+3.8°0 (ethanol, c=1.25). The free amine (0.232 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.9 followed by precipitation with diethyl ether from dichloromethane to give 0.205 g of the monohydrochloride salt as a hygroscopic light yellow powder. Calc. for C32H39N3O2HCl H2O: C, 69.61; H, 7.67; N, 7.61; Cl, 6.42. Found: C, 69.51; H, 7.73; N, 7.47; Cl, 6.52.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[C:18](O)(=[O:20])[CH3:19]>>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][C:11]=1[C:18](=[O:20])[CH3:19]
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: CC(=O)O
Agent: FB(F)F
Product: CC(=O)c1cc(C2CCCCC2)ccc1O
Reaction time: 0.25 h

Procedure:
35.25 g of 4-cyclohexyl-phenol were added in small amounts at 5° to 10° C. to a solution of 46 g of boron trifluoride in 110 ml of concentrated acetic acid and the mixture was held at 50° C. for 15 minutes and then at 75° C. for 21 hours. The mixture was poured into ice and the aqueous phase was extracted 3 times with 200 ml of ether. The ether phase was treated with powdered sodium bicarbonate and was stirred for 16 hours and was then filtered. The filtrate was washed with water until the wash water was neutral, dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was pressure chromatographed over silica gel and was eluted with a 1-4 ether-petroleum ether (b.p.=60° to 80° C.) mixture to obtain 39.9 g of 1-(2-hydroxy-5-cyclohexylphenyl)-ethanone melting at <50° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10]1
Reactant: COCCCOC(c1ccccc1)C1CCCNC1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCOC(c1ccccc1)C1CCCN(CC(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
3-((3-Methoxypropoxy)(phenyl)methyl)piperidine HCl salt (63 mg, 0.212 mmol) was mixed with methyl bromoacetate (20 μL), K2CO3 (75 mg, 2.5 equiv.), and anhydrous DMF (3 mL). The mixture was stirred overnight at rt. LC-MS indicated the reaction was complete. The mixture was diluted with EtOAc and washed with water. The water layer was extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over Na2SO4. After concentration, the residue was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-10% methanol in dichloromethane gradient to afford methyl 2-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)acetate (19 mg, 27% yield). LC-MS (3 min) tR=1.07 min, m/z 336 (M+1).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[CH2:11][CH2:12][CH2:13][C:14]#[N:15]>O.C(O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][S:9][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCl
Reactant: SCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CCCCSCc1ccco1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 94.1 %

Procedure:
A solution of sodium hydroxide (12.7 g) in water (50 ml) and ethanol (50 ml) was added dropwise over 30 minutes to a solution of furanylmethyl mercaptan (34.25 g) and 4-chlorobutyronitrile (31.58 g) in ethanol (150 ml) under nitrogen at 10° C. (ice-bath). The temperature rose slightly (to 18° C.) and the solution went cloudy. It was stirred at room temperature for 6.5 hours and allowed to stand for 20 hours. Ethanol was removed by evaporation at reduced pressure. The residue was dissolved in water (100 ml) and the solution was extracted with chloroform . The combined extracts were washed with water, dried (MgSO4) and chloroform evaporated at reduced pressure. The residual light-brown liquid was vacuum-distilled to give 4-(2-furanylmethylthio)butyronitrile (51.16 g), b.p.0.05 mm 112°-5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([C:23]3[CH:22]=[N:21][C:20]([F:19])=[CH:25][CH:24]=3)=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccc(F)nc2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (1 eq), 2-fluoro-5-pyridineboronic acid (1.1 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M Na2CO3 aqueous solution (3 eq) and an equal volume of acetonitrile was heated to 100° C. in a sealed microwave reactor for 30 min. Reaction mixture was concentrated, then crude product was purified by flash chromatography to give 4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine. MS (Q1) 365 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:7]([CH3:23])=[CH:6]2.[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH2:20][CH2:21][N:26]3[CH2:27][CH2:28][CH2:25][CH2:24]3)=[CH:16][CH:17]=1)[C:7]([CH3:23])=[CH:6]2
Reactant: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 4-[4-(5-Methoxy-2-methylindol-1-yl)phenyl]but-3-yn-1-ol (60 mg, 0.19 mmol) in methylene chloride (1 mL) at 0° C. was added triethylamine (54 μL, 0.39 mmol) and methanesulfonylchloride (18 μL, 0.39 mmol). After the solution was stirred at 0° C. for 2 hours, pyrrolidine (163 μL, 1.95 mmol) was added and the reaction was allowed to warm to room temperature overnight. After the reaction was quenched with water, the organic layer was dried over MgSO4, and concentrated. The residue was purified by HPLC to give the desired indole (2.8 mg). LC-MS (C24H26N2O calc'd 358) m/z 359 (M+H); 1H NMR (300 MHz, CDCl3) d 7.53 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.7, 9.0 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 2.92-2.83 (m, 4H), 2.76 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][C@H:25]([CH3:29])[CH2:26][NH:27][CH3:28])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]>>[OH:3][CH2:2][C:1]([N:27]([CH2:26][C@H:25]([O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:30])=[C:7]([CH3:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2)[CH3:29])[CH3:28])=[O:5]
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: O=C(O)CO
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Yield: 81 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-methyl-4-({5-[(1R)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-yl}amino)phenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide as an orange solid in 81% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.15 (s, 3H), 2.96 (s, 3H), 3.35 (dd, 1H), 4.02 (s, 2H), 4.21 (m, 2H), 5.18 (m, 1H), 6.83 (d, 1H), 7.27 (m, 1H), 7.38 (s, 1H), 7.46 (d, 1H), 7.92 (t, 1H), 8.70 (s, 1H), 9.52 (s, 1H), 10.68 (s, 1H); Mass spectrum MH+ 397.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:15]O)=[CH:4][CH:3]=1.Cl.CCO>CO.[Zn]>[NH2:15][CH2:14][C:5]1[C:6]([F:13])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1c(Cl)ccc(CN)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1cnc(NC2CC2)nc1
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc(NC2CC2)nc1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine (as prepared above) and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp: 136-137° C.; 1H NMR (300 MHz, CDCl3) δ: 8.40 (2 H, s), 8.21 (1 H, s), 7.96-7.99 (1 H, d, J=9.0 Hz), 7.52-7.55 (1 H, d, J=9.0 Hz), 7.49-7.52 (1 H, d, J=9.0 Hz), 7.23-7.26 (1 H, d, J=9.0 Hz), 7.15-7.18 (1 H, d, J=9.0 Hz), 5.81 (1 H, s), 5.28 (1 H, s), 3.57 (2 H, s), 2.78 (1 H, s), 2.55 (8H, brs), 2.46 (3 H, s), 2.32 (3 H, s), 0.83-0.87 (2 H, m), 0.56 (2 H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H32N7: 478.2714. found: 478.2718.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[H-].[Na+].[CH3:33]I>CN(C=O)C>[CH3:33][O:30][CH2:29][C:4]1[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Reaction time: 0.17 h

Procedure:
To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (170 mg, 0.40 mmol) in DMF (1 mL) was added NaH (31.7 mg, 60% in mineral oil, 0.79 mmol) at room temperature, and then the mixture was stirred for 10 min. To the mixture was added MeI (25 uL, 0.40 mmol) at room temperature, and then the mixture was stirred for 2.5 h. The reaction was quenched by half saturated aqueous solution of KHSO4, and diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed successively H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, without need of any further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=3.79 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.34 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.60-4.64 (m, 1H), 4.44-4.54 (m, 2H), 3.73-3.86 (m, 1H), 3.41-3.52 (m, 1H), 3.30 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 1.51-1.78 (m, 2H), 1.34-1.51 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:22])[F:21])[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M223) (320 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (183 mg,71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>O1CCOCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][CH2:22][CH2:21][C:20]#[N:23])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: C=CC#N
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#CCCSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Yield: 60.6 %

Procedure:
In 15 ml of dioxane was dissolved 2.1 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindole-1-on, and 1.5 g of acrylonitrile, together with several drops of triethylamine, was added, followed by heating at 85° to 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residual, oily substance was purified by means of column chromatography with the use of silica gel (acetone:hexane=1:3), thereby producing 1.5 g of the subject compound in white crystals, m.p. 101°-103° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Br)cc1
Yield: 92 %

Procedure:
Ethyl(4-bromophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(4-bromophenyl)acetate (15 g, 45.6 mmol) and 4-mercaptophenol (5.75 g, 45.6 mmol); 15.39 g white solid. mp: 55.6° C.; Yield 92%; MS: 365.1 (M−H)−
Reaction SMILES: [CH:1]([N:3]([CH3:7])[C:4](=[O:6])[CH3:5])=[CH2:2].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:7][N:3]([CH2:1][CH2:2][P:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](=[O:6])[CH3:5]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CN(C)C(C)=O
Product: CC(=O)N(C)CCP(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 94 %

Procedure:
A 100 ml 3-necked round bottomed flash was heated to 100° C. under a nitrogen atmosohere and 7.14 g diohenylphosphine (38.4 mmole), 0.15 g 2,2'-azobis (2-methyloropionitrile), and 3.77 g N-vinyl-N-methyl acetamide (38.1 mmole) from Polysciences were added in the stated sequence. The reaction was maintained at 100° C. for 45 minutes under a nitrogen atmosphere and then evacuated (1 mm) for 24 hours at 100° C. A viscuous oil resulted whose infrared spectrum disolayed a strong γ(CO) band at 1645 cm-1 and a small γ(P--H) band at 2300 cm-1 due to a small amount of diphenylphosphine impurity. The elemental analysis was the following: calculated (found); C, 71.58 (69.89); H, 7.02 (7.15); N, 4.91 (4.57); P, 10.87 (10.97). The yield was 94%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:12]
Reactant: OCCc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1CCO
Reaction time: 8 h
Yield: 60.5 %

Procedure:
4.4 g of 2-hydroxyphenethyl alcohol was dissolved in 80 ml of N,N-dimethylformamide, and 15.3 g of ethyl iodide and 4.7 g of potassium carbonate were added. After stirring was continued at 70° C. overnight, the solution was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 3.2 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:25][CH2:24][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCCCC1
Yield: 57 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclooctylamine (0.113 ml, 0.81 mmol), and acetic acid (0.1 ml) were used to give 82.9 mg (0.24 mmol, 57% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12](/[CH:14]=[CH:15]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:13]=2)[N:3]=1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (200 mg, 0.93 mmol, 1.0 eq.) in degassed DMF (4.0 mL) was added 2-chloroquinoline (148 mg, 0.93 mmol, 1.0 eq.) followed by palladium acetate (32.0 mg, 47.5 mol, 0.050 eq.) and triethylamine (1.20 mL, 4.65 mmol, 5.0 eq.). The reaction was heated at 100° C. for 48 hours and cooled to room temperature. The reaction was quenched by the addition of water (5.0 mL) and ethyl acetate (5.0 mL) was added and the mixture was filtered through Celite. The organic layer was separated and the aqueous layer was washed with ethyl acetate (2×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (10-40% ethyl acetate in hexanes) to afford (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.19 (br d, 1H, J=8.5 Hz), 8.13 (d, 1H, J=16.0 Hz), 8.11 (br d, 1H, J=8.3 Hz), 7.87 (br s, 111), 7.81 (br dd, 1H, J=8.0, 1.0 Hz), 7.78-7.68 (m, 3H), 7.55 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 2.94 (s, 3H), 2.77 (s, 3H), 2.44 (s, 3H). LRMS mz (M+H+) 343 found, 343 required. m.p. 153-155° C.