Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH3:9])[NH:4][N:3]=1.[ClH:10].[C:11](=[NH:16])(OCC)[CH3:12]>C(#N)C>[ClH:10].[CH2:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:11](=[NH:16])[CH3:12])[CH:6]=1)[CH2:8][CH3:9]
Reactant: CCOC(C)=N
Reactant: CCCc1cc(N)n[nH]1
Agent: Cl
Solvent: CC#N
Product: CCCc1cc(NC(C)=N)n[nH]1
Reaction time: 1 h

Procedure:
A 11.5 g portion of 3-amino-5-propyl-1H-pyrazole was dissolved in 60 ml of acetonitrile, and 12.8 g of ethyl acetimidate hydrochloride was added to the above solution with cooling on an ice bath. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(Oc2cc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nn2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 4-methoxyphenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (180.1 mg, 94.7%). Melting point: 146.7-148.2° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=[O:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO>O1CCCC1>[C:1]([NH:8][C@H:9]([CH2:13][OH:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of Boc-norvaline (25.0 g, 0.115 mol) in tetrahydrofuran (461 mL), cooled to 0° C., was added borane/tetrahydrofuran complex (461 mL of a 1.0M solution in tetrahydrofuran) dropwise. After 1 h at 0° C., the solution was warmed to room temperature over a period of 1.5 h. TLC indicated that the reaction was complete. Methanol was added to quench the reaction. The solution was concentrated to yield the title compound (22.56 g, 96%) as a foamy syrup. TLC of the products indicated satisfactory purity. Rf=0.34 (40% ethyl acetate/hexanes).
Reaction SMILES: C1(C)C(C([O:9][C@@H:10]2[C@@H:14]([CH2:15][O:16]C(C3C(C)=CC=CC=3)=O)[S:13][C@@H:12]([N:26]3[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[CH2:11]2)=O)=CC=CC=1.C[O-].[Na+]>CO>[C@@H:12]1([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[S:13][C@H:14]([CH2:15][OH:16])[C@@H:10]([OH:9])[CH2:11]1
Reactant: Cc1ccccc1C(=O)OC[C@H]1S[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A solution of 3',5'-di-O-toluoyl-4'-thiothymidine (formula β-17) (150 mg, 0.30 mmol) in anhydrous MeOH (30 mL) was stirred at room temperature with a freshly prepared solution of sodium methoxide (32.5 mg, 0.60 mmol) in MeOH (7.5 mL). A TLC aliquot at 3 hours showed complete consumption of starting material (TLC CHCl3 -MeOH 95:5). The solution was rendered neutral with Dowex 50W-X8 (H+) ion-exchange resin, the suspension was filtered, and the resin was washed with MeOH. The filtrates were combined and evaporated to dryness, and methyl p-toluate was removed at 50° C./0.01 torr. Crystallization of the residue from absolute EtOH gave pure 4'-thiothymidine (61 mg, 78%), mp 213°-215° C.; TLC 9:1 CHCl3 -MeOH, Rf =0.40; MS z/e 258 (M+1)+, UV λmax pH 1 272 (10.3), pH 7 272 (10.2), pH 13 271 (10.3 ); 1H NMR (Me2SO-d6, 300 MHz) δ1.80 (S, 3H, C-5, CH3), 2.10-2.24 (m, 2H, H-2'), 3.24-3.32 (m, 1H, H-4'), 3.50-3.66 (m, 2H, H-5'), 4.38 (br s, 1H, H-3'), 5.16 (br t, 1H, 5'-OH), 5.24 (d, 1H, 3'-OH, J=4 Hz), 6.30 (dd, 1, H-1', J=6.5 and 8 Hz), 7.32 (s, 1H, H-6), 11.32 (br s, 1H, H-3); 13C NMR (Me2SO-d6, 300 MHz) δ12.14 (C-5, CH3) 40.93 (C-1', JC,H =132.33 Hz), 59.01 (C-4', JC,H =143.3 Hz), 59.93 (C-1', JC,H =161.74), 63.51 (C-5'), 73.40 (C-3') 109.82 (C-5), 136.70 (C-6, JC,H =179 Hz), 150.59 (C-4) 163.37 (C-2) Anal Calcd. for C10H13N2O4S: C, 46.68; H, 5.09;N, 10.88; S, 12.46. Found: C, 46.59 H, 5.56; N, 10.74; S, 12.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](I)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:65][C:66]1[CH:71]=[CH:70][N:69]=[CH:68][C:67]=1[CH3:72].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10]([NH:65][C:66]3[CH:71]=[CH:70][N:69]=[CH:68][C:67]=3[CH3:72])[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: Cc1cnccc1N
Reactant: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine (106 mg, 0.28 mmol, 1 eq) in dioxane (5 ml) was added Pd(OAc)2 (3 mg, 0.01 mmol, 0.05 eq) followed by BINAP (13 mg, 0.02 mmol, 0.075 eq), 4-amino-3-picoline (40 mg, 0.37 mmol, 1.3 eq) and Cs2CO3 (138 mg, 0.42 mmol, 1.5 eq). The reaction mixture was heated to 80° C. for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite® and the crude material was purified by flash column chromatography (4:1/ethyl acetate:hexane-100% ethylacetate) to afford [2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine, i.e. compound of formula (39) (30 mg, 30%) as a white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To N,N-diisopropylamine (13 mL, 93 mmol, Aldrich) in tetrahydrofuran (200 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (55 mL, 88 mmol, Aldrich). The reaction mixture was warmed to 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (17.1 g, 58.4 mmol, from Step 1) in tetrahydrofuran (86 mL) was added dropwise over 30 minutes. The reaction mixture was then stirred for 1 hour at −78° C., and methyl iodide (7.3 mL, 120 mmol, Aldrich) was added dropwise over 5 minutes. The reaction was allowed to warm to 5° C. over 3 hours, then cooled to −20° C. and quenched by the addition of 1 N HCl. EtOAc was added, and the solution was stirred for 15 minutes and left at ambient temperature overnight. The layers were separated and the organic layer was washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a wet orange solid that was then triturated with MeOH (18 mL). The solid was isolated by filtration, washed and dried at 40° C. under high vacuum for 2.2 h to give 14.4 g of product. Additional amount of product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-40% EtOAc in hexanes) afforded 1.87 g. (Yield: 16.3 g, 91%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([C:11]#[C:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:10]=1)CCC.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.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:31]1([C:6]2[S:7][C:8]([C:11]#[C:12][C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[CH:17]=3)=[CH:9][CH:10]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Brc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C#Cc2cc3ccccc3s2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C(#Cc1cc2ccccc2s1)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a stirred solution of 1.0 gram (0.0019 mole) of tributyl 5-(benzothien-2-ylethynyl)thien-2-yltin and 0.33 gram (0.0021 mole) of bromobenzene in 10 ml of tetrahydrofuran was added a catalytic amount of bis(triphenylphosphine)palladium(II) chloride. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 18 hours. After this time the reaction mixture was cooled to ambient temperature, and then it was subjected to column chromatography on silica gel. Elution was accomplished with hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.28 gram of 2-(5-phenylthien-2-ylethynyl)benzothiophene; m.p. 185°-186.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](C)(C)C)[C:5]([O:7][CH3:8])=[O:6].C>CO.[Cu](I)I>[O:1]1[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:12]=[CH:13]1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Agent: I[Cu]I
Solvent: CO
Product: COC(=O)c1ccc2ccoc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15 g, 16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA (2.34 ml, 16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added portion-wise and the reaction is heated at 75° C. for 3 h. DARCO (2 g) is added and the reaction is stirred at 95° C. for an additional 2 h, then overnight at RT. The reaction is filtered, concentrated to a brown oil and the crude material is chromatographed over 300 g slurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 2.05 g (70%) of methyl 1-benzofuran-6-carboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) δ 3.97, 6.84, 7.65, 7.78, 7.98, 8.22 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[O:19])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:27]([N:16]1[C:17]2[C:13](=[C:12]([CH:18]=[O:19])[CH:11]=[CH:10][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:15]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc2c(C=O)ccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
500 mg of 7-benzyloxy-4-formylindole is combined with 50 mg of 4-dimethylaminopyridine, 0.7 ml of triethylamine, 0.5 ml of acetic anhydride, and 10 ml of dichloromethane and agitated for 24 hours at room temperature. The reaction mixture is then diluted with 50 ml of dichloromethane, washed with concentrated sodium bicarbonate solution; the organic phase is dried and concentrated. The residue is recrystallized from isopropanol, thus obtaining 400 mg of 1-acetyl-7-benzyloxy-4-formylindole, mp 77°-78° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>[Pd].CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCNCC1C
Yield: 100 %

Procedure:
A mixture of 21 parts of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled twice, yielding 23 parts (100%) of ethyl 2-methyl-1-piperazinecarboxylate; bp. 95°-98° C. at 66.5 pa (int. 37).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21](Br)=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=c1cccc[nH]1
Product: Cc1nc(-n2ccccc2=O)sc1C(=O)NCc1ccccc1
Yield: 48 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 48% yield: mp 180-182° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.83 (t, J=5.9 Hz, 1H), 8.71 (dd, J=7.3, 1.7 Hz, 1H), 7.65-7.59 (m, 1H), 7.37-7.18 (m, 5H), 6.74 (d, J=9.3 Hz, 1H), 6.60-6.55 (m, 1H), 4.39 (d, J=5.9 Hz, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.9, 162.0, 161.6, 154.1, 150.2, 139.9, 132.6, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5; (ES+) m/z 326.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1c(O)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2sc1=O

Procedure:
7-(3,5-Dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3,5-dichlorophenylboronic acid under conditions analogous to Example 7(a). The crude product was purified by silica gel chromatography (eluting with 5%-60% EtOAc in CH2Cl2) to provide 7-(3,5-dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester. MS ESI(−) m/e: 378.98 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[C:5]=1[F:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:19])=[C:6]2[C:7]([CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10]2)=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CN1CCN(CCCBr)CC1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 71.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and 1-(3-bromopropyl)-4-methylpiperazine (112 mg, 0.81 mmol) were converted to the title compound (180 mg, 70%). 1H NMR (CD3OD) δ 8.67 (d, J=2.0 Hz, 1H), 8.33 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.38-7.30 (m, 5H), 5.21 (s, 2H), 4.00 (s, 3H), 3.82-3.78 (m, 4H), 3.50 (br s, 2H), 2.35-2.12 (m, 13H), 1.71-1.64 (m, 6H), 1.41-1.27 (m, 4H), 1.00-0.87 (m, 6H); MS(ESI+) m/z 632.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=O)[CH2:9][O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[S:22])[CH2:9][O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[CH:2]=1
Reactant: O=C(COc1c(Cl)cc(Cl)cc1Cl)Nc1cccnc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: S=C(COc1c(Cl)cc(Cl)cc1Cl)Nc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-3-pyridyl-2,4,6-trichlorophenoxyacetamide, 33.4 gm, is added to 200 ml of toluene. 22.2 gm of phosphorus pentasulfide (P2S5) is then added to the system. The system is exposed to microwave radiation throughout in order to aid in the dispersion of the phosphorus pentasulfide. The reaction is stirred for 16 hours at ambient temperature. The reaction is then stopped and the solution filtered. The toluene is removed by stripping to give the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.[OH-].[K+].O>C(O)C>[F:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:3]2[CH2:2][O:22]2)[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate IV, EXAMPLE 3, 3.5 g, 0.010 moles, 1 equivalent) followed by absolute ethanol (60 mL) and cooled to 0°. To this mixture is added potassium hydroxide (0.73 g, 0.013 moles, 1.25 equivalents) dissolved in absolute ethanol (10 mL) over 1 hr and the resulting suspension is warmed to 15-20° and stirred for 1 hr. At this time, water (100 mL) is added and the reaction contents are cooled to −5° and stirred for 30 min. The solids are collected by filtration and washed with cold water (2×25 mL) then dried under reduced pressure at 450 to give the title compound, mp=133°; NMR (DMSO-d6) δ 7.03, 3.61, 2.68-2.98 and 1.33; CMR (DMSO-d6) δ 163.72, 161.29, 155.55, 143.35, 112.65, 101.80, 78.17, 53.42, 52.71, 44.90, 36.98 and 28.36.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:30]([OH:31])[CH2:29][C:23]3[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=CCc1c(Cl)cccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)Cc2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of butyl lithium in hexane (5.1 mL; 2.5M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at -70° C. and the solution is then stirred at -70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below -60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g),in the form of a white solid, m.p. 87°-89° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.CN(C=O)C.Br[CH2:25][CH2:26][CH2:27][Cl:28]>[Cl-].[Na+].O>[Cl:28][CH2:27][CH2:26][CH2:25][N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Temperature: 65 °C

Procedure:
A solution of 2-(trifluoromethyl)-10H-phenothiazine (2.04 g, 7.6 mmol) and DMF (16 mL) was mixed with CS2CO3 (7.5 g, 22.9 mmol) and 1-bromo-3-chloropropane (1.1 mL, 11.5 mmol) The reaction mixture was heated at 65° C. for 12 h. Once no starting material was observed by analytical LCMS, EtOAC (250 mL) and brine (250 mL) were added. The organic layer was separated, and the aqueous layer was washed with EtOAC (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, and concentrated to afford the title compound.
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[CH:18]3)=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[O:21][C:20]([CH3:26])([CH3:25])[CH:19]4[O:2][CH:18]4[C:17]=3[CH:16]=2)=[CH:28][CH:29]=1
Reactant: O=C([O-])O
Reactant: CC1(C)C=Cc2cc(CC(=O)NCc3ccc(Cl)cc3)ccc2O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
700 ml of a saturated aqueous sodium hydrogen carbonate solution was added to a solution of 21.92 g of the N-4-chlorobenzyl-2-(2,2-dimethyl-2H-chromen-6-yl) acetamide obtained above in 600 ml dichloromethane. A total of 31.6 g MCPBA (72%) was added in portions to this receiving solution and stirred for 16 hours at room temperature. The organic phase was separated, washed twice with a 5%-strength aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and substantially completely evaporated at reduced pressure. Drying in an oil pump vacuum yielded N-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide as crude oil, which was used without further purification or characterization for the subsequent reaction.