Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:30][N:31]=[C:32]=[O:33]>CN(C=O)C.C(Cl)Cl>[C:19]([C:16]1[S:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:1]3[CH2:6][CH2:5][N:4]([C:32]([NH:31][CH3:30])=[O:33])[CH2:3][CH2:2]3)[CH:8]=2)=[N:18][CH:17]=1)#[N:20]
Reactant: CN=C=O
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
12-3 (0.25 g, 0.88 mmol) was dissolved in a minimal amount of DMF (2 mL) and DIEA (0.57 g, 4.38 mmol) before it was diluted with methylene chloride (5 mL). Then a methylene chloride solution (1 mL) of methylisocyanate (0.050 g, 0.88 mmol) was added. A precipitate quickly formed and was filtered off, washed with methylene chloride and air dried to afford 43-1. Hi-Res MS: calc: 345.1241 found: 345.1269. 1H-NMR (DMSO-d6): 12.09(s, 1H); 8.44(s, 1H); 8.26(s, 1H); 6.52(d, 1H); 6.21(s, 1H); 3.54(m, 4H); 3.40(m, 4H); 2.58(d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]>C(#N)C.O.Cl>[CH2:19]([NH:23][CH2:24][CH2:25][C:6]1[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCc1c(Cl)nc(C)nc1Cl
Reactant: CCCCNCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNCCc1nc(C)nc(Cl)c1CC
Yield: 88.3 %

Procedure:
A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009 g, 5.28 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.540 g, 5.31 mmol) and heated at reflux overnight. The mixture was diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate and washed with brine, dried and concentrated to give 1.193 g of yellow oil which was purified through silica gel column chromatography to give 1.157 g (86%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.13 (t, 3H), 1.18 (t, 3H), 1.1-1.33 (m, 2H), 1.4-1.6 (m, 2h), 2.41 (s, 3H), 2.62 (q, 2H), 3.25-3.48 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:33])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>>[NH:38]1[C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C:10]3[C:9](=[O:26])[N:8]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:7]([CH3:33])=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:16]=2)=[N:25][N:40]=[N:39]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCC[Sn](=O)CCCC
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
Process 3: To the toluene (3 mL) solution of 4′-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (335 mg, 0.77 mmol), trimethylsilylazide (2.64 g, 22.9 mmol) and dibutyltin oxide (96 mg, 0.386 mmol) were added, and stirred at 80° C. for 24 hrs under argon atmosphere. The reaction solvent was distilled off and the resulting residues were separated and purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the target compound (224 mg, 61%) as a pale yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([OH:20])[CH:7]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][C:32](=[O:33])[N:31]([CH3:35])[CH3:30])[CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N(C)C)c1)NC(=O)OC(C)(C)C

Procedure:
(S)-3-(4-Benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (401 mg) was dissolved in dichloromethane (8 ml) and N,N-dimethylcarbamoyl chloride (0.092 ml, leg) added. Triethylamine (0.14 ml, 1 eq) was added and the mixture was stirred and heated under reflux. The reaction was monitored by HPLC/MS and further portions of N,N-dimethylcarbamoyl chloride and triethylamine were added in order to complete the reaction. After a total of 8 hours reflux the reaction mixture was evaporated to dryness and absorbed onto silica gel. Chromatography, eluting with mixtures of ethyl acetate-hexane afforded (S)-3-(4-Benzyloxy-3-dimethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester as an oil, 315 mg; Rf 0.14 (ethyl acetate-hexane 1:3); HPLC/MS retention time 3.89 min, m/z 473 (MH+). Crystallisation from ethyl acetate-hexane gave (S)-3-(4-benzyloxy-3-dimethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonyl-amino-propionic acid methyl ester as a white solid, 126 mg; NMR (500 MHz, CDCl3) 1.42 (9H, s), 2.95 (3H, s), 2.98-3.04 (5H, m), 3.70 (3H, s), 4.52-4.54 (ca 1H, m), 4.97-5.00 (ca 1H, br d), 5.05 (2H, s), 6.88-6.92 (3H, m), 7.28-7.40 (5H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OC2CCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 mL) was heated at 80° C. for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated in ethanol using palladium(II) hydroxide as catalyst. The product with the molecular weight of 177.25 (C11H15NO) was obtained in this way; MS (ESI): 178 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenylboronic acid (10.0 g, 48.6 mmol) and 4-bromophenol (4.20 g, 24.3 mmol) in dichloromethane (250 ml) over 4 A molecular sieves was added copper (II) acetate (4.41 g, 24.3 mmol), diisopropylethylamine (21 ml, 121 mmol) and pyridine (10 ml, 121 mmol). The reaction mixture was stirred 12 hours at room temperature under positive pressure of dry air and concentrated in vacuo. The resulting residue was resuspended in ethyl acetate and 0.5 M HCl. The organic layer was extracted with water and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexanes) provided 5.07 g 1-bromo-4-(4-(trifluoromethoxy) phenoxy) benzene (63% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=9.3 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.99 (d, J=9.3 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1([CH2:8][S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[N:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CO>[NH3:12].[CH:19]1[C:20]2[C:15](=[CH:14][C:13]([NH:12][S:9]([CH:8]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:11])=[O:10])=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: NC1CCCCC1
Reactant: O=S(=O)(CC1(Cl)C=CC=CC1)Nc1ccc2cnccc2c1
Solvent: CO
Product: N
Product: O=S(=O)(Nc1ccc2cnccc2c1)C(NC1CCCCC1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To 1-chloro-N-(isoquinolin-6-yl) phenylmethanesulfonamide in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and cyclohexylamine is added and stirred at 45° C. After 2-4 hours or when TLC indicated completion of the reaction, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3 (sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 2% NH3(2M) in MeOH/3% MeOH/CH2Cl2) gives N-(isoquinolin-6-yl)cyclohexylamino phenylmethanesulfonamide (E50).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][N:4]=1.[Na+].[I-]>CO.[Pd]>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1)[CH3:10]
Reactant: C=Cc1ccc(OC)nc1
Agent: [Pd]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(=O)[nH]c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a solution of 2-methoxy-5-vinyl-pyridine (2 g) in anhydrous MeOH was added Pd/C (10 wt %, 100 mg). The mixture was stirred under H2 atmosphere for 5 hours before it was filtered through a pad of celite. The solvent was removed in vacuo and the residue was taken directly into next step without further purification. The crude product from previous step was dissolved in anhydrous MeCN. To this solution was added NaI (3.3 g, 21.9 mmol) and TMSCI (2.8 mL, 21.9 mmol). The resulting mixture was heated to 65° C. for 5 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (1.5 g, 83% yield). 1H NMR (300 MHz, CDCl3): δ 1.17 (t, J=7.5 Hz, 3 H), 2.39–2.49 (m, 2 H), 6.50–6.58 (m, 1 H), 7.15 (s, 1 H), 7.35–7.45 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 2 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (40.0 mg, 0.126 mmol, described in Intermediate 5) in EtOAc (10 mL) was added triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenated at 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 130 mmol) in anhydrous methylene chloride (450 mL), cooled in an ice bath, is added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous methylene chloride) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) is added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction is cooled in an ice bath. Water (300 mL) is added, maintaining the temperature of the reaction below 25° C., and the reaction is stirred at room temperature for 18 hours. The reaction mixture is extracted with methylene chloride, and the organic layer is separated, washed with water, dried, filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:10].Br[C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>C(O)CCC.O.[Pd](Cl)Cl>[CH2:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:33]3[C:34]([C:35]#[N:36])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:10]
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2ccccc2n1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Triethylamine (13.8 ml) was added to a mixture of 4-[(2-ethylquinolin-4-yloxy)methyl]phenylboronic acid hydrochloride (12.74 g), 2-bromobenzonitrile (5.92 g) and palladium chloride (0.13 g) in butanol (80 ml) and water (40 ml) and the mixture was heated at reflux for 3 hours. The hot reaction mixture was filtered through diatomaceous earth and the filtrate was stirred while allowing to cool to ambient temperature. The mixture was then cooled to 4° C. for 30 minutes. The solid which crystallised was collected by filtration, washed with cold butanol (16 ml) and water (2×16 ml) and then dried at 55° C. to give 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (10.8 g); m.p. 161°-162° C.; NMR (CDCl3): 1.4(t,3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m,3H), 7.6-7.8(m,6H), 8.0(d,1 H), 8.25(d,1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[H][H]>C(#N)C>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
To a solution f (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in acetonitrile (200 ml) were added 5% platinium on activated carbon (4.0 g) and water (4 ml) under nitrogen atmosphere. The mixture was stirred at 10° C. in a hydrogen gas flow until 2.2 equivalents of hydrogen had been taken up. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and concentrated in vacuo to give (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di-(p-anisyl)methyl-2-azetidinone as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1

Procedure:
To a solution of 4-cyanobenzaldehyde (20.0 g, 152.5 mmol) and ethylene glycol (25.5 mL, 457.5 mmol) in toluene (250 mL) was added p-toluenesulfonic acid (300 mg). The flask was equipped with a Dean-Stark trap and the mixture heated to reflux. After 5 hr the mixture was concentrated. The residue was taken up in ethyl acetate and washed with saturated NaHCO3, water (2×), and brine. The organic layer was dried (MgSO4), filtered, and concentrated to give 4-(1,3-dioxolan-2-yl)benzonitrile as a clear oil which solidified under vacuum: 1H-NMR (500 MHz, CDCl3): δ 7.67 (2H, d, J=8.06 Hz), 7.59 (2H, d, J=8.30 Hz), 5.85 (1H, s), 4.13-4.05 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[CH:56][CH:57]=[CH:58][C:50]=2[F:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 84 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (117 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-fluoro-α-methylbenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 78%). Mass spectrometry value (ESI-MS, m/z): 524 (M++1)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O1CCCC1.[Cu]I>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(-n2cncn2)cc(C)c1Br
Temperature: 130 °C

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (500 mg), 1,2,4-triazole (340 mg), potassium carbonate (770 mg), and copper(I) iodide (232 mg) in N-methyl-2-pyrrolidinone is stirred at 130° C. over night. More potassium carbonate (770 mg) and copper(I) iodide (232 mg) are added and the mixture is heated to 150° C. for 4 h. After cooling to room temperature the mixture is diluted with tetrahydrofuran and filtered. The filtrate is concentrated in vacuo and purified by HPLC on reversed phase to give the title compound. LC (method 7): tR=0.99 min; Mass spectrum (ESI+): m/z=252, 254 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH3:17])[N:3]=1
Reactant: CC(O)c1cccc(F)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Yield: 108.8 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and 1-(3-fluorophenyl)ethanol (308 mg, 2.2 mmol) in dioxane (5 mL) was added NaH (55% in oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred over night. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying (K2CO3), filtration, and concentration in vacuo gave the title compound as an oil (0.55 g) that was used directly in the next step. MS m/z 254 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][CH:53]=[C:45]([C:44]([F:43])([F:54])[F:55])[CH:46]=2)[N:13]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethyl benzoic acid is added and agitation is carried out for 6 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 307 mg of expected product is collected.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:34](O)([CH3:36])[CH3:35]>ClCCl.CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH:34]([CH3:36])[CH3:35])=[O:19])=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)C1(c2ccc(C(=O)O)cc2)CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoic acid (12) (0.219 g, 0.72 mmol) in dichloromethane (5 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.3 ml, 3.44 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 15 minutes and at 40° C. for 1 hour, then the volatiles were evaporated and the residue was dried in vacuo. The residue (0.247 g) was dissolved in tetrahydrofuran (4 ml) and 4-dimethylaminopyridine (0.176 g, 1.43 mmol) and isopropanol (0.35 ml, 4.57 mmol) were added to the resulting solution. The mixture was stirred overnight, supplemented with benzene (50 ml), successively washed with water (30 ml), brine (20 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silica gel with toluene-ethyl acetate (97:3) as eluent to give the title compound (0.226 g, 91%) as an oil. 1H NMR (CDCl3, HMDSO) δ: 1.01-1.87 (8H, m); 1.34 (6H, d, J=6.5 Hz); 1.34 (9H, s); 2.17-2.61 (2H, m); 5.23 (1H, sept, J=6.5 Hz); 7.46 (2H, d, J=8.8 Hz); 7.98 (2H, d, J=8.8 Hz).