Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[F:31])[C:24]([O:26][CH3:27])=[O:25].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.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][N:5]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[F:31])[C:24]([O:26][CH3:27])=[O:25])[CH2:4][C@H:3]1[O:2][CH3:1])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc(F)c(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 61.5 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate obtained in Example (160a) (100 mg, 0.38 mmol), methyl 3-bromo-4-fluorobenzoate (264 mg, 1.13 mmol), palladium acetate (25.5 mg, 0.11 mmol), BINAP (141 mg, 0.23 mmol) and cesium carbonate (370 mg, 1.13 mmol), to obtain 97.4 mg of the title compound as a yellow oily substance. mass spectrum (ESI): m/z 417 (M+H)+.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:29][NH2:30].O>C1COCC1.C(O)(=O)C>[CH3:13][C:4]1([CH3:14])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([CH2:11][NH:30][CH3:29])[CH:9]=[CH:10][C:5]1=2
Reactant: CN
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CNCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (370 mg, 1.95 mmol) in THF (15 mL) at rt was added NaBH(OAc)3 (827 mg, 3.9 mmol) followed by methylamine alcoholic solution (30%, 1.0 mL). Several drops of acetic acid were added to the reaction mixture to pH of 6. The mixture was continued to stir at rt overnight. Water (20 mL) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3,3-dimethyl-6-((methylamino)methyl)benzo[c][1,2]oxaborol-1(3H)-ol (300 mg; yield 75%) as a colorless oil. MS: m/z=206.1 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([CH3:40])[C:38]=1O)[C:34]#[N:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)[CH2:14][O:15][C:38]3[C:37]([CH3:40])=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[CH3:30])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C#N)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of a gradient of heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (27%). MS (Turbo Spray): m/z=556.178 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[C:21]([NH:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36])=[O:22].[CH2:37](OC(OCC)OCC)C>>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:23]3[C:21](=[O:22])[C:3]4[C:2](=[CH:20][CH:19]=[C:5]([O:6][C@H:7]5[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]5)[CH:4]=4)[N:1]=[CH:37]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1N
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 18 which is concerned with the preparation of starting material, tert-butyl (3S)-3-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}pyrrolidine-1-carboxylate was reacted with triethylorthoformate to give tert-butyl (3S)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; NMR Spectrum: (DMSOd6) 0.53 (m, 2H, 0.68 (m, 2H), 1.40 (s, 9H), 2.14 (m, 5H), 2.84 (m, 1H), 3.50 (m, 4H), 5.20 (s, 1H), 7.52 (m, 3H), 7.72 (d, 1H), 7.81 (s, 1H), 7.88 (m, 1H), 8.17 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+H+ 527.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[C:23]1([O:29][CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:30][O:29][C:23]1[CH:28]=[CH:27][C:26]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Product: COc1ccc(C(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a stirred solution of PPA (2.0 g, 20 mmol) were added 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 5.0 mmol) and anisole (1.0 g, 10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 80° C. for 3 h, quenched with ice cold water and stirred for another 10 minutes. The precipitated solid was filtered, and then the solid was stirred in 10% NaOH solution for 1 h, extracted with DCM (2×50 mL). The combined organic layers were washed with water (2×10 mL) and brine, concentrated, and dried under vacuum to afford 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (1.85 g, 90%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][C:19]=1[F:22]
Reactant: C#CCCn1nc2ccc(F)c(F)c2n1
Reactant: Brc1ccccn1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1F
Yield: 58.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 41 mg (0.14 mmol, 60%) of 4,5-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24]
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 80.7 %

Procedure:
A mixture of [4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness to yield crude title compound (354.0 mg, 343%). The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (84.0 mg, 81.5%). MS (ESI) mass calcd. for C22H25FN8O2, 452.49; m/z found 453.3 [M+H]+. 1H NMR (CDCl3): 7.88-7.79 (m, 2H), 7.72 (d, J=6.7, 1H), 7.54-7.41 (m, 1H), 7.19-7.08 (m, 1H), 5.02-4.92 (m, 1H), 3.96-3.86 (m, 1H), 3.87-3.83 (m, 3H), 3.81-3.50 (m, 5H), 3.43-3.19 (m, 2H), 3.15-3.09 (m, 6H)), 3.09-2.91 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[H-].[Na+].Cl[CH2:17][C:18](=O)[CH3:19]>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[C:9]2[C:18]([CH3:19])=[CH:17][O:13][C:8]=2[CH2:7]1
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccco1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-furyl)cyclohexane-1,3-dione (mp155-156° C.; 0.89 g) in DMF (18 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (15 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-furyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.23 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=C(F)C=2)=NOC=1C)=O)C>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2cccnc2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Product: Cc1onc(-c2cccnc2)c1CO
Yield: 66.5 %

Procedure:
As described for example 88d, 5-methyl-3-pyridin-3-yl-isoxazole-4-carboxylic acid ethyl ester (7.9 g, 34 mmol), instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, was converted, to the title compound (4.3 g, 67%) which was obtained as a light yellow liquid. MS: m/e=191.3 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3](OCC)=[O:4].[H-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([Br:21])=[CH:13][C:12]=1Br>CN(C=O)C>[Br:21][C:14]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]2[NH:10][C:3](=[O:4])[CH2:2][S:1][C:12]=2[CH:13]=1
Reactant: COC(=O)c1nc(N)c(Br)cc1Br
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-mercaptoacetate (18.4 ml) in DMF (650 ml) was ice-cooled and treated with sodium hydride (6.78 g of a 60% dispersion in oil). After 1 hour methyl 6-amino-3,5-dibromopyridine-2-carboxylate (50 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was partitioned between EtOAc and water (2 liters each), shaken, separated and the EtOAc along with solid that crystallised out washed with water (2×1 liter). The EtOAc was evaporated to low volume, solid filtered, washed with water and EtOAc and dried. The filtrate was separated, EtOAc dried and evaporated. The residue was taken up in AcOH and heated to 100° C. overnight, then evaporated. The white solid was triturated uder EtOAc, filtered off, washed with a little EtOAc and dried (Na2SO4). Combining the 2 batches of ester gave 33.35 g (70%). MS (APCl−) m/z 223 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(Cl)Cl.CC#N.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Temperature: -50 °C

Procedure:
Following the procedure described for (2S,3S)-4a, a sample of (S)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one ((S)-10a, 4.5 g, 0.024 mol), was dissolved in CH2Cl2 (75 mL) and treated with Proton sponge (6.3 g) and cooled to −50° C. Next, triflic anhydride (4.5 mL, 32 mmol) was added slowly, and the reaction mixture was stirred at 0° C. for an additional hour. The resulting orange slurry was transferred by syringe to another flask containing a solution of 2-amino-2-methyl-1-propanol, (4.7 g, 0.052 mol) in CH3CN. After purification, 3.3 g (78%) of the (2R,3R)-4a was isolated and converted to 2.7 g of the Hemi-L-tartrate salt (>99% ee): mp 128-131° C.; [α]23D −13.0° (c 0.79, CH3OH). Characterization data is similar to data reported in Fang, Q. K. et al., Tetrahedron: Asymmetry 2000, 11, 3659-3663.
Reaction SMILES: O[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].C(#N)C.C[Si](Cl)(C)C.[I-].[Na+]>CCCCCC>[F:22][C:21]([F:23])([F:24])[C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:10]=[C:9]([CH:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:14]=[CH:13][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC(O)(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Product: CC(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 4.8 grams (0.014 mole) of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile in 40 mL (0.760 mole) of acetonitrile was cooled to 0° C., and 9.4 grams (0.086 mole) of trimethyl-silyl chloride was added slowly. Upon completion of addition, the reaction mixture was stirred for about 15 minutes, and then 40 mL of hexane was added. After this time the reaction mixture was again stirred for 15 minutes, and 13.0 grams (0.086 mole) of sodium iodide was added. The reaction mixture was then stirred as it was allowed to warm to ambient temperature. Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was not complete. The reaction mixture was then warmed to reflux where it stirred for two hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated and washed with an aqueous dilute solution of sodium metabisulfite to remove iodine. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 25% ethyl acetate in hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 3.2 grams of 5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][N:12]=[C:11]([C:23]([NH:25][N:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([NH2:34])=[O:33])[C:27]3=[O:35])=[O:24])[CH:10]=2)C=CC=CC=1>CN(C)C=O.[Pd]>[OH:15][C:14]1[C:9](=[O:8])[CH:10]=[C:11]([C:23]([NH:25][N:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([NH2:34])=[O:33])[C:27]2=[O:35])=[O:24])[NH:12][CH:13]=1
Reactant: NC(=O)N1CCCN(NC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cn2)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)N1CCCN(NC(=O)c2cc(=O)c(O)c[nH]2)C1=O

Procedure:
3-[[[4,5-bis(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-tetrahydro-2-oxo-1(2H)-pyrimidinecarboxamide (27.45 g, 57.7 mmol), dissolved in 750 ml N,N-dimethylformamide, was hydrogenated for 1.5 hours over 10 g palladium on activated carbon. The catalyst was removed by filtration and the solvent distilled off in vacuo. The residue was triturated twice with ether to give two batches (15.5 g and 4.0 g) of the desired product, melting point 215°-220° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:33][C@@H:32]2[C@:19]([CH3:36])([CH2:20][CH2:21][C@H:22]3[C@H:31]2[CH2:30][CH:29]=[C:28]2[C@:23]3([CH3:35])[CH2:24][CH2:25][C@H:26]([OH:34])[CH2:27]2)[C@H:10]1[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCCCC1=O.O>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:33][C@@H:32]2[C@:19]([CH3:36])([CH2:20][CH2:21][C@H:22]3[C@H:31]2[CH2:30][CH2:29][C:28]2[C@:23]3([CH3:35])[CH2:24][CH2:25][C:26](=[O:34])[CH:27]=2)[C@H:10]1[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 87.4 %

Procedure:
A mixture of 16β-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (6.7 g, 12 mmol) and 1-methylpiperidone (25 mL) in toluene (500 mL) was heated to reflux temperature and 50 ml toluene was distilled off. Aluminium triisopropyl oxide (9.8 g, 48 mmol) in toluene (50 mL) was then added dropwise and the whole heated at refux for 4 hours. After cooling, water (200 mL) was added and the aqueous layer separated and extracted with diethyl ether. The combined organic layers were washed with water (100 mL), dried over magnesium sulphate and concentrated to give residue which was purified by recrystallization from methanol to give 16β-(tert-butyldimethylsilyloxy)cholest-4-en-3-one (5.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C=C(C=Cc1ccc([N+](=O)[O-])cc1)c1cccc(C#N)c1
Solvent: C1CCOC1
Product: COC(=O)CC(CCc1ccc(N)cc1)c1cccc(C#N)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
Part C. Methyl 3-(3-cyanophenyl)-5-(4-nitrophenyl)-2,4-pentadienoate (0.441 gm, 1.32 mmol) was dissolved in THF and degassed with N2. A catalytic amount of 10% Pd/C was added and the solution placed on a Parr shaker at 45 p.s.i. for 1 hour. After filtering through Celite, the solvent was removed under vacuum and the residue chromatographed on silica gel (10% ethyl acetate/methylene chloride) to yield methyl 3-(3-cyanophenyl)-5-(4-aminophenyl)pentanoate 0.220 gm (54%) of the product. MS: 309(M+H)+ ; 1H NMR (CDCl3): 1.9 (m, 2H), 2.35 (t, 2H), 2.6 (m, 2H), 3.15 (m, 1H), 3.55 (3H), 6. 60 (d, 2H), 6.85 (d, 2H), 7.5 (m, 4H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Product: CCOC(=O)c1ccc(Nc2nc(NC3CCCCC3)nc3[nH]cnc23)cc1

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 0.86 ml of cyclohexylamine in place of trans-1,4-diaminocyclohexane. 121 mg of the expected product are thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([NH:29]C(OC)=O)([CH3:28])[CH2:26][OH:27])=[C:18]([Cl:34])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O1CCCC1.CO>O>[NH2:29][C:25]([CH3:28])([CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:17][C:18]=1[Cl:34])[CH2:26][OH:27]
Reactant: COC(=O)NC(C)(CO)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)(CO)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Reaction time: 96 h
Yield: 66.8 %

Procedure:
The compound of Example 206 (527 mg) was dissolved in a mixed solvent composed of a 5 mol/L aqueous solution of potassium hydroxide (2 mL), tetrahydrofuran (2 mL) and methanol (3 mL). This mixture was refluxed and stirred for 4 days. Subsequently, the reaction mixture was diluted with water and was extracted with ethyl acetate. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate, and was then concentrated. The resulting residue was purified on a silica gel column chromatography (aminated silica gel, ethyl acetate:ethanol=20:1) to give the desired product as a pale yellow oil (311 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>CCO.[Pd]>[NH2:25][C:24]1[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[O:28])=[CH:18][CH:17]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3[N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1

Procedure:
The product from Example 2 (720 mg, 2.18 mmol) was hydrogenated (balloon apparatus) as a solution in 30 mL of 1:1 EtOH:CH2Cl2 over 10% Pd/C overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.04-8.08 (m, 2H), 7.95 (dd, J=4.4 Hz, 1.7 Hz, 1H), 7.70-7.84 (m, 2H), 7.36-7.40 (m, 2H), 7.19 (dd, J=8.2 Hz, 1.7 Hz, 1H), 7.11 (dd, J=8.1 Hz, 4.4 Hz, 1H), 1.29 (s, 9H); MS (ESI+) m/z 346 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1Br

Procedure:
To a solution of 2-bromo-5-fluorobenzoic acid (9) (21.90 g, 100 mmol) in methanol (100 mL) was added conc. H2SO4 (2 mL). The mixture was heated at reflux for 21 h. Most of the solvent was evaporated and diluted with water (200 mL). The mixture was extracted with EtOAc (150 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-bromo-5-fluorobenzoate (10).