Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH3:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].CC/C=C/CC>CN(C=O)C>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC/C=C\CC
Agent: CC/C=C/CC
Solvent: CCC=CCC
Solvent: CN(C)C=O
Product: C=CCCCC

Procedure:
The 3-hexene feedstock was assumed to have a composition of 33 wt % cis-3-hexene and 67 wt % trans-3-hexene. The normal boiling points for 1-, 2-, and 3-hexene are listed in Example 2. The normal boiling for DMF, the extraction solvent in this example, is 152° C. (305° F.). The isomerization reaction was assumed to occur at the bottom of the column. The column was assumed to have 150 theoretical stages, a kettle reboiler, and a total condenser. The operating conditions for the column consisted of a pressure of 7 atm, condenser temperature of 140° C. (283° F.), and reboiler temperature of 232° C. (450° F.). In addition, 100 lb/hr of DMF was added to the 10th theoretical stage of the column (near the top). This resulted in a column with a diameter of 11.8 ft and a reflux ratio of 518. For this case, the 1000 lb/hr 3-hexene feed resulted in 980 lb/hr of 99 wt % 1-hexene product. The column bottoms contained 91 wt % DMF, which can be recycled back to the column. A detailed material balance is shown in the following table. RXFEED is the distillation column feed stream, SOLVENT is the DMF extractive distillation solvent stream, BOTTOMS is the distillation column bottoms stream, and 1-HEXENE is the product stream, which is obtained from the top of the column.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:21]1[C:25](B(O)O)=[CH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCCCC1>[S:21]1[C:25]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)=[CH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(CCNc2cc(-c3cc4ccccc4s3)nc(OC)n2)cc1
Yield: 42.5 %

Procedure:
By proceeding in a similar manner as above in Example 10(a) but using (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (150 mg), benzo[b]thiophene-2-boronic acid (182 mg), Cs2CO3 (590 mg) and tetrakis(triphenylphosphine)palladium (0) (58 mg), and subjecting the crude reaction product to flash column chromatography on silica gel eluting with a mixtures of 20 to 100% EtOAc and cyclohexane, there is prepared (6-benzo[b]thiophen-2-yl-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [85 mg, 42% yield, Example 10(g)]. LCMS: RT=10.39 minutes, MS: 392 (M+H). IC50=5.1 nM
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:25][CH3:26])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:40][CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@@H:9]([C@:10]3([O:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:25][CH3:26])[CH:5]=[CH:6]2
Reactant: CCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN[C@@H]2C5
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN(CCc1ccccc1)[C@@H]2C5
Yield: 59.5 %

Procedure:
A mixture of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 76, 476-480,1993) (3.0 g, 7.88 mmol), potassium carbonate (3.9 g, 28.2 mmol), 2-phenylethyl bromide (1.41 ml, 10.4 mmol), and of 20 ml anhydrous NN-dimethyl formamide was stirred at 80° C. (bath temperature) for 2h. After cooling and addition of 130 ml of H2O, the mixture was extracted with diethyl ether (3×60 ml). The combined organic layers were washed with H2O(3×70 ml), dried over Na2SO4 and evaporated. The residue (3.6 yellow oil) was crystallized from MeOH to afford 2.1 g (70%) of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methyl-17-(2-phenyl)ethylmorphinan-6-one (compound 3). M.p. 86-89° C. IR (KBr): 1725 (CO) cm-1. CI-MS: m/z 448 (M+ +1). 1H-NMR (CDCl3): δ 7.21 (m, 5 arom. H), 6.64 (d,J=8.2 Hz, 1 arom. H, 6.54 (d, J=8.2 Hz, 1 arom. H.), 3.85 (s, OCH3), 1.60 (s, CH3 --C(5)), 1.12 (t, J=6.8 Hz, CH3). Analysis calculated for C28H33NO4 (447.55): C 75.14, H 7.43, N 3.13; found: C 75.04, H 7.69, N 3.26.
Reaction SMILES: [N:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])=[N+:2]=[N-:3].C[O:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(OC)OC.O>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([O:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:7][OH:8])(=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: [N-]=[N+]=NC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC(CO)COC(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
Neat 23 (1.48 g, 12.65 mmol) was dissolved in CH2Cl2 (127 mL) and treated with a catalytic amount of p-toluene sulfonic acid monohydrate (0.048 g, 20 μmol) and (trimethoxymethyl)benzene (3.26 mL, 18.98 mmol) in CH2Cl2 at room temperature for 1 hr. After the formation of the orthoester was complete, a stoichiometric amount of water (340 μL, 18.98 mmol) was added to the mixture. The mixture was then stirred for 40 min and concentrated in vacuo. Purification of the residue by silica gel flash chromatography using 25% EtOAc/hexanes gave 2.6 g of monoacylated product 27 (93% yield) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 8.03-8.06 (m, 2H), 7.58 (tt, J=1.6, 2.0, 1.6 1H), 7.43-7.47 (m, 2H), 4.54 (dd, J=4.4, 12.0 Hz, 1H), 4.46 (dd, J=6.8, 12.0 Hz, 1H), 3.85-3.91 (m, 1H), 3.80 (dd, J=4.8, 11.6 Hz, 1H), 3.73 (dd, J=6.0, 11.6 Hz, 1H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-:21].[Li+]>CN(C=O)C.CS(Cl)(=O)=O>[Cl:21][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: [Cl-]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C and treated with 16.56 mL (0.213 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then was poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: [N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:28][O:29]CC3C=CC=CC=3)[CH2:19][O:20]CC3C=CC=CC=3)[C:14]=2[N:15]=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:19][OH:20])[CH2:28][OH:29])[C:14]=2[N:15]=1)(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)Nc1nc2c(ncn2COC(COCc2ccccc2)COCc2ccccc2)c(=O)[nH]1
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Yield: 44.5 %

Procedure:
To a solution of N2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine (4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added 20% palladium hydroxide on carbon as a slurry in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for 38 hours then filtered through celite and concentrated to a white solid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205-208° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20]CC)=[O:19])=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:20])=[O:19])=[C:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1

Procedure:
General Procedure 2 A solution of ethyl 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (Compound 1, 873 mg, 2.83 mmol) and NaOH (2.2 g, 56 mmol) in EtOH (10 ml) and H2O (10 ml) was heated to 90° C. for 16 h. The reaction was quenched with 6M HCl (10 ml), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes to 20% MeOH-EtOAc) to yield 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 2) as a reddish brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:10]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:22]([C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[OH:15][C:11]1[C:10]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[C:9]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22]([C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[O:23])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1Sc1cccc(O)c1-c1nnn[nH]1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2cccc(O)c2-c2nnn[nH]2)cc1
Yield: 60.8 %

Procedure:
In 10 ml of toluene was suspended 0.63 g of 3-(2-aminophenylthio)-2-(1H-tetrazol-5-yl)phenol (prepared in Reference Example 12)-followed by addition of a solution of 0.58 g of ethyl 4-chloroformylphenoxyacetate in 2 ml of toluene, and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was subjected to silica gel column chromatography using 0.5% methanol-chloroform as the eluent to give 0.66 g of the title compound as white crystals, m.p. 155°-157° C.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C=O)C>[C:3]1([C:9]2[C:13]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(Cc3ccccn3)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottom flask cooled to 0° C. dry DMF (2 ml) was added under nitrogen. To the above mixture compound tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2 ml) was slowly added and allowed to stir at 0° C. for 30 minutes. 2-Chloromethyl pyridine (300 mg) in DMF (1 ml) was slowly added to the above mixture at 0° C. The reaction mixture was allowed to stir at room temperature for overnight and quenched with ice. The product was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with water, brine, dried over sodiumsulphate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 6% ethyl acetate in hexane, to afford tert-butyl 4-(3-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)piperazine-1-carboxylate as half white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[NH2:36][O:37][CH3:38].Cl.CCN(C(C)C)C(C)C>CCO>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=[N:36][O:37][CH3:38])[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:2]
Reactant: CON
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=NOC)c1)NC(=O)c1c(Cl)cccc1Cl
Yield: 45.8 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-acetyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.12 g) in EtOH (5 mL) were added NH2OMe HCl salt (24 mg) and DIEA (60 mg). The mixture was refluxed for 2 h and evaporated. The residue was diluted with EtOAc, washed with 1N HCl, dried, and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 2:1)to give 0.058 g of N-(2,6-dichlorobenzoyl)-3-[1-(methoxyimino)ethyl]-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 534 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[C:13]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=O)[CH:9]1[CH2:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6]2)=[O:4].O.[NH2:30][NH2:31]>CO>[CH3:1][O:2][C:3]([C:5]12[C:13]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[N:30][NH2:31])[CH:9]1[CH2:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2(C)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2(C)c1ccccc1
Yield: 90 %

Procedure:
A solution of 3 g (7.95 mmol) of methyl(3aRS,4SR,7aRS)-2-benzyl-4-methyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate and of 1.55 cm3 (31.8 mmol) of hydrazine hydrate in 30 cm3 of methanol was brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in dichloromethane, washed with three times 30 cm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 2.8 g (89%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono4-methyl-4-phenyloctahydroisoindole-3a-carboxylate were thus obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][OH:28])=[NH:26])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=O)[CH3:33].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:32]([O:34][C:35]([C:36]1[O:28][N:27]=[C:25]([C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([C:6]3[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]4[CH:10]=[CH:11][C:12]([C:14]5[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=5)=[CH:13][C:8]=4[N:7]=3)[CH:23]=2)[N:26]=1)=[O:39])[CH3:33]
Reactant: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C(=N)NO)c2)n3C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(-c2cccc(-c3nc4cc(-c5cncc(OC)c5)ccc4n3C(C)(C)C)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3-[1-tert-Butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (0.500 g, 1.20 mmol) is dissolved in DMF (5 mL). Chloro-oxo-acetic acid ethyl ester (0.177 g, 1.30 mmol) is added followed by diisopropyl-ethylamine (1.5 mL). The reaction mixture is stirred at room temperature for 2 hours then heated at 110° C. for 16 hours. The solvent is removed in vacuum. The residue is purified by flash chromatography (silica gel 40 g, eluted with 0-100% ethyl acetate in hexane) to give the title compound (0.454 g, 76%). LCMS (ESMS): m/z 498.61 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([N:24]([CH3:35])[C:25]3[CH:34]=[CH:33][C:28]4[N:29]=[C:30]([CH3:32])[O:31][C:27]=4[CH:26]=3)=[O:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([N:24]([CH3:35])[C:25]3[CH:34]=[CH:33][C:28]4[N:29]=[C:30]([CH3:32])[O:31][C:27]=4[CH:26]=3)=[O:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (example 70) (4.0 g, 8.469 mmol) in DCM (30 mL) was added BBr3 (4.8 mL, 50.8 mmol) at 0° C. The reaction mixture was stirred at rt overnight then diluted with water (150 mL), neutralized with NaHCO3, then extracted with DCM (3×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated to yield 2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (2.9 g, 74%) (459.36 [M+H]).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(=O)[C:24]([Cl:26])=[O:25].[Cl-].[Ca+2].[Cl-]>ClCCl.O>[Cl:26][C:24]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)=[O:25]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing the product of example 1B (2.46 g, 10.0 mmol) and AlCl3 (2.66 g, 20.0 mmol) in 30 mL of dichloromethane at 0° C. was added oxalyl chloride (5 mL, 2 M solution in dichloromethane, 10 mmol). The mixture was stirred at room temperature for 30 minutes. After this time the reaction mixture was poured into an ice-cold solution containing calcium chloride (3 g) in 100 mL of water. The reaction mixture was stirred for 2 h and was extracted with dichloromethane (2×100 mL). The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (ethyl acetate/hexane, 1/8) to afford the title compound as a colorless oil. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (m, 2H), 1.19 (t, J=7.06 Hz, 3H), 1.47 (m, 2H), 1.57-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.47 (m, 1H), 4.07 (q, J=7.06 Hz, 2H), 7.35 (d, J=8.29 Hz, 2H), 7.85 (d, J=8.29 Hz, 2H).
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)Oc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: C[Si](C)(C)Oc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
5.35 g (0.22 mole) magnesium was added to 10 ml tetrahydrofuran and 0.35 ml CH3I under N2 and heated to initiate the Grignard reaction. A solution of 49.0 g (0.2 mole) p-bromophenyoxytrimethylsilane and 63 ml tetrahydrofuran was added over a 11/2 hour period. The reaction mixture was refluxed one additional hour and then cooled to room temperature. 22.8 g (0.21 mole) chlorotrimethylsilane was added to the reaction mixture. Once again the mixture was refluxed 1 hour and then cooled. 100 ml distilled water was slowly added, stirred, and separated. The organic phase was washed with two 50 ml portions of water and finally 50 ml of brine. The organic solution was dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator under reduced pressure. Vacuum distillation gave 28.7 g of p-trimethylsilylphenoxytrimethylsilane, bp 132 degrees Celsius at 27 mm Hg.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.CCCCCC>CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
N-tert-Butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide can be then produced by dissolving N-tert-Butyl-6-chloro-4-(4-fluoro-2-methyl-phenyl)-nicotinamide in dimethylsulfoxide and potassium carbonate, followed by the addition of thiomorpholine. The resulting suspension is stirred, cooled to room temperature, and partitioned between ethyl acetate and half-saturated aqueous sodium chloride solution. The phases are then separated and the organic phase washed with half-saturated aqueous sodium chloride. The aqueous phases are then extracted with ethyl acetate. The combined organic extracts are dried and concentrated in a rotary evaporator to produce a yellow oil. This oil is heated with the dropwise addition of n-hexane to obtain a refluxing suspension, which can be cooled to room temperature and further stirred at 0° C. for about one hour. The precipitate is filtered off, washed with cold n-hexane:ethyl acetate 9:1, and dried in a vacuum oven to yield N-tert-butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide as a light beige powder.
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CS(O[CH2:52][CH2:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)(=O)=O>>[CH:55]1([CH2:54][CH2:53][CH2:52][N:44]2[CH2:45][CH2:46][N:41]([C:33]3[CH:34]=[C:35]([F:40])[C:36]([O:38][CH3:39])=[CH:37][C:32]=3[F:31])[CH2:42][CH2:43]2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCCC3CCCCC3)CC2)cc1F
Yield: 97.6 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (5.72 g) and 3-cyclohexylpropyl methanesulfonate (5.52 g), to provide crude 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (8.618 g).