Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][C:13]([CH3:25])([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:14]#[CH:15]>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]([CH3:25])([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[C:14]#[C:15][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Ic1ccc2ccccc2n1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1ccc2ccccc2n1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
5.1 g of 2-iodoquinoline were added at room temperature to a solution of 18 mg of palladium(II) chloride, 52 mg of triphenylphosphine and 38 mg of copper(I) iodide in 100 ml of diethylamine. 3,7 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were added. After stirring at room temperature for 18 hours the mixture was evaporated and the residue was dissolved in ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 5.8 g of 4-[1,1-dimethyl-3-(2-quinolyl)-2-propynyloxy]benzonitrile as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC1CCCN(C)C1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCCN(C)C1
Yield: 91 %

Procedure:
A mixture of 6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)-3,4-dihydroquinazolin-4-one (2.72 g, 8.9 mmol), thionyl chloride (90 ml) and DMF (0.5 ml) was stirred and heated to reflux for 45 minutes. The mixture was evaporated and the residue was azeotroped with toluene. The residue was taken up in water and basified to pH8 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (4×400 ml). The combined organic extracts were washed in turn with a saturated aqueous sodium hydrogen carbonate solution, water and brine, dried (MgSO4) and evaporated. The residue was dried overnight at 40° C. under vacuum to give 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline (2.62 g, 91%) as a solid; NMR: (DMSOd6) 1.1 (m, 1H), 1.42-1.96 (m, 5H), 2.09 (m, 1H), 2.15 (s, 3H), 2.6 (d, 1H), 2.8 (d, 1H), 3.98 (s, 3H), 4.1 (d, 2H), 7.35 (s, 1H), 7.42 (s, 1H), 8.84 (s, 1H); Mass: M+H+ 322.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@H:11]([CH2:13][OH:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]2[N:17]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C@@H:11]([CH2:13][OH:14])[N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[N:17]=2)[CH:5]=[N:6][CH:7]=1
Reactant: OC[C@@H]1CC[C@H](c2cncc(F)c2)N1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Temperature: 90 °C
Yield: 14 %

Procedure:
A mixture of ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol (0.910 g, 4.64 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 1.05 g, 4.64 mmol) and DIEA (1.10 mL, 6.00 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by reverse phase column chromatography (0-50% acetonitrile/water) followed by normal phase column chromatography (2-5% MeOH/DCM) to afford ethyl 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.250 g, 14% yield) as a viscous, clear oil. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl.[OH-].[NH4+].[CH4:26]>CO.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([O:16][CH3:26])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: C
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Reaction time: 8 h

Procedure:
A chilled solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]salicylic acid (148 g, 0.45 mol) in methanol is saturated with hydrogen chloride gas, warmed to and held at room temperature overnight and poured onto ice. The aqueous mixture is adjusted to about pH 7.5 with concentrated ammonium hydroxide solution and extracted with methylene chloride. The combined organic extracts are washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, treated with 10 g of silica gel, filtered and concentrated in vacuo to obtain a dark gum. The gum is dissolved in a methanol-water solution, treated with charcoal, filtered and crystallized to give the title product as an offwhite solid (102.3 g 66.2% mp 62°-64° C.).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]=[O:5].C(N(CC)CC)C.[CH2:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[CH2:15][CH2:14]1.Cl>O1CCCC1>[OH:22][C:17]1[C:18]([CH:4]=[O:5])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13]2
Reactant: C=O
Reactant: Oc1cccc2c1CCC2
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(c1O)CCC2
Temperature: 72.5 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred suspension Magnesium chloride (71.0 gm, 0.745 mole) and Para-formaldehyde (33.6 gm, 1.12 mole) in Tetrahydrofuran (200 ml), Triethylamine (104 ml, 0.745 mole) was added at room temperature and stirred for 30 minutes. To the reaction mixture; the solution of Indan-4-ol (50 gm, 0.373) in Tetrahydrofuran (100 ml) was added at room temperature and heated to 70-75° C. for 6 hours. To the reaction mixture, 2N Hydrochloric acid (600 ml) was added and extracted with Ethylacetate (2×500 ml). The Ethylacetate layer was washed with water (300 ml), dried over Sodium sulphate and further it was distilled under vacuum to give viscous oil (52.0 gm) which becomes solid upon keeping.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>O>[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])=[CH2:1])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Solvent: O
Product: C=C(C)c1ccc(-c2ccc(OC(C)=O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
10 ml of acetic anhydride was charged in a flask provided with a reflux condenser and a stirrer. Then, 1 g of 4-hydroxy-4'-isopropenylbiphenyl obtained in Example 2 was added thereto and the mixture was stirred at 80° C. for 1 hr to effect the reaction. The reaction solution was poured into water and the resulting crystals were separated and recrystallized from methanol to obtain 0.72 g of 4-acetoxy-4'-isopropenylbiphenyl (53) in the form of white crystals. ##STR158##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:19]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:19][CH:16]([CH3:17])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(-c2ccccn2)c(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (120 mg, 0.5 mmol) in benzene (1 mL) and 30% HBr/Acetic acid (1 mL) was cooled to 0° C. and was treated with a solution of bromine (0.024 mL, 0.5 mmol) in benzene (0.5 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[CH3:35][O:36][C:37]([C:39]1([C:42](OC)=[O:43])[CH2:41][CH2:40]1)=[O:38]>CCCCCC>[CH3:35][O:36][C:37]([C:39]1([C:42]2([OH:43])[O:22][N:21]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:24])[CH3:23])=[CH:8][CH:9]=3)[CH:14]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: COC(=O)C1(C(=O)OC)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Temperature: -9 °C
Reaction time: 0.05 h

Procedure:
An oven-dried 1 L three-neck flask equipped with magnetic stir bar, nitrogen gas inlet valve, and digital thermometer probe, and addition funnel had been charged with 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone oxime (Compound B, 26.6 g) and anhydrous THF (140 mL.) The reaction vessel is submerged in an ice-methanol bath equipped with a thermometer reading −18° C. The internal solution temperature is cooled to −9.0° C. A solution consisting of 2.5 M n-butyllithium in hexane (31 mL, 78 mmol) is added dropwise over 25 minutes (bath temperature −18 to −16° C., internal mixture temperature −9.0 to −0.6° C.), over which time the solution color turned from yellow after addition of the first few drops to orange at the first endpoint. The reaction mixture is stirred for three minutes as the internal mixture temperature cooled to −3.3° C. (bath temperature −14° C.) Another 31 mL of 2.5 M n-butyllithium in hexane is added over 11 minutes (bath temperature −14 to −16° C., internal mixture temperature −3.3 to −0.3° C. with a peak temperature in that time period of +0.2° C.) The reaction mixture is stirred for 31 minutes as the internal mixture temperature cooled to −10.1° C. (bath temperature −14° C.) Cyclopropane-1,1-dicarboxylic acid dimethyl ester (26.0 mL) is added over less than one minute to give an internal mixture temperature of +4.6° C. (bath temperature −13° C.) The reaction mixture is stirred for one hour and is quenched with the addition of brine solution (100 mL.) The layers are separated and the organic phase is dried over anhydrous magnesium sulfate and is concentrated under reduced pressure to afford an oil (59.9 g.) The product is purified by flash silica gel column chromatography to afford the foam product (24.0 g.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH3:10]
Reactant: CCC(O)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1Br

Procedure:
With the exception of three compounds, the styrene compounds disclosed herein to be utilized for preparing the α-chloro oximes ae known and their preparations are published in the prior art. The compounds not previously prepared are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of a catalytic quantity of p-toluenesulfonic acid to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl) benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[C:35]([F:40])[CH:34]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[C:35]([F:40])[CH:34]=1)[CH3:23]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: CN(C)Cc1ccccc1-c1ccc(N)c(F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)Cc1ccccc1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 55, 90 mg, 0.28 mmol) and 4-(2-dimethylaminomethyl-phenyl)-2-fluoro-phenylamine (80 mg, 0.33 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.050 mL, 0.55 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (38 mg). MS 549.1 and 551.2 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3OC)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3OC)cc2)cc1)C(=O)O
Yield: 88.2 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (750 mg), which is the product of Example 42, was reacted with aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to give the title compound (625 mg) as a pale orange powder.
Reaction SMILES: [CH3:1][C@:2]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.P(OCC)(OCC)[O:24]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[OH:24][CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C@@:2]1([CH3:1])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: CCOP(OCC)OCC
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (10.0 g, 33.0 mmol) and triethyl phosphite (6.78 mL, 39.6 mmol) in anhydrous tetrahydrofuran (165 mL), lithium bistrimethylsilylamide (46.1 mL, 46.1 mmol, 1.0M solution in tetrahydrofuran) was added at −5° C., and the mixture was stirred at the same temperature for 30 minutes. After bubbling oxygen gas into the reaction mixture for 2 hours, saturated aqueous solution of ammonium chloride (150 mL) was added to the mixture in an ice bath, and the mixture was concentrated under reduced pressure. Water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (hexane ethyl acetate=1:1→1:4) to obtain 9.61 g (91.3%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), triethylamine (0.4 g) and toluene (50 g) was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and washed with water. The toluene layer was separated and concentrated under reduced pressure. Analysis of the resulting product revealed that it contains the compound (I) in a purity of about 77% and a large amount of a compound of the following formula as the impurity: ##STR6## Purification of the above product by silica gel column chromatography gave the compound (I) (13.7 g).
Reaction SMILES: C(OC(=O)[N:7]=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:21]2)[C:11]2[CH:39]=[CH:40][CH:41]=[CH:42][C:10]=2[N:9]1[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:28]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:23]1[CH2:22][CH2:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:11]3[CH:39]=[CH:40][CH:41]=[CH:42][C:10]=3[N:9]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:8]2=[NH:7])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To [1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (100 mg, 0.14 mmol) at rt was added 25% TFA in dichloromethane (5 ml). The reaction was stirred for 1 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC and then partitioned between saturated NaHCO3 and dichloromethane. The organic phase was separated, washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (2.8 mg, 3%). HPLC-MS 626 [M+1]+, 324.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH3:45][O:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:49]2[CH2:50][CH2:51][CH2:52][C@@H:47]([O:46][CH3:45])[CH2:48]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CO[C@@H]1CCCNC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CO[C@@H]1CCCN(C(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C#N)[C@H]2c2ccc(C#N)cc2S(C)(=O)=O)C1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with (3R)-3-methoxypiperidine (44.2 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (45 mg, 57% of theory).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[F:28][C:29]([F:38])([F:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2cccc(C(F)(F)F)c2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 3-(trifluoromethyl)benzyl chloride to form 1-(3-trifluoromethylbenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)piperazine, mp 133°-135° C.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Clc1ccc2c(c1)OCc1ccccc1C2=CBr
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: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccccc4COc4cc(Cl)ccc43)cc2[nH]1
Yield: 70.1 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3-chloro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 40 mg, 0.124 mmol) (prepared essentially as described in Preparation 55), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (31 mg, 0.118 mmol), Na2CO3 (2M in water, 148 □L, 0.295 mmol), dioxane (1 mL), and Pd(PPh3)4 (7 mg, 0.006 mmol). Purify the crude product on silica gel (12 g) eluting with 2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 31 mg (69%) of the title compound as a white solid. HPLC (ISO80-10) t=2.85min, 99%; MS [ES] 373 (M−H); 1H-NMR (DMSO-d6) 10.57 (s, 1H), 10.47 (s, 1H), 7.56 (dd, 2H, J=7.8, 6.1 Hz), 7.35 (t, 1H, J=7.5 Hz), 7.24 (t, 1H, J=7.7 Hz), 6.98 (m, 3H), 6.82 (d, 1H, J=4.4 Hz), 6.69 (m, 2H), 6.57 (s, 1H), 5.89-4.79 (br d, 2H).