Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=1)=[O:17])[CH2:9]2
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc(NC(=O)C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(O)C(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
300 mg (2.14 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 300 mg (1.43 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 180 mg (0.71 mmol) of [(4′-aminobiphenyl-4-yl)amino](oxo)acetic acid [CAS Registry No. 100872-66-0] in 11 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., the reaction mixture is concentrated in vacuo, and the residue is dissolved in water and acetonitrile and purified by preparative HPLC. The concentrated product fractions are mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 64 mg (20.3% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][N:19](C(OCC5C=CC=CC=5)=O)[CH2:20][CH2:21][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[S:6]1[CH:2]=[CH:3][CH:4]=[C:5]1[C:7]1([C:12]2[N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]3=[N:14][N:13]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCc2nnc(C3(c4ccc(Cl)s4)CCCC3)n2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: c1csc(C2(c3nnc4n3CCNCC4)CCCC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
Benzyl 3-[1-(5-chloro-2-thienyl)cyclopentyl]-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepine-7-carboxylate (565 mg) was dissolved in a mixed solvent of methanol (10 ml) and 1,4-dioxane (5 ml). After palladium hydroxide (86 mg) was added thereto, the whole was stirred under a hydrogen atmosphere of 1 atm at room temperature for 48 hours to obtain 3-[1-(2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (190 mg).
Reaction SMILES: [ClH:1].Cl.C([S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:9]/[C:8]/1=[CH:26]\[C:27]1[N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:30]=[N:29][CH:28]=1)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[ClH:1].[CH:16]1([C:14](=[O:15])[CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([SH:6])/[C:8](=[CH:26]/[C:27]3[N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:30]=[N:29][CH:28]=3)/[CH2:9]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:17][CH2:18]1
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 54 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)piperidine hydrochloride (4.15 g) in ethanol (50 ml) with stirring under ice-cooling for one hour and the resulting mixture was stirred at room temperature overnight under a tightly sealed condition. After concentration of the reaction mixture under reduced pressure, ethyl acetate and an aqueous sodium hydrogencarbonate solution were added to the residue. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as the eluent, and the crude fraction thus obtained was further purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid solution, 40:60, v/v). The fraction obtained was neutralized with an aqueous sodium hydrogencarbonate solution. The resulting free base was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford the free base of the title compound (1.93 g, yield: 54%) as a pale yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(OCC)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: C[Si](C)(C)CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[Si](C)(C)CCC(=O)Cl
Reaction time: 16 h
Yield: 68.9 %

Procedure:
In a flask were place 13.4 g (0.0918 mole) of 4,4-dimethyl-4-silapentanoic acid, 100 mL of diethyl ether, and two drops of N,N-dimethylformamide. To this solution, which was cooled in an ice/water bath, was added 13.98 g (0.110 mole) of oxalyl chloride in diethyl ether in a dropwise manner. Upon completion of addition, the temperature was allowed to rise to ambient conditions, and the mixture was stirred for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 10.42 g of 4,4-dimethyl-4-silapentanoic acid chloride as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.I[CH2:25][CH3:26]>O.CN(C)C=O>[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19]([CH2:25][CH3:26])(=[O:21])=[O:20])[CH:18]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: CCI
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Sodium sulfite (4.94 g, 39.2 mmol) and sodium bicarbonate (3.46 g, 41.2 mmol) in water (100 mL) were heated to 75° C. 3-bromo-2-chloropyridine-5-sulfonyl chloride (6.00 g, 20.6 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75° C. for 1 hour after complete addition. The mixture was concentrated under vacuum. N,N-Dimethylformamide (37.5 mL), sodium bicarbonate (3.46 g, 41.2 mmol) and iodoethane (1.658 mL, 20.62 mmol) were added. The resulting mixture was heated to 75° C. for 2 hours then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by flash chromatography (silica gel, 100% heptane to 100% ethyl acetate) to provide the title compound (3.15 g, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (M+): m/z=448.0, tR (minutes, Method F)=2.72. [α]D20=+42.52 (c=3.8 mg/mL,CHCl3)
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([F:11])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.[CH:12]12[O:17][CH:16]1[CH2:15][CH2:14][CH2:13]2>C1COCC1.[Cu]I>[F:9][C:7]1[CH:8]=[C:3]([C@H:15]2[CH2:14][CH2:13][CH2:12][C@@H:16]2[OH:17])[CH:4]=[C:5]([F:11])[C:6]=1[F:10]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C1CC2OC2C1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: O[C@H]1CCC[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a suspension of magnesium (2.88 g, 118 mmol) in THF (110 mL) was slowly added 5-bromo-1,2,3-trifluorobenzene (25 g, 118 mmol). After the addition, the reaction mixture was heated at reflux for 2 h. To this reaction mixture, copper (I) iodide (1.506 g, 7.91 mmol) and 6-oxabicyclo[3.1.0]hexane (9.93 g, 118 mmol) dissolved in THF (20 mL) were added dropwise. The reaction mixture warmed upon the addition of the epoxide. The reaction was stirred at rt for 2 h at rt. The reaction mixture was quenched by the addition of a solution of ammonium chloride. Ether was added and the organic layer was collected, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give (1S,2R)-2-(3,4,5-trifluorophenyl)cyclopentanol (20.2 g, 93 mmol, 79% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:24]([OH:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=12)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:9][CH:8]=3.C[N+]1([O-])CCOCC1.CCOCC>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:25]=[C:24]1[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=32)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:28]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](CCC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(=O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A suspension of 4,4-dimethyl-5α-chola-8,14-dien-3β,24-diol (500 mg, 1.29 mmol), N-methylmorpholine-N-oxide (600 mg, 5.2 mmol), TPAP (45 mg, 0.13 mmol) and crushed molecular sieves (2 g) in dichloromethane (5 mL) was stirred for 30 minutes at room temperature. Addition of ether (15 mL) and filtration through kieselguhr gave a dark brown solution which was concentrated under reduced pressure and purified by chromatography (Eluant: 3 hexane: 1 ethyl acetate) to give the 3-oxo-4,4-dimethyl-5α-chola-8,14-dien-24-aldehyde (345 mg, 70%) as a white solid with melting point 96.5-97° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15][CH3:16])[CH:6]=1.CO.C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15]([CH3:16])=[O:48])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CSC)c2n1
Solvent: ClCCl
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CS(C)=O)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from example 12 (150 mg) was dissolved in DCM (10 ml) and methanol (2 ml) and mCPBA (0.1 g) added. The mixture was stirred at rt for 3 h then purified by RPHPLC, which afforded the title compound. Yield 50 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)n1ccc2cc(O)ccc21
Yield: 96.2 %

Procedure:
A mixture of 2-(5-benzyloxy-indol-1-yl)-2-methyl-propionic acid ethyl ester (15.6 g) and Pd/C (5%, 1.93 g) in ethanol (190 mL) is stirred under 60 PSI of hydrogen overnight. Filtration and concentration yields the title compound (11 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([N+:14]([O-])=O)=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=O.C(NC1C=C(C([N+]([O-])=O)=CC=1C)C(O)=O)=O>C(O)=O.[Pd]>[CH3:13][C:12]1[C:4]2[NH:3][CH:1]=[N:14][C:5]=2[C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1NC=O
Agent: [Pd]
Agent: Cc1cc([N+](=O)[O-])c(C(=O)O)cc1NC=O
Solvent: O=CO
Product: Cc1ccc(C(=O)O)c2nc[nH]c12
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 3-(Formylamino)-4-methyl-2-nitrobenzoic acid (18) and 3-(Formylamino)-4-methyl-6-nitrobenzoic acid (18b) in a ratio of about 66:34 (9.999 g, 44.56 mmol) and Pd/C (10%, 2 g, 4 mol % Pd) in 75% aqueous formic acid (120 mL, 0.5M) is heated at reflux for about 15 hours. The reaction mixture is then cooled to ambient temperature and filtered through a pad of Celite, and the filtrate is concentrated in vacuo to a beige solid. The solids are triturated in hot methanol (50 mL), cooled slowly to ambient temperature, and filtered to give 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22) as beige solid (5.564 g, 98% Yield, based on amount of 3-(Formylamino)-4-methyl-2-nitrobenzoic acid (18) in the starting material mixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:27][C:28]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: COc1cccc2c1CCN(C(=O)NC(C)(C)C)C2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 50 mL round-bottomed flask was added 5-methoxy-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 143 μmol, from step 3), CH2Cl2 (2 mL), t-butylisocyanate (16 μL, 143 μmol, Aldrich). The solution was stirred at RT for 5 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give N-tert-butyl-5-methoxy-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 407 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH:25]([O:28]C)[CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:30])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.I[Si](C)(C)C>C(#N)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH:25]([OH:28])[CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:30])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC1CCc2nc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(=O)n2C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CC(O)CC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
A mixture of 8.5 parts of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 14 parts of iodotrimethylsilane and 40 parts of acetonitrile was stirred overnight at 70° C. Another portion of 2.8 parts of iodotrimethylsilane was added and the reaction mixture was stirred for a while at 90° C. and then overnight at reflux temperature. After cooling, the whole was evaporated. The residue was taken up in ethanol and the whole was evaporated again. The residue was taken up in water and treated with a sodium hydroxide solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was solidified in ethanol. The product was filtered off and dried, yielding 0.3 parts (3.7%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-7-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one; mp. 156.2° C. (Compound 7)
Reaction SMILES: [C:1]([CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)C(O)=O)([OH:3])=[O:2].[Br:24]Br>CCOCC.C1(C)C(C)=CC=CC=1>[Br:24][CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]([OH:3])=[O:2]
Reactant: BrBr
Reactant: O=C(O)C(CC12CC(c3ccccc31)c1ccccc12)C(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=C(O)C(Br)CC12CC(c3ccccc31)c1ccccc12

Procedure:
α-Carboxy-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with bromine in ether, and the corresponding brominated compound was refluxed in xylene to give α-bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid. α-Bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with thionyl chloride and then with N-benzyl-N-hydroxyethylamine to give α-bromo-β-(9,10-dihydro-9,10-methano-9anthryl)propionic acid N-benzyl-N-hydroxyethylamide, I.R., 3400, 3060, 3045, 2860, 1640, 1360, 1158, 1048, 1012, 698 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 407.47; mp: 141.0-142.0° C.; 1H-NMR (DMSO) δ: 8.73-8.71 (1H, m), 8.14 (1H, t, J=7.0 Hz), 7.61-7.56 (2H, m), 7.46 (1H, s), 7.26 (1H, d, J=8.1 Hz), 7.05 (1H, d, J=8.1 Hz), 6.92 (1H, dd, J=15.8, 7.0 Hz), 6.38 (1H, d, J=15.8 Hz), 2.42 (3H, s), 2.25-2.10 (1H, m), 1.80-1.55 (5H, m), 1.40-1.05 (5H, m).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([CH3:69])=[CH:65][C:64]=1[O:70][CH3:71].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][C:66]([CH3:69])=[CH:65][C:64]=3[O:70][CH3:71])[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: COc1cc(C)ccc1OCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)O
Solvent: CCCCO
Product: COc1cc(C)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 74.8 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.5 g (0.015 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol, 3.2 g (0.015 mole) of 1-chloro-3-(2-methoxy-4-methylphenoxy)propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 5.4 g (75%) of the title compound as a white solid, mp 121°-122° C. (2-propanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][CH3:23])=[C:16](B(O)O)[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(O)C(O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:13]=[C:12]([Cl:11])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH3:23])[N:3]=[C:4]([NH:9][CH3:10])[N:5]=1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(O)C(C)O
Solvent: O
Product: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(NC)n1
Temperature: 70 °C
Reaction time: 60 h
Yield: 91.5 %

Procedure:
To an argon saturated solution of N-(4,6-dichloro-pyrimidin-2-yl)-methyl-amine (200 mg, 1.1 mmol), 5-chloro-2-ethoxy-phenylboronic acid (248 mg, 1.21 mmol) and palladium acetate (38 mg, 0.16 mmol) in dimethyl ethylene glycol (20 ml) was added a solution of sodium carbonate (240 mg, 2.2 mmol) in water (5 ml) followed by triphenylphosphine (66 mg, 0.33 mmol). After stirring at 70° C. under an argon atmosphere for 60 hours, the mixture was filtered through a pad of celite under suction and the filtrate was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided [4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-yl]-methyl-amine (300 mg, 90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:31])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=3)[N:21]=[C:8]2[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:6]=1[CH3:42])=[O:4].[CH3:43][NH:44][CH3:45]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:31])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:44]([CH3:45])[CH3:43])=[CH:25][CH:24]=3)[N:21]=[C:8]2[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:6]=1[CH3:42])=[O:4]
Reactant: CNC
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(CBr)cc3)c(=O)n2C1c1ccc(C#N)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(CN(C)C)cc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
Intermediate 15 (105 mg, 0.16 mmol) was dissolved in THF (3 ml), and then dimethylamine (2 M in THF, 400 μl, 0.8 mmol) was added. The reaction mixture was stirred at RT for 16 hours and then filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 5-8% MeOH in DCM and gave the title compound as a white solid (72 mg).