Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:61])[C:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63](OC(N1CCCC1C(O)=O)=O)(C)(C)C.COC(NC(C1C=CC=CC=1)C(O)=O)=O.COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([CH3:63])[CH2:44][N:43]6[C:47](=[O:61])[CH:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(C)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.70 (M+H+).
Reaction SMILES: [K].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Br:8][C:9]([CH2:11]Br)=[CH2:10]>C1(C)C=CC=CC=1.O>[Br:8][C:9](=[CH2:10])[CH2:11][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: O=C1CCCN1
Reactant: C=C(Br)CBr
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(Br)CN1CCCC1=O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a suspension of 5.0 g (40.6 mmol) of pyrrolidinone potassium salt prepared from Example 1 in 40 mL of toluene, solution of 5.24 mL (2 equiv.) of 2,3-dibromopropene in 10 mL of toluene was added dropwise for 1 hour in water bath and the reaction mixture was reacted at 60˜70° C. for 2 hours. Upon completion of the reaction, the mixture was cooled to 0° C. and filtered to remove solid. It was then concentrated under reduced pressure and purified by separation with silica gel column chromatography (ethyl acetate/n-hexane (1:1)) to obtain 5.30 g (64% yield) of 1-(2-bromoallyl)-pyrrolidin-2-one. To degassed solution of 1.0 g (4.90 mmol) of 1-(2-bromoallyl)-pyrrolidin-2-one prepared in the above in 50 mL of ethanol/benzene (1:1), 5 mol% (172 mg) of ditriphenylphosphine palladium dichloride, degassed solution of 7.35 mL of 2N sodium carbonate and 3-pyridyl-tributyltin, dimethyl borate, trimethyl borate lithium salt, boronic acid propanediol ring ester (2 equiv.), etc. were added. The mixture was reacted for 15 minutes at room temperature, followed by heating at reflux for 18 hours. After concentrating under reduced pressure, it was extracted with ethyl acetate for three times and washed with brine for two times. The concentrated solution was purified by separation with silica gel column chromatography (ethyl acetate followed by methylene chloride/methanol (20:1)) to obtain 810 mg (82% yield) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one. Ozones were added to solution of 100 mg (0.494 mmol) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one at −78° C. to obtain 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one, which was the same as synthesized in Example 20.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][OH:5])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCO)c1ncccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
2-(Methylamino)ethanol (3.04 ml) is added to a mixture of 2-chloro-3-nitropyridine (3.00 g) and of potassium carbonate (5.22 g) in acetonitrile (90 ml) at 0°. The mixture is stirred for 2.5 hr at 20°-25° and additional 2-(methylamino)ethanol (1.5 ml) is added. The mixture is stirred for 1.5 hr, concentrated to a gum and diluted with methylene chloride (85 ml) and water (20 ml). The layers are separated and the organic phase is washed with water and dried over magnesium sulfate. Removal of solvent under reduced pressure gives the title compound, NMR (CDCl3) 8.27, 8.14, 6.76, 4.38, 3.88 and 2.87δ.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][S:18]([NH:21][C:22]1([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:20])=[O:19].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:28]3[CH:27]=[CH:26][C:25]([C:22]4([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH2:24][CH2:23]4)=[CH:30][CH:29]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: CS(=O)(=O)NC1(c2ccc(B(O)O)cc2)CC1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1(c2ccc(Oc3ccc4c(c3)S(=O)(=O)NC3CCCN43)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension composed of 290 mg (1.21 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 465 mg (1.82 mmol) of the compound obtained in Step D, 330 mg (1.82 mmol) of copper(II) acetate, 294 μl (3.64 mmol) of pyridine and about 3.5 g of 4 Å molecular sieve in 35 ml of CH2Cl2 is stirred for 5 hours at ambient temperature. The reaction mixture is filtered and rinsed with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly applied to a silica column, eluting with a mixture of CH2Cl2/acetone 96/4. The fractions containing the expected compound are collected and evaporated and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the title compound is collected in the form of a white powder.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][OH:37])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: C1CO1
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Clomiphene (6.06 g, 14.9 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to -40° C. t-Butyl lithium (1M in pentane, 24 mmol) was added slowly. After 5 minutes, ethylene oxide (14.6 ml, 290 mmol) was added, and the reaction mixture was stirred for 6 hours, poured into water and extracted with ether. The ether layer was evaporated and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield trans product (1.96 g, 27.1%, oil): and cis product (1.56 g, 21.5%, oil): Assignment of 1HNMR for aliphatic protons are presented in Table 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][N:21]([CH3:31])[C:22]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)=[O:23]>C(#N)C>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:22]([N:21]([CH3:31])[CH3:20])=[O:23])[CH:25]=2)[N:8]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN(C)C(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Yield: 83 %

Procedure:
To 2-methylthio-4,6-dichloro-5-nitropyrimidine, a compound of formula (A), (5.0 g, 20.8 mmol) in 200 mL acetonitrile at 0° C. was added cesium carbonate (8.82 g, 27.1 mmol) followed by the addition of 3-(dimethylaminocarbonyl)phenol (3.44 g, 20.8 mmol), a compound of formula (B), and the reaction mixture was stirred for 16 hours. The volatiles were evaporated and the residue chromatographed on silica gel (CH2 Cl2 /ethyl acetate, 7:12) to afford 6.3 g (83% yield) of 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[NH3:12].[S-2].[Na+].[Na+]>O>[NH2:12][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: N
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: Cc1cc(C(=O)O)cc(N)n1
Temperature: 155 °C

Procedure:
2-chloro-6-methylisonicotinic acid (9 g), of aq ammonia (44 ml), of Cu(II)SO4 (0.9 g) and of sodium sulphide (0.32 g) are added to an autoclave and heated to 155° C. overnight. The crude product is suspended in water to yield 2-amino-6-methylisonicotinic acid (3.6 g). HPLC: Rt=0.37 min (method D)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([C:5](Cl)=[O:6])[C:3]1([CH3:9])[CH3:8].Cl.[O:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:13][O:12][NH:14][C:5]([CH:4]1[C:2]([CH3:10])([CH3:1])[C:3]1([CH3:9])[CH3:8])=[O:6]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)C1C(C)(C)C1(C)C
Yield: 75 %

Procedure:
Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) (4 g; 25 mmol) dissolved in 20 ml of dry dichloromethane was slowly added to a stirred and dry dichloromethane solution of methoxylamine hydrochloride (2.5 g; 30 mmol) and triethylamine (6.3 g; 50 mmol). After the addition, the reaction mixture was stirred for 2 hr at room temperature. Dichloromethane was evaporated under vacuum, 10 ml of water was added and the products were extracted using 30 ml of ethyl acetate. The organic fraction was dried over MgSO4, filtered and evaporated under vacuum. The product was crystallized using 20 ml ethyl acetate and 30 ml petroleum ether to afford 3 g (75% yield) and its chemical structure was identified by elemental analysis and spectroscopic methods.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[S:14])[NH2:13])=[CH:6][CH:5]=1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C(O)C>[Cl:17][CH2:18][C:19]1[N:13]=[C:12]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:1])[F:16])=[CH:9][CH:8]=2)[S:14][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)C=Cc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)cs2)cc1
Yield: 15.5 %

Procedure:
12.7 g (48.3 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylthioamide, 18.4 g (145 mmol) 1,3-dichloroacetone and 120 ml ethanol were refluxed for 4 h. After evaporation the residue was purified by chromatography on silica gel (ethyl acetate/isohexane 1:10) to yield 2.40 g 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-thiazole as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid methyl ester (8.4 g; 50 mmol) in DMF (100 ml)were added potassium carbonate (14.0g; 100 mmol) and 2-chloromethylpyridine hydrochloride (8.2 g; 50 mmol), and the resulting mixture was stirred at 50° C. for 24 h. The mixture was then poured into water, extracted with ethyl acetate, the acetate layer was washed with water, brine and concentrated in vacuo. The residue was purified on silica gel column (hexane-ethyl acetate 1:1) to provide 9.5 g of 4-(2-pyridylmethoxy)phenylacetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][N:7]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[C:21]1([CH2:20][CH2:19][S:16]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:3]3[CH:2]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2cnccn2)CC1

Procedure:
EXAMPLE 90 was prepared from (3-chloro-pyrazin-2-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=361.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:18])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: CC(=O)CCCCl
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCl)OCCc2c1[nH]c1ccccc21
Reaction time: 1 h

Procedure:
To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl3) δ1.33 (3H); 1.93 (4H), 2.75 (2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.C(OCC)C>[C:18]([Si:15]([O:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=1)([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromophenol (59.6 mmol; 15 g) and imidazole (65.5 mmol; 4.5 g) were dissolved in dichloromethane (150 mL) and tert-butyl-dimethylsilylchloride (65.5 mmol; 9.9 g) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with diethyl ether, and filtered. The organic solution was washed with saturated ammonium chloride, saturated sodium hydrogen carbonate, and water and dried and evaporated to dryness. Yield: 22 g. HPLC-MS: m/z: 366.9 (M+); Rt: 3.09 min.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CC(C)=O.C(Cl)Cl>[C:4]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
20 ml of a 50% strength solution of diketene in acetone are added dropwise to 32.5 g of N-[2-(2-hydroxyethoxy)-ethyl]-4,4-diphenylpiperidine and about 0.1 g of N,N-dimethylaminopyridine in 200 ml of methylene chloride at the boiling point, with vigorous stirring. After boiling under reflux for 1 h, the solution is allowed to cool and is concentrated to constant weight under a high vacuum. The pale yellow viscous coil which remains is used for the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=O)c1ccc(Cl)cc1
Product: CCOC(=O)C=CC(C)c1ccc(Cl)cc1

Procedure:
The synthesis of intermediates leading to different values of m and X is within the capability of one skilled in the art. Example 3 details the method of making the compound wherein X is --CH(CH3)-- and m is 2. This synthesis starts with the reduction of 2-(4-chlorophenyl)propionic acid with lithium aluminum hydride, producing 2-(4-chlorophenyl)propanol. Oxidation of this alcohol with pyridinium chlorochromate in methylene chloride produces 2-(4-chlorophenyl)propionaldehyde. This aldehyde is then reacted with (carbethoxymethylene)triphenylphosphorane, yielding ethyl 4-(4-chlorophenyl)-2-pentenoate. Hydrogenation of this ester in the presence of platinum oxide produces ethyl 4-(4-chlorophenyl)pentanoate which is then hydrolyzed with sodium hydroxide to the corresponding pentanoic acid (II). The remaining steps of this synthesis are shown in Schema 1.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]1=[O:11].S(Cl)([Cl:14])=O>>[Cl:14][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]1=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Nc1ccn(CCO)c(=O)n1
Product: Nc1ccn(CCCl)c(=O)n1

Procedure:
B] 1-(2-Chloroethyl)-4-amino-2-1H-pyrimidinone was prepared according to example 14C from 3.8 g 1-(2-hydroxyethyl)-4-amino-2-1H-pyrimidinone and 60 ml thionyl chloride. 3.2 g (97%) of crude product were obtained and used without further purification. Recrystallization was omitted in this case due to decomposition. Rf: 0.51 (ethyl acetate/acetone/acetic acid/H2O 6:2:1:1).
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:12]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CC=CCC=1>CCO.[Pd]>[ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:12]2[CH2:18][CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCNC3)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 2,7-dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride in EtOH was added 10% Pd/C (1 equiv) followed by 1,4-cyclohexadiene (5 equiv). The mixture was heated at 85° C. for 5 h, filtered and concentrated. The residue was dissolved in CH2Cl2 and treated with Dowex 550A resin. After 1 h, the resin was removed by filtration and the filtrate was concentrated. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (MeOH-d4): 7.70-7.67 (m, 2H), 7.36-7.35 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.17 (m, 1H), 4.42 (s, 2H), 4.26 (s, 2H), 3.48 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H).
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(CCCCCc1ccccc1)C(=O)O
Solvent: CC(=O)O
Product: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
2-isopropyl-7-phenylheptanoic acid (1.0 g; prepared as the intermediate for the compound of example 1 (b)) was dissolved in anhydrous acetic acid (5ml). The solution was cooled in an ice-bath. Fuming nitric acid (0.4 ml) was dropped into the solution. The solution was stirred for 30 mins. Anhydrous acetic acid was quenched by adding potassium hydroxide to the reaction solution. The reaction solution adjusted to pH 6.0~7.0 was extracted with ethyl acetate. The ethyl acetate layer separated was washed with water, followed by saturated brine, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (850 mg) having the following physical data:
Reaction SMILES: [C:1]([CH2:6][C:7]([CH3:19])([CH3:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([CH3:19])[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O
Product: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1

Procedure:
This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 20.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:13][CH3:14])=[O:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:13]([S:11]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])=[O:12])[CH3:14]
Reactant: C1COCCN1
Reactant: CCS(=O)c1cc(Cl)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 100 °C
Yield: 58.1 %

Procedure:
4-Chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.31 g, 1.36 mmol), morpholine (0.36 ml, 4.09 mmol) and potassium carbonate (0.24 g, 1.77 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 100° C. for 16 h. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 50% ethyl acetate/hexane) to yield 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.22 g, 0.79 mmol, 58%).