Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:31])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 59.2 %

Procedure:
A 500 ml round bottom flask equipped with nitrogen inlet and magnetic stirrer is charged with 40 g (0.132 mol) of product from Example 2 and 24.97 g (0.233 mol) of 2,6-lutidine. To this is slowly added (exothermic) 185 ml (1.98 mol) of phosphorous oxychloride. The flask is fitted with a condenser and the mixture is heated to reflux. After refluxing for 18 hours the material is cooled, concentrated, and the mixture was poured into 150 g of ice slowly. The ice mixture was then poured into 200 ml of 10% HCl (aqueous) and extracted twice with ether. The combined ether layers were washed with 10% NaOH (aqueous), dried (MgSO4), and concentrated in vacuo affording a black oil. The residue was kugelrohr distilled at 67 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 85° C.) afforded 25.15 g (60%) of product, nD25 1.4185. Anal. Calc'd. for C10H6Cl1F6N1O2 : C, 37.35; H, 1.88; N, 4.36. Found: C, 37.51; H, 1.74; N, 4.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].N1C=CC=CC=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:25])=[O:6]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NNC(=O)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NNC(=O)c1cccc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzohydrazide (1 equivalent) and pyridine (2 equivalents) in CH2Cl2 at 0° C. was added a CH2Cl2 solution of 3-nitrobenzoyl chloride (1 equivalents) and stirred at 0° C. for 1 h and then at room temperature for overnight. The resulting solution was concentrated and diluted with water, basified with NaHCO3, the solid was filtered, washed with water, dried and analyzed to obtain N′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide. 1H NMR (DMSO-d6): δ 10.99 (s, 1H), 10.79 (s, 1H), 8.73 (bs, 1H), 8.43 (bdd, 1H, J=1.2 and 8.1 Hz), 8.33 (bdd, 1J, J=8.4 Hz), 7.95 (s, 1H), 7.87 (m, 2H), 7.67 (bdd, 1H, J=1.2 and 8.1 Hz), 7.57 (t, 1H, J=7.8 Hz); LCMS: purity: 85%; MS (m/e): 320 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([OH:37])[C:12]2[C:13](=[O:34])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]4[O:28]C(C)(C)[O:30][CH:31]=4)[CH:18]=3)[O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[CH2-]C(C)=O>C(O)(=O)C>[OH:37][C:35]1[C:12]2[C:13](=[O:34])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:18]=3)[O:16][C:11]=2[CH:10]=[C:9]([OH:8])[CH:36]=1
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(OCc4ccccc4)cc3o2)cc1OCC1=COC(C)(C)O1
Agent: [CH2-]C(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1OCC(O)CO
Temperature: 0 °C
Yield: 111.9 %

Procedure:
The 36 g of compound obtained in Example 9 are added to 200 ml of a mixture of water and acetic acid (1/1) and the whole is heated at reflux until the mixture becomes homogeneous, after which refluxing is maintained for a further 15 minutes. The disappearance of the acetonide is verified by thin-layer chromatography, then the mixture is cooled to 0° C., and the precipitate formed is filtered and then dried, yielding 30 g of the expected compound of 98% purity. Recrystallisation of that compound from a mixture of isopropanol and water yields the pure product, m.p.: 215°-218° C.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1N2CN3CN(C2)C[N:12]1C3.C(Cl)(Cl)[Cl:22]>>[ClH:22].[NH2:12][CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CBr)C1CCCCC1
Reactant: ClC(Cl)Cl
Reactant: C1N2CN3CN1CN(C2)C3
Product: Cl
Product: NCC(=O)C1CCCCC1
Temperature: 48 °C
Yield: 80 %

Procedure:
According to M6, 2.7 g (13.2 mmol) of 2-bromo-1-cyclohexylethanone (Tetrahedron, 48, 1, 67-78, 1992) are mixed with 1.92 g (13.7 mmol) of hexamethylenetetramine in 20 ml of chloroform. The mixture is heated at 48° C. for 4 hours and then evaporated to dryness. The residue is taken up in 20 ml of ethanol and 9 ml of 36% hydrochloric acid. After leaving overnight at room temperature, the reaction medium is filtered. The filtrate is evaporated to dryness to give an oil which is crystallized from diethyl ether. After filtration and drying, 2.08 g (80%) of 2-amino-1-cyclohexylethanone hydrochloride are obtained in the form of a paste.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1C.[H][H].[CH:15]1C=CC=CC=1>>[CH3:15][C:7]1[CH:6]=[CH:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH:8]=1
Reactant: c1ccccc1
Reactant: Cc1ccc2ccccc2c1C
Reactant: [H][H]
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
A method for isomerizing dimethylnaphthalene (DMN) in the gaseous phase in the presence of a solvent comprising an aromatic hydrocarbon having a boiling point of at most 150° C., e.g., benzene, under atmospheric pressure by using a catalyst comprising a hydrogen-form of mordenite. According to the method, the objective 2,6-DMN can be produced with a minimal content of impurities and the 2,6-DMN can be stably produced in high selectivity and high yield under mild reaction conditions for a long period of time, while suppressing side reactions.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1)(=O)[CH3:2].[BH4-].[Na+].[OH2:13]>CO>[OH:13][CH2:2][CH:1]=[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][NH:5]1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC=C1C=CC(Br)=CN1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
2-acetyl-5-bromopyridine (1 g, 5.0 mmol) (Bioorg. Med. Chem., 13, 2005, 6763-6770.) is dissolved in methanol (10 mL), and stir at room temperature. NaBH4 (0.57 g, 15 mmol) is added in batches and stir at room temperature for 10 minutes. TLC (petroleum ether/ethyl acetate=10:1) is used to monitor the reaction. Once the reaction is completed, add water (15 mL) into the reaction solution, and stir for 0.5 hours. After that, methanol is evaporated, extract with dichloromethane (25 mL×3), merge the organic phases, followed by anhydrous Na2SO4 drying and filtering. The solvent is evaporated to obtain 0.93 g of oily liquid (Compound 42-A). The yield is 91.9%.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](=O)([O-:39])[O:15][CH:16](C1C=CC=CN=1)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1.[F:41][C:42]([F:67])([F:66])[C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([N:1]([C:52]1[CH:51]=[CH:50][C:49]([C:46]2[CH:45]=[CH:44][C:43]([C:42]([F:41])([F:66])[F:67])=[CH:48][CH:47]=2)=[CH:54][CH:53]=1)[C:14]([O:15][CH3:16])=[O:39])[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])OC(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccccn1
Reactant: Cc1c(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccn(C(=O)[O-])c1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h

Procedure:
To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHCO3 (0.067 g, 0.8 mmol) in H2O (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M−NH4]+; (ESI) m/z: 396 [M−H]−. 1H NMR (DMSO-d6): δ 1.11 (d, J=6.4 Hz, 3H), 3.97 (dd, J=3.5, 8.9 Hz, 1H), 4.05-4.12 (dq, J=3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 12.59 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc(Br)c1
Product: O=C(Nc1cccc(Br)c1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 84.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol)according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.96 g, 87%). EI-MS m/z 350(M-H)-
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][CH:12]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH3:26])[CH2:13][CH:14]([OH:20])[C:15]#[C:16][CH:17]([OH:19])[CH3:18]>C(O)C.[Pd]>[CH3:11][CH:12]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH3:26])[CH2:13][CH:14]([OH:20])[CH2:15][CH2:16][CH:17]([OH:19])[CH3:18]
Reactant: CCC/C=C\CC(C)CC(O)C#CC(C)O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCC/C=C\CC(C)CC(O)CCC(C)O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
At room temp., 550 mg (0.516 mmol) of 10% palladium on barium sulphate and 200 mg (1.55 mmol) of quinoline were added to a stirred solution of 7.60 g (33.9 mmol) of this (9Z)-7-methyltridec-9-en-3-yne-2,5-diol in 170 mL of ethanol. The flask was evacuated and flushed with nitrogen three times, and three times evacuated and flushed with hydrogen. The resulting reaction mixture was then stirred for 2 h under an atmosphere of hydrogen at ambient pressure and temperature, prior to evacuation and ventilation with nitrogen. The reaction flask was opened to air, and the catalyst filtered off by suction over a pad of Celite. After removal of the solvent in a rotary evaporator under reduced pressure, the resulting crude product (6.87 g) was purified by flash chromatography (100 g of silica gel, pentane/ether, 1:1, Rf=0.10) to afford 6.15 g (80%) of (9Z)-7-methyltrideca-9-ene-2,5-diol as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][NH:14][CH3:15].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CC#N>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:14]([CH3:15])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.4 %

Procedure:
A mixture of 4-acetylbenzoic acid (40 g, 244 mmol), 40% aqueous dimethylamine (33.0 g, 292 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.1 g, 292 mmol), 1-hydroxybenzotriazole hydrate (44.8 g, 292 mmol) and N,N-diisopropylethylamine (85 mL, 487 mmol) in CH3CN (400 mL) was stirred at room temperature for 15 h then concentrated. The residue was dissolved in ethyl acetate (1000 mL), washed with H2O (2×200 mL), brine (200 mL), dried (MgSO4) and concentrated to provide 4-acetyl-N,N-dimethylbenzamide (24 g). The crude product was taken to the next step without purification.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: O=C(Cl)C1CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NC(=O)C3CC3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate B-1, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with cyclopropanecarbonyl chloride gave the title compound as a light yellow solid. MS: 376.5 (M+H+).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: OCCNCCO
Reactant: Fc1ccc(CCl)cc1
Product: OCCN(CCO)Cc1ccc(F)cc1

Procedure:
2-[(4-Fluoro-benzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (15.7 g, 150 mmol), and 4-fluoro-benzyl chloride (14.4 g, 100 mmol) 20 g of the product was isolated. Yield 20 g, (93%%); yellow oil; MS: 215 (M+)+.
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCCl.CN(C1C=CN=CC=1)C>[F:36][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:43](=[O:45])[CH3:44])=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(NCc3ccccc3)nc2)cc1OC(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N(Cc1ccccc1)c1ccc(C(Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cn1
Reaction time: 24 h
Yield: 26.9 %

Procedure:
To a solution of 4-(2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(benzylamino)3-pyridyl]ethyl)pyridine from Example 1 (100 mg, 0.2 mmol) in 3 mL of 1,2-dichloroethane, was added 0.077 mL (0.96 mmol) of pyridine followed by 0.012 mg (0.1 mmol) of DMAP and 0.056 mL (0.6 mmol) of acetic anhydride. The solution was stirred 24 h at reflux, quenched with water and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/ethyl acetate) to afford 29 mg (27%) of the acetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (Aldrich) (1.45 g, 8.90 mmol), 4-methoxybenzylamine (Alfa Aesar) (1.278 mL, 9.78 mmol), and triethylamine (1.488 mL, 10.67 mmol) in DMF (10.0 mL) was stirred at 25° C. for 18 h. The resulting mixture was partitioned between EtOAc (300 mL) and half-saturated aqueous NaHCO3 (80 mL). The organic layer was separated, sequentially washed with water (2×80 mL) and brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 120 g, 0 to 100% EtOAc/Hexanes) furnished 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.30 g, 8.72 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.41 Hz, 2H); 6.89 (d, J=8.61 Hz, 2H); 6.18 (s, 1H); 4.42 (br. s., 2H); 3.81 (s, 3H); 2.50 (s, 3H). m/z (ESI, +ve ion) 264.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:28]([F:30])[F:29]>CN(C=O)C.C(OCC)(=O)C>[F:29][CH:28]([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:8][CH:9]=1
Reactant: FC(F)Cl
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)F)cc1

Procedure:
A solution of Step 1 intermediate, Intermediate 10 (400 mg, 1.548 mmol) in DMF (15 ml) was treated with Cs2CO3 (1.513 g, 4.645 mmol) slowly at room temperature. The reaction temperature was raised to 80° C. at which the chloro-difluoro-methane (ClCHF2) gas was passed into the reaction mixture till TLC indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and purified using column chromatography to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 2.20 (s, 3H), 7.18-7.22 (m, 2H), 7.25 (s, 1H), 7.37-7.40 (m, 2H), 7.55 (d, J=5.1 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 309.45 (M+H)+.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]2(O)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.CO>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3c4c(cccc24)CC3)CC1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1cc2c3c(ccc(C4CCNCC4)c3c1)CC2
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate (0.44 g, 1.24 mmol) in dichloromethane (4 mL) was added triethylsilane (1.10 mL, 6.22 mmol) under nitrogen. The mixture was cooled to −30° C. then trifluoroacetic acid (0.48 mL, 6.22 mmol) added dropwise, maintaining the temperature below −25° C. After 2.5 h, the reaction mixture was allowed to warm to 0° C. and additional trifluoroacetic acid (0.48 mL, 6.22 mmol) added over 5 min. The reaction mixture was allowed to warm to room temperature and left to stir for 3 days. Ice was then added to the reaction mixture, followed by potassium hydroxide to a pH of 14, and the resultant slurry extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to yield a yellow oil. The oil was dissolved in methanol and loaded onto an SCX-2 column. The column was washed with methanol, then a 2N solution of ammonia in methanol. Concentration in vacuo of the ammonia solution yielded 4-(1,2-dihydro-5-acenaphthylenyl)piperidine as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:4]1([CH3:14])[CH:10]2[CH2:11][C:7]([CH3:12])([CH2:8][CH2:9]2)[CH2:6][C:5]1=[O:13])[CH:2]=[CH2:3].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH3:14])[CH:10]2[CH2:11][C:7]([CH3:12])([CH2:8][CH2:9]2)[CH2:6][CH:5]1[OH:13])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C(=O)CC2(C)CCC1C2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCC1(C)C(O)CC2(C)CCC1C2
Temperature: 75 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-Allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-one (288 g, 1.5 mol, obtained as above in EXAMPLE IV) was added to a solution of Red-Al (65%, 506 g, 1.5 mol) in toluene at 75° C. The reaction mixture was aged for 3 hours while the temperature was maintained at 75° C., then cooled to room temperature, and subsequently quenched with a solution of sodium bicarbonate (NaHCO3). Distillation of the organic layer provided 4-allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-ol (288 g, 1.5 mol), which was then added to a MSA solution (30 g) in toluene (500 mL) and heated to reflux for 3 hours. The reaction mixture was subsequently washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 2,4,8-trimethyl-5-oxa-tricyclo[6.2.1.0*2,6*]undecane (170 g) having a boiling point of 62° C. at a pressure of 0.3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[NH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]1=[O:20])[CH3:27]
Reactant: O=c1[nH]cc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O

Procedure:
650 mg (2.15 mmol) of 5-(5-chloro-2-thienyl)-1-(2-fluorobenzyl)-1,3-dihydro-2H-imidazol-2-one from Example 236A, 516 mg (4.21 mmol) of ethyl chloroacetate and 582 mg (4.21 mmol) of potassium carbonate are stirred in 12 ml acetonitrile for 7 hrs at 80° C. The reaction solution is diluted with ethyl acetate and washed three times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtration from the drying agent, the filtrate is concentrated in vacuo. After purification by flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate first 5:1, then 1:1), 610 mg (74% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncc(Br)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ncc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 94.2 %

Procedure:
The title compound (0.51 g, 94%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.30 g, 1.45 mmol), 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate (0.45 g, 1.21 mmol), 2M Na2CO3 (7 mL) and Pd(PPh3)4 (15 mg, 0.013 mmol) in DME (7 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.92 (s, 2H), 8.06 (d, 2H, J=8.3 Hz), 7.92 (d, 2H, J=8.5 Hz), 4.33 (d, 2H, J=6.6 Hz), 4.20-4.10 (m, 2H), 3.15 (s, 3H), 2.90-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 448 (M+H).