Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(O[Cl:15])(C)(C)C>C(Cl)Cl>[Cl:15][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Cl)c1
Yield: 31.3 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. The solution, stirred under nitrogen, was cooled in an ice-water bath while t-butylhypochlorite (1.95 g., 18 mmoles) in 25 ml. of methylene chloride was added dropwise. The reaction was stirred for 1 hour at room temperature, filtered and evaporated to an oil. The oil was chromatographed (100 g. silica gel with ethyl acetate-1/hexane-7 as eluant). The column elution was monitored by thin layer chromatography (silica gel plates with chloroform-8/ethyl acetate-2 as eluant). Cuts containing pure product (Rf 0.4) were combined and evaporated to yield crystalline methyl 5-chloropyrrole-3-carboxylate (900 mg., m.p. 92°.95° C., m/e 159/161).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 97.6 %

Procedure:
In a manner similar to that of Example 1(g), starting with 700 mg (1.8 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]carbamate in 10 ml of dioxane, 700 mg (60%) of the desired product, with a melting point of 158° C., are obtained.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>P([O-])([O-])([O-])=O>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
The activity of the MIase was measured by the following method. First, 200 μl of an enzyme solution that had been diluted as appropriate was added to 200 μl of 200 mM mannose solution dissolved in a 100 mM phosphate buffer (pH7.0), and an enzyme reaction was performed at 50° C. Then, the enzyme reaction was stopped by boiling for 10 minutes, and the composition of the saccharide was analyzed by HPLC. The amount of the enzymes that produce 1 μmol of fructose for 1 minute under these conditions was defined as one unit.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2Cl)=N/O)ccc1=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(F)cc2Cl)=N/O)ccc1=O

Procedure:
The title compound was prepared in analogy to example 166, from (E)-5-{3-(4-bromo-phenyl)-3-(2-chloro-4-fluoro-phenyl)-1-(hydroxyimino)-propyl}-1-methyl-1H-pyridin-2-one (example 410) and 4-carboxyphenylboronic acid (CAS RN 14047-29-1). The compound was purified by silica gel chromatography using a MPLC system eluting with a gradient of dichlormethane:methanol (100:0 to 90:10). The resulting yellow solid was purified by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (10:90 to 95:5) followed by another preparative HPLC purification (Reprosil Chiral-NR column) using 80% n-heptane:20% EtOH (containing 0.5% formic acid) as eluant to give the desired compound as a colourless solid, MS (ESI+): m/z=505.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH2:13]([OH:19])[CH2:14][O:15][CH2:16]CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:19][CH2:13][CH2:14][O:15][CH2:16][CH2:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCOCCO)c1ccc(O)c(Cl)c1
Yield: 70.1 %

Procedure:
A 500-ml eggplant type flask was charged with 50 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 285 g of diethyleneglycol and further with 2.5 g of PTS (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was heated with stirring on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. Thereafter, excess diethylene glycol therein was removed by means of vacuum distillation. The residue therein was poured into ice water and the precipitated crystals were recrystallized using benzene/ethanol to obtain 49 g of 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]-ester (melting point: 77.5° to 78° C.). To 100 ml of an acetonitrile solution containing 30 g of the 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]ester, 57.2 g of N-methylpyrrolidone and further 36 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred for 8 hours at 40° C. to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water, and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethyl acetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid [2-(2-methacryloyloxyethoxy)ethyl]ester (melting point: 57° to 58.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11].C(O)C>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:11][CH3:10])=[CH:6][CH:7]=1
Reactant: CN
Reactant: ClCc1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: CNCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
A mixture of the product of Example 4(b), 2-chloro-5-chloromethylpyridine, (8.1 g, 0.05 mol), methylamine (60 ml of a 30% w/v solution in water, 0.5 mol) and ethanol (100 ml) was heated, with stirring, under reflux for 5 hours. The reaction mixture was then cooled to ambient temperature (20° C.) and the solvent removed by evaporation under reduced pressure to give a brown oil. The product, N-(6-chloro-3-pyridylmethyl)-N-methylamine, was isolated from this oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v methanol/dichloromethane as eluent, as a brown oil (5.96 g, 76.1%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:38])=[N:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:38])=[N:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(OC2CCOCC2)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1nc(OC2CCOCC2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-bromo-2-methyl-6-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 15) in analogy to Example 1a): MS (ISN): 493.1 and 495.3 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[NH:16][C@@H:15]([CH3:20])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[I:36])[CH2:32][CH2:31][CH2:30]2>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][C:35]=3[I:36])[CH2:32][CH2:31][CH2:30]4)[C@@H:15]([CH3:20])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Reactant: BrCc1cc2c(cc1I)CCC2
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 104 mg; 0.318 mmol) was treated with sodium hydride (60% in oil; 11.9 mg; 0.297 mmol) and 5-(bromomethyl)-6-iodoindane (Intermediate 24; 100 mg; 0.297 mmol) as described for Intermediate 23 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=583.8 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.90 (s, 2H), 7.87 (s, 1H), 7.72 (s, 1H), 7.19 (s, 1H), 5.43 (dd, J=11.8, 1.7 Hz, 1H), 4.96 (d, J=15-8 Hz, 1H), 4.47 (d, J=16 Hz, 1H), 3.69-3.62 (m, 1H), 2.90-2.86 (m, 4H), 2.43-2.38 (m, 1H), 2.12-2.05 (m, 2H), 2.00-1.92 (m, 1H), 1.25 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.O>C(O)C>[CH2:20]([O:19][CH2:18][C:13]1[N:14]([CH2:15][CH2:16][CH3:17])[C:10]2[C:9]3[CH:8]=[C:7]([O:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:21]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate (prepared as described in Example 410, 2.9 g, 6.0 mmol) and 4 M ethanolic hydrogen chloride (15 mL) in ethanol (20 mL) was heated at reflux for 2 hours. The solution was allowed to cool to ambient temperature and was concentrated under reduced pressure to approximately 17 mL, causing a solid to form. Water was added to dissolve the solid and the remainder of the ethanol was evaporated under reduced pressure. The aqueous solution was adjusted to approximately pH 13 with 50% aqueous sodium hydroxide, then was extracted with chloroform. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was recrystallization from acetonitrile to yield 1.25 g of 2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles, mp 176-178° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]([O:20]C)=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[O:6][CH2:5][CH2:4][O:3]1.CO.[OH-].[K+].Cl>O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:11][CH2:12][C:13]([C:18]([OH:20])=[O:19])([CH2:16][CH2:17]2)[CH2:14][CH2:15]3)[O:6][CH2:5][CH2:4][O:3]1
Reactant: COC(=O)C12CCC(CCCC3(C)OCCO3)(CC1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CCCC23CCC(C(=O)O)(CC2)CC3)OCCO1

Procedure:
Methyl 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate (4-C) (1.0 g, 3.38 mmol) was stirred in a solution of 90% methanol and 10% water (50 mL). Excess potassium hydroxide (2.0 g) was added. The mixture was refluxed overnight. The cooled mixture was acidified with 1N hydrochloric acid (100 mL) and then washed twice with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4). Ethyl acetate was removed in vacuo yielding pure 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (4-D).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: CN(C)CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(C=NCCCN(C)C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 104 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g), N,N-dimethyltrimethylenediamine (306.6 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 4.5 hours. The resultant solution was washed with water and dried. The solvent was removed from the solution to give brown oil (1.4748 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-[3-(N,N-dimethylamino)propyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH3:11])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C.C1CCCCC=1>[CH:21]([O:20][P:14]([CH2:13][O:12][C@@H:10]([CH3:11])[CH2:9][OH:8])([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])([CH3:22])[CH3:23]
Reactant: CC(C)OP(=O)(CO[C@@H](C)COCc1ccccc1)OC(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)OP(=O)(CO[C@@H](C)CO)OC(C)C
Yield: 104.1 %

Procedure:
A solution of (S)-1-O-benzyl-2-O-[(diisopropylphosphono)methyl]-1,2-propanediol (8.20 g, 23.8 mmol) in 1:1 ethanol/cyclohexene (80 mL) was treated with 20% palladium hydroxide on carbon (4.0 g), and the mixture was heated at reflux for 18 hours. The reaction mixture was then filtered through a 1" pad of Celite, and the filtrate was concentrated in vacuo to give 6.3 g of the title compound as a clear, colorless oil which was used in the following reaction without purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[C:7](=[O:21])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=[CH:10][C:11]=1Br>CN(C)C=O>[N:1]([C:11]1[CH:10]=[CH:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:7](=[O:21])[C:6]=1[Br:5])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(Br)c(Br)ccn1Cc1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Temperature: 60 °C
Yield: 98 %

Procedure:
Sodium azide (1.08 g, 16.62 mmol) was suspended in N,N-dimethylformamide (10 mL) and a stock solution of 3,4-dibromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 1) in N,N-dimethylformamide (33.0 mL, 0.33 M) was added and the resulting mixture was heated to 60° C. for 4 hours. Ice water (30 mL) was added and the aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organics were washed with H2O (3×50 mL), brine (2×25 mL), dried over MgSO4, concentrated, and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford an off-white solid (3.50 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (820 mg) in THF (12 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 7.0 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (850 mg). A solution of 4 N hydrochloric acid in ethyl acetate (25 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (2.45 g) in ethyl acetate (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (150 mg) was added to a solution of the residue in methanol (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.25 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][CH:2]([Br:23])[C:3](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].C1CCN2C(=NCCC2)CC1>CS(C)=O>[Br:23][C:2]([Br:1])=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CC(Br)(c1ccccc1)C(Br)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(=C(Br)Br)c1ccccc1
Yield: 69.4 %

Procedure:
A solution of 1,1,2-tribromo-2-phenyl-3-phthalimidopropane (1.22 g) and DBU (0.50 g) in DMSO (50 ml) is heated at 85° for 4 hours. Work-up as described in Example 19 C gives 1,1-dibromo-2-phenyl-3-phthalimidopropene (0.71 g): colorless needles; m.p. 154°-155°;
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Br:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCN(c2cccc(Br)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.9 %

Procedure:
1M NaOH aq. (2 mL) was added to a solution of methyl 1-(3-bromophenyl)pyrrolidine-3-carboxylate in THF-MeOH (1 mL-1 mL). After stirring the mixture at room temperature for 13 hours, the mixture was concentrated. The residue was diluted with 1M NaOH aq. and washed with ether. The aqueous layer was acidified with 1M HCl aq. and extracted with DCM (3×). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford desired product (293 mg, 83.9%) as yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]=[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCN(CC2CCC=C(c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)methyl]cyclohexanone (Example A) (5.9 g) in 400 mL of tetrahydrofuran is added a solution of phenylmagnesium bromide (9.13 mL, 3.0M in diethyl ether), dropwise under nitrogen, at 0° C. The mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and quenched with 250 mL of 10% aqueous hydrochloric acid solution. The solvent is evaporated in vacuo and the residue partitioned into chloroform/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate and filtered. The filtrate is treated with trifluoroacetic acid (4.2 mL) and stirred overnight at room temperature. The solvent is evaporated in vacuo, and the residue is partitioned into ethyl acetate/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography to give 3.9 g of (±) -1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine; mp 90°-95° C. as an off-white solid (Example 1) and 2.7 g of (±)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]pyridine; mp 124°-126° C. as a tan solid (Example 1a).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O:17][CH2:18][CH2:19]Br>>[CH3:16][O:17][CH2:18][CH2:19][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COCCBr
Reactant: COC(=O)c1ccc2ccccc2c1O
Product: COCCOc1c(C(=O)OC)ccc2ccccc12

Procedure:
By alkylating methyl 1-hydroxy-naphthalene-2-carboxylate analogously to Example 1 (g) with 2-bromoethyl methyl ether there was obtained methyl 1-(2-methoxy-ethoxy)-naphthalene-2-carboxylate, which was subsequently converted analogously to Example 5 (b)-(c) firstly into [1-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanol and then into 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene, which was finally obtained as a beige solid; MS: 250 (M)+.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:11](O)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(#N)C.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:12]2[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)C1CCc2ncnc(O)c21
Solvent: CC#N
Product: CC(C)C1CCc2ncnc(Cl)c21
Temperature: 80 °C
Yield: 26 %

Procedure:
A solution of 5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (4.29 g, 24.09 mmol) in acetonitrile (94.75 mL, 1814 mmol) was treated with POCl3 (6.62 mL, 72.28 mmol). The mixture was heated at 80° C. overnight. No reaction was observed by LC-MS or HPLC. An additional 3 equivalents of POCl3 were added, and the reaction was heated at 80° C. for 4 hours. The reaction was charged with an additional 10 equivalents of POCl3 and TEA (6.716 mL, 48.18 mmol) and heated at 80° C. overnight. The reaction was cooled to room temperature, and the solvent and POCl3 were removed under reduced pressure. The residue was taken up in DCM and was carefully added to stirring saturated NaHCO3. The mixture was stirred for 1 hour to confirm complete neutralization. The organics were combined and washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (25% EtOAc/Hexane) to yield 4-chloro-5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.23 g, 26%). LCMS (APCI+) m/z 196.9 [M+H]+; Rt=3.57 min