Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]1
Reactant: CC(C)Br
Reactant: COCC1(Nc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Yield: 42.6 %

Procedure:
A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamine and 72 parts of N,N-dimethylacetamide is stirred and refluxed for 10.25 hours. After cooling, the formed N,N-diethylethanamine hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:22]2[NH:21][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 30.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-trifluoromethylphenyl)-3-oxopropionate (15.0 g) and 1-aminomethylnaphthalene (9.6 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-(4-trifluoromethyl-phenyl)imidazole-4-carboxylate (6.4 g). 5.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (30 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-(4-trifluoromethylphenyl)imidazole-4-carboxyic acid (3.4 g), melting point 166° C. (decomposition).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[O:8]1[CH:12]2[CH:11]=[CH:10][CH:9]1[CH:2]1[CH:3]2[C:4](=[O:5])[O:6][C:1]1=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(O3)C12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Protected-maleimide functional initiator was synthesized by following literature.4 Maleic anhydride (10.0 g, 0.1 mol) was suspended in 30 mL of toluene and the mixture warmed to 80° C. Furan (11.3 mL, 0.15 mol) was added via syringe and the turbid solution was stirred for overnight. The mixture was then cooled to ambient temperature white solids formed during standing were collected by filtration and washed with 2×30 mL of diethyl ether afforded 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (1) as white needless. Yield: 12.35 g (74%). 1H NMR (500 MHz, CDCl3, δ) 6.55 (s, 2H, CH═CH, bridge protons), 5.45 (s, 2H, —CHO, bridge-head protons), 3.15 (s, 2H, CH—CH, bridge protons). 13C NMR (CDCl3, δ): 169.9, 137.0, 82.2, 48.7.
Reaction SMILES: Cl[CH2:2][Si:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH:6]=[CH2:7])[CH:4]=[CH2:5].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[K]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:4]([Si:3]([CH:6]=[CH2:7])([CH2:2][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[CH2:5]
Reactant: c1c[nH]cn1
Reactant: C=C[Si](C=C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: C=C[Si](C=C)(Cn1ccnc1)c1ccc(-c2ccccc2)cc1

Procedure:
To a solution of 1.14 g (0.004 mol) of chloromethyl(4-phenylphenyl)divinylsilane in 10 ml of toluene is added 0.54 g (0.005 mol) of potassium imidazole and 0.05 g of tetrabutylammonium bromide. The mixture is refluxed under nitrogen for two days, cooled, diluted with ether-hexanes, and washed with water and brine. Removal of solvent gives an oil which is purified by silica gel chromatography, eluting with 9:1 dichloromethane-ether, to give the title compound.
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5].P(Cl)(Cl)([Cl:25])=O>>[CH3:2][O:3][C:4]([C:6]1[C:7]([Cl:25])=[N:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5]
Reactant: COC(=O)c1c(CCl)c2cc3c(cc2[nH]c1=O)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (Intermediate 5, 360 g, 1.16 mol), as a suspension in phosphorus oxychloride (1.8 kg). The mixture is heated to reflux generating a black solution. After being heated at reflux for 20 h, the reaction mixture is allowed to cool to ambient temperature and transferred to a 25-L separatory funnel containing 18 L of ice water. After being stirred vigorously.for 1.5 h, the precipitate is collected on a Buchner funnel, washed with water (3 L) and dried in vacuo. at 50° C. yielding 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a dark crystalline solid: mp 130-132° C. 1H NMR (CDCl3, 200 MHz) d 4.05 (s, 3H), 4.42 (s, 4H), 4.81 (s, 2H), 7.50 (s, 2H). Elemental analysis: Calculated for C14H11Cl2NO4: C 51.24, H 3.38, N 4.27. Found: C 51.10, H 3.34, N 4.33.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1>COCCOC.O.CCO>[Cl:37][C:38]1[CH:43]=[C:42]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9](=[O:14])[CH:8]=[C:7]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Reactant: OB(O)c1cccc(Cl)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(-c3cccc(Cl)c3)ccc2o1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (about 1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). 3-Chlorophenyl boronic acid (6.3 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 3 mg (11%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 469 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.84-1.91 (m, 2H), 2.25 (br d, 2H), 3.16-3.23 (m, 2H), 3.61 (br d, 2H), 3.84-4.01 (m, 3H), 5.43 (s, 1H), 6.37-6.43 (m, 1H), 6.89 (d, 1H), 7.34-7.94 (m. 12H), 8.41 (d, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16](Cl)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:19]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20].C1(C)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)C.C(Cl)Cl>[C:19]([C:23]1([OH:29])[CH2:24][CH2:25][N:26]([C:16]([CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)=[O:17])[CH2:27][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C1(O)CCNCC1
Reactant: O=C(Cl)C1c2ccccc2CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)C1(O)CCN(C(=O)C2c3ccccc3CCc3ccccc32)CC1
Reaction time: 24 h

Procedure:
3 Parts of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carboxylic acid chloride and 1.75 part of 4-tert-butyl-4-piperidinol are admixed in 15 parts by volume of toluene and then 1.5 part of triethylamine is added. The resultant mixture is stirred, at 75° C. under a nitrogen atmosphere for about 1.5 hour and then 5 parts by volume of methylene chloride is added. The mixture is stirred for about 24 hours, and then concentrated on a rotary evaporator to give a tan solid. The solid is redissolved in chloroform, washed with 1 N hydrochloric acid twice, saturated sodium bicarbonate solution, and brine, dried with magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil upon trituration with ethyl ether, affords 4-tert-butyl-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]-4-piperidinol, as a white solid, melting at about 189°-190.5° C. after recrystallization from cyclohexane. This compound is represented by the following structural formula ##STR26##
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].CN(C=O)C.OOS([O-])=O.[K+].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>O>[CH3:8][NH:7][C:5]([C:4]1[C:3]2[N:12]([CH3:13])[C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:1][C:2]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=Cc1cccnc1
Reactant: CNC(=O)c1cccc(N)c1NC
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cccc2nc(-c3cccnc3)n(C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-amino-N-methyl-2-(methyl-amino) benzamide (18; 0.2 g, 0.0011 mol) in the mixture of DMF (5 ml) and water (1 ml) was added OXONE® (0.81 g, 0.0013 mol) and followed by nicotinaldehyde (0.13 g, 0.00122 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated on a high vacuo pump and purified by column chromatography on silica gel to afford the desired product N,1-dimethyl-2-(pyridin-3-yl)-1H-benzimidazole-7-carboxamide as brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.0 (s, 1H), 8.76-8.75 (d, J=4.0 Hz, 1H), 8.59 (bs, 1H), 8.25-8.23 (d, J=7.6 Hz, 1H), 7.81-7.8 (d, J=7.6 Hz, 1H), 7.64-7.61 (m, 1H), 7.35-7.27 (m, 2H), 3.79 (s, 3H), 2.85-2.84 (d, J=4.4 Hz, 3H). LCMS (ES) m/e MS (M+1-267) Purity: 98.5%.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([N:18]([CH2:22][CH:23]=[CH2:24])[C:19](=[O:21])[CH3:20])=[C:6](Br)[CH:5]=1)(=[O:3])[CH3:2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC#N.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([N:18]1[C:7]2[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[C:23]([CH3:24])=[CH:22]1)(=[O:21])[CH3:20]
Reactant: C=CCN(C(C)=O)c1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(C)cn(C(C)=O)c2cc1OCc1ccccc1
Yield: 53.4 %

Procedure:
A solution of N-(4-acetyl-5-benzyloxy-2-bromo-phenyl)-N-allyl-acetamide (0.662 g, 1.65 mmol), P(o-tolyl)3 (0.028 g, 0.092 mmol) and triethylamine (0.34 ml, 2.24 mmol) in MeCN (15 ml) was flushed with nitrogen, followed by the addition of a Pd(OAc)2 (0.005 g). The reaction was microwaved for 500 sec. at 150° C. The crude mixture was diluted with EtOAc, washed with water and dried over MgSO4. Purification by column chromatography in hexane/EtOAc (1:1) afforded (0.283 g, 54%) a cream solid. LC/MS: RT=2.742 min. 322 (MH+), 344 (MNa+), 280 (MH+-Ac).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1)[CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccc(OB(O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in methylene chloride (15 ml) was added 4-(2-propoxyethoxy)phenylboric acid (0.67 g) and molecular sieves 4A (0.8 g), and the resulting mixture was stirred for 5 minutes. To the reaction mixture were added cupric acetate (0.27 g) and triethylamine (1.04 ml), and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. The resulting solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.23 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([OH:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][N:6]1[CH2:5][CH2:4][C:3]([C:2]([F:1])([F:10])[F:11])([OH:9])[CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: OC1(C(F)(F)F)CCNCC1
Product: OC1(C(F)(F)F)CCN(CCCCl)CC1

Procedure:
A solution of 4-(trifluoromethyl)piperidin-4-ol and 1-bromo-3-chloropropane are reacted using the procedure for Example OO to afford 1-(3-chloropropyl)-4-(trifluoromethyl)piperidin-4-ol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:29][CH3:30]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:29][CH3:30])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCI
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OCC
Yield: 77.7 %

Procedure:
A mixture of 7.8 g (0.0246 mol) of product of Example 35, 3.5 g of K2CO3, 20 g of iodoethane, and 100 ml of acetone was held at reflux for 2 days and concentrated. The reaction mixture was treated with 150 ml of water and extracted with 200 ml of ether. The ether extract was dried and concentrated. The residual solid (7.5 g) was recrystallized from hexane at low temperature to give 6.6 g (77.7%) of product; mp 72.5°-74° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:15][CH:16]([C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[OH:17])[C:11](=[O:14])[CH2:12]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1>[CH2:3]([N:10]1[C:11](=[O:14])[CH2:12][O:17][CH:16]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C(O)CN(Cc2ccccc2)C(=O)CCl)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C2CN(Cc3ccccc3)C(=O)CO2)OCCO1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.75 g) in tetrahydrofuran (50 ml) was added a solution of 2-[2-(N-benzyl-N-chloroacetylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (5.35 g) in tetrahydrofuran (15 ml) under ice-cooling. The mixture was heated under reflux for 4 hours and poured into a mixture of ice-water (100 ml) and ethyl acetate (150 ml). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of hexane and ethyl acetate (7:3, V/V) to give 4-benzyl-2-(2-methyl-1,3-dioxolan-2-yl)-5-oxomorpholine (4.65 g) as a syrup.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:67][CH:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: NC1CCCCC1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (302 mg, 0.81 mmol), HATU (343 mg, 0.90 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Cyclohexylamine (0.105 mL, 0.92 mmol) was then added and stirring continued at room temperature for 17 hours. LC-MS indicated abot 50% conversion so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (343 mg, 0.90 mmol) were added. After about 10 minutes more cyclohexylamine (0.105 mL, 0.92 mmol) was added, and the mixture was stirred for an additional 1.5 hours, then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 10-40% EtOAc in hexanes gradient) to give the title compound (328 mg) as a yellow oil. LC-MS (ES) m/z=453 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([Cl:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (677 mg), 2,6-dichloro-4-nitrophenol (700 mg) and triphenylphosphine (1150 mg) in dichloromethane (40 ml) was added dropwise diethyl azodicarboxylate (0.67 ml) in an ice bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=6/1 as an eluant to give the desired compound (950 mg, yield 72%) as a colorless solid.
Reaction SMILES: C(OCC)(=[O:3])C.[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=2[CH:20]=1)[CH3:8].C1(CCCC2C=C[N+]([O-])=CC=2)C=CC=CC=1.Cl[O-].[Na+]>>[O:3]1[C@H:14]2[C@@H:15]1[C:16]([CH3:19])([CH3:18])[O:17][C:12]1[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:20][C:13]=12
Reactant: CCOC(C)=O
Reactant: CCc1ccc2c(c1)C=CC(C)(C)O2
Agent: [Na+]
Agent: [O-]Cl
Agent: [O-][n+]1ccc(CCCc2ccccc2)cc1
Product: CCc1ccc2c(c1)[C@H]1O[C@H]1C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution (2 mL) of ethyl acetate containing 100 mg (0.53 mmol) of 6-ethyl-2,2-dimethyl-2H-1-benzopyran (synthesized according to the method described in Jananese Patent Application Laid-open No. Sho 62-273972), salen manganese complex (17 mg, 0.016 mmol), 4-(3-phenylpropyl)-pyridineoxide) (12 mg, 0.053 mmol) and aqueous sodium hypochlorite solution (0.96 g, 1.14 Kg/mol, 1.1 mmol) were added at room temperature, and stirred for two hours at room temperature. After Celite filtration upon addition of water, organic phase was separated, washed with aqueous saturated sodium chloride solution, and dried over anhydride sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (chloroform) to obtain 75 mg of the intended compound in brown oily substance (Yield 69%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36](F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:40](OC1C=CC(B(O)O)=CC=1)C>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:40])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@]4(C)COC(=O)N4)ccc23)cc1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 70% yield using 4-(ethoxy)phenylboronic acid as the reagent.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:41][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:39])[CH3:40])=[CH:36][CH:37]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(N)c1ccc(F)cc1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccc(F)cc1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-fluorophenyl)-1-methylethylamine (prepared as described in Preparation 10f) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CI.CC(C)([O-])C.[K+]>C1COCC1.[NH4+].[Cl-]>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cc(Br)c2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (8-bromo-quinolin-6-yl)-acetonitrile from Step 1 (1.0 eq) in THF (0.12M) at −78° C., was added MeI (2.3 eq) followed by potassium t-butoxide (2.3 eq). After 2 h at −78° C., the resulting mixture was warmed to 0° C. and was poured in saturated aqueous NH4Cl, then extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc, 3:1) afforded the title compound as a white solid.