Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:6]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].[NH4+].[Cl-]>C1COCC1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cc(F)c(F)c(-n2cnc(I)c2)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)cc(F)c2F)cn1
Reaction time: 1.5 h

Procedure:
A solution of 4-iodo-1-(2,3,5-trifluorophenyl)-1H-imidazole (0.140 g, 0.43 mmol) in 2 mL of THF under Ar was chilled in an ice/water bath 5 min. Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.225 mL, 0.45 mmol) was added, the bath was removed, and the pale yellow solution was stirred for 1.5 h. Tributyltin chloride (0.055 mL, 0.20 mmol) was added all at once, and the pale yellow solution was stirred 1 h. A sat. aq. NH4Cl solution (10 mL) was added, and the mixture was extracted with two 10 mL portions of EtOAc. The combined organic layers were washed with 10 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to give 4-tributylstannanyl-1-(2,3,5-trifluoro-phenyl)-1H-imidazole as a yellow oil which was used without further purification.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.CN.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[N+:16]([CH3:19])([O-:18])=[O:17]>CO.CCCCCC.C(OC(=O)C)C>[N+:16]([CH:19]=[CH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)([O-:18])=[O:17]
Reactant: O=Cc1cccs1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: O=[N+]([O-])C=Cc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
Sodium acetate (3.6 g, 43.90 mmol) and methylamine hydrochloride (3.01 g, 44.57 mmol) were added to a stirred solution of thiophene-2-carbaldehyde (5 g, 44.64 mmol) in methanol (95.64 mL). This was followed by dropwise addition of nitro methane (108.08 g, 1770.14 mmol) over a period of 5 minutes. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was partitioned between water and DCM. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (5% ethylacetate in hexane) afforded 1 g of the product (15% yield).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH2:16]([C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:36])[CH:24]2[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:21]=1[C:37]([O:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:17]([CH3:19])=[O:18].[CH3:53][S:54](Cl)(=[O:56])=[O:55]>CCCCCC.O1CCCC1.C(OCC)(=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH:40]([O:39][C:37]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:20]=1[CH:16]=[C:17]([O:18][S:54]([CH3:53])(=[O:56])=[O:55])[CH3:19])[CH:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:23]2=[O:36])=[O:38])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: CS(=O)(=O)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)OS(C)(=O)=O
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A 1.6M solution of butyllithium in hexane (10.3 cc) is added, in the course of 10 minutes, to a solution of 2,2,6,6-tetramethylpiperidine (2.33 g) in tetrahydrofuran (15 cc) at 20° C. The mixture is stirred for 20 minutes at 20° C. and then cooled to -70° C. A solution of 3-acetonyl-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (7.61 g) in tetrahydrofuran (20 cc) is then added in the course of 15 minutes. The mixture is stirred for a further 20 minutes at -70° C. and hexamethylphosphorotriamide (15 cc) is then added in the course of 3 minutes, followed by a solution of methanesulphonyl chloride (4.5 cc) in tetrahydrofuran (10 cc) in the course of 3 minutes. The mixture is stirred for 45 minutes at -70° C., the temperature is then left to rise to 0° C. and the mixture is diluted with ethyl acetate (300 cc). The solution is washed successively with a saturated solution of sodium bicarbonate (100 cc) and distilled water (100 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (150 g) (diameter of the column: 3.7 cm; height: 30 cm). Elution is carried out with a 22/78 (by volume) ethyl acetate/cyclohexane mixture (2.5 liters), 100 cc fractions being collected. Fractions 12 to 20 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-mesyloxy-prop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.2 g) in the form of a hard, pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=C(N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Reaction time: 30 h

Procedure:
The crude methyl N-[(S)-1-(4-methoxyphenyl)ethyl]-3-amino-3-(3-pyridyl)propenoate, (40.6 g, 130 mmol) was dissolved in methanol (200 mL) and mixed with 20% Pd(OH)2/C (4.1 g). The mixture was hydrogenated under atmospheric pressure for 30 h. The mixture was diluted with ethyl acetate (50 mL) and filtered through celite (20 g) to remove the catalyst. The celite was washed with hot (70° C.) ethyl acetate(200 mL). The combined filtrate was concentrated under reduced pressure to near dryness to an oily residue. Crude amine (27.5 g) was dissolved in hot ethyl acetate (40 mL). The resulting hot yellow solution was filtered and rinsed with 15 mL of hot ethyl acetate. The clear solution was concentrated to <50 mL and allowed to stand at room temperature overnight. The resulting white crystalline solid was collected by filtration and washed with cold ethyl acetate (EtOAc) (˜15-20 mL), then air dried. Yield of isolated solid: 15.5 g. HPLC analysis showed >99% desired diastereomer. A second crop was obtained from the filtrate after concentration to about 20 mL. Yield: 1.7 g identical by HPLC to first crop; total yield: 17.2 g (62.5%)
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:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=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]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)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: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 90 °C
Yield: 64 %

Procedure:
[4-(Methylsulfonyl)phenyl]boronic acid (0.69 g, 3.40 mmol) was added to a solution of 4-bromophenol (0.5 g, 2.83 mmol) in DME (25 mL), followed by addition of 2M Na2CO3 (25 mL) and Pd(PPh3)4 (0.17 g, 0.14 mmol). The reaction mixture was heated at 90° C. for 3 h, then cooled to ambient temperature, and extracted with ether. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an off-white solid. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane to give 0.45 g (64%) of 4′-(methylsulfonyl)-4-biphenylol as a white solid. Alternatively, 4′-(methylsulfonyl)-4-biphenylol was prepared from 4-bromophenyl methyl sulfone (2 g, 8.5 mmol), (4-hydroxyphenyl)boronic acid (1.76 g, 12.75 mmol), 2M Na2CO3 (100 mL) and Pd(PPh3)4 (0.1 g, 0.08 mmol) in DME (100 mL) in a manner similar to the conditions above. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.6 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.92 (s, 1H), 3.08 (s, 3H); LRMS (ESI), m/z 249 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:30]([O-:32])=[O:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=[CH:33][C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:30]([O-:32])=[O:31])=[C:25]([CH:29]=1)[C:26]([N:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[S:5]1(=[O:15])=[O:16])=[O:27]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)c2ccccc2N(C(=O)c2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2[N+](=O)[O-])S1(=O)=O
Yield: 48 %

Procedure:
To a stirred solution of 3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide (2.4 g, 0.01 mole) and tricthylamine (1.1 g, 0.011 mole) in a mixture of toluene (100 ml) and chloroform (100 ml) was added 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole). The reaction was heated for 24 hours and then the solvent was removed. The residue was taken back up into chloroform and extracted three times with sodium hydroxide and finally with water. The organic solution was dried and evaporated to give 2.8 g of an oil which was triturated with petroleum ether to give a solid which was recrystallized from chloroform-petroleum ether to give a white solid, mp 125°-8° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[C:13]([O:17][C:18](=[O:21])[CH2:19][NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C.O>[C:13]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)(C)OC(=O)CN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)c1ccccc1N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of isatoic anhydride (25 g, 0.15 mol) in DMF (250 ml), glycine tert butyl ester (30.64 g, 0.18 mol) is added, followed by the dropwise addition of triethylamine (52 ml, 0.37 mol) over a period of 30 minutes. The resulting suspension is heated at 50° C. for 3 hours, 60° C. for 30 minutes, then at 70° C. for 30 minutes. The reaction mixture is then allowed to cool to RT and treated with water (300 ml). The resulting solution is stirred at RT for 30 minutes, diluted further with water (200 ml), and the product extracted with EtOAc (2×500 ml). The organic extracts are combined, washed with water (2×300 ml), brine (1×300 ml), dried (MgSO4), filtered, concentrated in vacuo, and dried under vacuum to give the title compound as a peachy white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[S:2]([OH:4])(=[O:13])(=[O:3])[CH3:1].[S:2]([OH:4])(=[O:13])(=[O:3])[CH3:1].[CH3:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13]
Reactant: CS(=O)(=O)Cl
Agent: Cc1cc(CCCO)cc(C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.2 g) in dichloromethane (2 ml) is added dropwise to an ice-cold solution of 3-(3,5-dimethyl-4-hydroxyphenyl)propanol (0.85 g) and triethylamine (1.6 ml) is methylene chloride (10 ml). The mixture is stirred for 0.5 hr and then diluted with an ice-cold aqueous solution of sodium bicarbonate. The phases are separated, the organic phase is dried over sodium sulfate and concentrated to give 3-(3,5-dimethyl-4-hydroxyphenyl)propanol bismesylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(CCl)N1CCOCC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available 2-chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2.[H][H]>[Pd].CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2
Reactant: [H][H]
Reactant: O=C1OCc2cc(C#CCOC3CCCCO3)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Yield: 98.6 %

Procedure:
A mixture of 5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one (1.0 g, 3.67 mmol) and 10% palladium on carbon (200 mg) in MeOH (15 ml) was shaken under 45 psi of hydrogen for 20 hours. The catalyst was removed by filtration through celite and rinsed with MeOH. The combined filtrates were evaporated to give 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one as a light yellow oil (1.0 g, 99%).
Reaction SMILES: [C@@H:1]1([O:12][C@@H:13]2[C@@H:22]([CH2:23][OH:24])[O:21][CH:16]([O:17][CH2:18][CH:19]=[CH2:20])[C@H:15]([OH:25])[C@H:14]2[OH:26])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CCl>N1C=CC=CC=1>[C:27]([C@@:15]1([OH:25])[C@@:14]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@H:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][O:11][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:6]([O:7][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:4]([O:5][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:2]2[O:3][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:22]([CH2:23][O:24][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:21][CH:16]1[O:17][CH2:18][CH:19]=[CH2:20])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CCl
Agent: Cl
Solvent: c1ccncc1
Product: C=CCOC1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.7 %

Procedure:
The compound (4.0 g, 10.46 mmol) synthesized in Example 2 (2a) was dissolved in pyridine (30 mL) and benzoyl chloride (12.1 mL, 104.24 mmol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was poured to 10% aqueous hydrochloric acid solution (20 mL) and methyl chloride (20 mL) and the organic layer was washed with 10% aqueous hydrochloric acid solution (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-5:2, V/V) to obtain the desired title compound (8.10 g, yield 70%) as a colorless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C)(C)C.[C:12]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)([O:14][CH3:15])=[O:13]>C(OCC)C>[C:12]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][CH:19]([OH:24])[CH2:18]2)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)N1C2CCC1CC(=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)N1C2CCC1CC(O)C2
Reaction time: 17.5 h

Procedure:
Under nitrogen atmosphere, 11.4 mg of LiAlH4, 0.15 ml of tetrahydrofran and then 85 μl of t-butylalcohol were placed in a reaction vessel. After standing the resulting mixture for 15 min. at room temperature, a tetrahydrofran solution of N-carbomethoxy-8-azabicyclo(3,2,1)octan-3-one prepared by the method as described in Referencial Example 3 (0.1 ml/2 mg) was added to the mixture and then continued stirring for 17.5 hrs.. To the reaction mixture, a moisture contained ethyl ether was added to stop the reaction and then the reaction mixture was subjected to extraction in several times with use of ethyl acetate. The combined extract was dried with use of Na2SO4 and concentrated to obtain N-carbomethoxy-8-azabicyclo(3,2,1)octan-3-ol, in crystal form.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].II.[I:31](O)(=O)=O>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[CH:25][C:26]([I:31])=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3)CC2)CC1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(I)cc3)CC2)CC1

Procedure:
To a mixed solution comprising 500 ml of acetic acid, 50 ml of carbon tetrachloride, 50 ml of concentrated sulfuric acid, and 100 ml of water were added 58.5 g of the (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene mentioned above, 22.1 g of iodine, and 18.4 g of iodic acid, and the mixture was stirred under a reflux for 2 hours. After cooled, the mixture was washed with a saturated aqueous solution of sodium thiosulfate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain a yellow-brown oily product. This product was purified by a column chromatography over an alumina by using heptane as an eluent. Further, it was recrystallized from heptane to obtain 9.7 g of 4-(trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)iodobenzene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C[Mg+].[Br-].[CH3:13]COCC>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:13])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (2.52 g, 13.74 mmol) in THF/NMP (86 mL/6 mL) was added Fe(acac)3 (485 mg, 1.37) and the mixture was cooled to 0° C. 3.0 M MeMgBr in Et2O (6.87 mL, 20.61 mmol) was added dropwise. After 30 min at 0° C., the reaction was complete and quenched with saturated aqueous NH4Cl solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10% EtOAc/Hex) gave the desired product as a white solid (1.45 g, 65%). 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH3:16]>>[CH3:16][N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][CH2:1][C:3]2[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=2)[CH2:20][CH2:19]1)[CH3:14]
Reactant: CN(C)CC1CCC(CN)CC1
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNCC2CCC(CN(C)C)CC2)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and {4-[(dimethylamino)methyl]cyclohexyl}methanamine. Aqueous work up gave the title compound as a yellow oil. Used without further purification. 1H NMR (300 MHz, chloroform-d): δ ppm 8.41 (d, 1H), 8.04 (s, 1H), 7.49 (d, 1H), 4.04 (q, 2H), 3.39 (s, 2H), 2.46 (m, 4H), 2.38 (d, 6H), 1.60 (m, 4H), 1.34 (t, 3H), 1.03 (m, 2H), 0.68 (m, 4H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccccc1-c1nc(Cl)c2ncc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 400 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one, 0.16 ml of phosphorus oxychloride, 221 mg of N,N-diisopropylethylamine and 6 ml of toluene was stirred at 100° C. for 30 minutes. The reaction mixture was cooled, and the precipitated solid was filtered. The resulting solid was sequentially washed with a saturated aqueous sodium bicarbonate solution, water and toluene, and then dried to obtain 320 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine (Compound of Present Invention 17).
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[C:20]([S@@:23](/[N:25]=[CH:1]/[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:24])([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1cccc(CCC(=O)OC(C)(C)C)c1C=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 305 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate in 3 ml of THF 3 ml were added 298 mg of (S)-2-methyl-2-propanesulfinamide and 0.62 ml of tetraethyl orthotitanate, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into ice water and the insoluble material was filtered through Celite. To the filtrate was added chloroform to carry out a layer separation operation. The organic layer was washed with water and subsequentially with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 336 mg of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-methylphenyl}propanoate.