Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[Cl:14])[CH3:2].[Br:16][C:17]1[C:18](Br)=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:15])[CH3:5])[CH3:2].[Br:16][C:17]1[CH:22]=[C:21]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:15])=[C:8]([Cl:14])[CH:9]=2)[CH:20]=[C:19]([OH:23])[CH:18]=1
Reactant: CCOC(=O)COc1ccc(S)cc1Cl
Reactant: Oc1cccc(Br)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(C)=O
Product: O=C(O)COc1ccc(Sc2cc(O)cc(Br)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(2-Chloro-4-mercapto-phenoxy)-acetic acid ethyl ester (3 g; 12.16 mmol), dibromophenol (3.67 g; 14.59 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.45 g; 0.49 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocenE (0.40 g; 0.73 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (6.74 mL, 48.64 mmol) and NMP (10 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 100° C. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate phase was washed twice with a 5% aqueous citric acid solution. The organic phase was dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (dichloromethane→dichlormethane: ethyl acetate (1:1)). Yield 1.8 g. HPLC-MS: m/z: 441.2 (M+Na); Rt: 2.34 min.
Reaction SMILES: [Se](=O)=[O:2].[CH:4](C1C=CC(N(CC)CC)=CC=1C)([C:11]1C=C[C:14](N(CC)CC)=[CH:13][C:12]=1[CH3:22])[C:5]1C=CC=C[CH:6]=1.CN(C)[CH:37]=[O:38]>>[CH3:6][C:5]1[C:37]([OH:38])=[C:13]([CH3:14])[C:12]([CH3:22])=[C:11]([CH:4]=1)[OH:2]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc(C(c2ccccc2)c2ccc(N(CC)CC)cc2C)c(C)c1
Reactant: O=[Se]=O
Product: Cc1cc(O)c(C)c(C)c1O
Yield: 234.9 %

Procedure:
After dissolving 45 mg of selenium dioxide, 0.4 g of a polycarbonate resin (having the same composition as the resin used for CTL in Example 1), and 280 mg of 4,4'-benzylidenebis(N,N-diethyl-m-toluidine) in 5 g of N,N-dimethylformamide and then dissolving therein 145 mg of trimethylhydroquinone, the solution obtained was immediately coated on an aluminum-vapor deposited polyester film (same as in Example 1) using a coating rod and dried for one hour under hot blast of 60° C. to form a photoconductive layer. The color of the photoconductive layer was deep red and the thickness was 8 μm. The photoconductive layer was heat-treated as in Example 1. The initial light discharge speed was 0.7 (V0 =-350 volts (saturated potential)).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 33b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 299-300° C. (isopropanol)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[N:10][CH:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])[CH3:4].[CH:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.Cl[C:31](OC(Cl)(Cl)Cl)=[O:32].[Na+].[Cl-]>O1CCCC1>[CH:25]1([CH2:28][O:29][C:31]([N:10]2[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:13]([CH3:14])[N:12]=[C:11]2[CH3:15])=[O:32])[CH2:27][CH2:26]1
Reactant: OCC1CC1
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC2CC2)C1c1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 36 %

Procedure:
On the other hand, 45 mg of 50% suspension of sodium hydride (0.94 millimole) in oil was suspended in 3 ml of anhydrous tetrahydrofuran. To the suspension 259 mg (0.85 millimole) of 5-ethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)dihydropyrimidine in 5 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred for further 5 minutes. To the solution the above reaction mixture of the above sodium hydride, cyclopropylcarbinol and trichloromethyl chloroformate was added at 0° C. After 15 minutes, saturated NaCl solution was added to the mixture and it was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on silica gel by thin layer chromatography (developer: chloroform/methanol 10:1) to obtain 122 mg (36% yield) of title compound.
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH:44]=O)[CH2:40][CH2:39]1>CCOCC>[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH:44]=[CH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:40][CH2:39]1
Reactant: CN1CCC(C=O)CC1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(C=Cc2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, a 250 mL three-necked round bottomed flask was fitted with a reflux condenser, an addition funnel and a gas inlet tube. A gentle flow of nitrogen was maintained throughout the reaction. To a stirred suspension of 1-naphthylmethyltriphenylphosphonium chloride (4.39 g, 0.01 mole) in 125 mL of anhydrous ether was added, dropwise through a syringe at 0°, an ethereal solution of n-butyllithium (3.85 mL of a 2.6M solution in hexanes). After the addition, the solution was stirred at room temperature for 2 hours as an orange-yellow precipitate formed. A solution of 1-methylpiperidine-4-carboxaldehyde (1.27 g, 0.01 mole) in 25 mL of ether was added dropwise. The reaction mixture became colorless and a white precipitate separated. The mixture was heated under reflux overnight, allowed to cool to room temperature, and the precipitate was removed by filtration. The precipitate was washed with 2×50 mL portions of ether. The combined ethereal filtrates were washed with 3×50 mL portions of water until the washings were neutral. The organic solution was dried (MgSO4) and evaporated in vacuo. The residue was dissolved in petroleum ether and the small amount of triphenyl phosphine oxide (0.1 g) that precipitated was removed. The petroleum ether solution was concentrated to give 1-methyl-4-(1-naphthylvinyl)piperidine as a thick syrup. (1.822 g, 73%): IR (KBr) 3060, 3040, 3000, 2940, 2850, 2780, 2740, 2680, 1920 (W), 1800 (W), 1725 (W), 1640 (W), 1590, 1510, 1465, 1445, 1380, 1280, 1200, 1140, 1120, 1070, 970, 850, 780, 720 and 700 cm-1 ; NMR (CDCl3) δ1.70 (m, 5H), 1.33 (m, 2H), 2.20 (s, 3H), 2.68 (m, 2H), 6.13 (d.d, J=6 Hz, 2H), and 7.40 (m, 7H). The strong absorption at 970 cm-1 in the IR spectrum and the NMR peak at δ6.13 indicated that the major product was the trans-naphthylvinylpiperidine. Gas chromatographic analysis showed that the product contained 87.3% of the trans and 12.7% of the cis isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28])([O-:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:27]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:26])[F:24])=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:28])=[O:29])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc(N)c2ncccc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc12
Yield: 73.1 %

Procedure:
In a similar fashion using route 18 general procedure 27, 5-methoxy-quinolin-8-ylamine 586 (280 mg, 1.6 mmol), 2-nitro-4-(trifluoromethyl) benzenesulfonyl chloride (600 mg, 2.0 mmol), pyridine (0.39 ml, 4.8 mmol) DMAP (cat.) and DCM (15 ml) gave the title compound (500 mg, 73%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.[C:30](=O)(O)[O-].[K+].[OH2:35]>CO>[OH:35][C@@H:3]1[C@@H:2]([O:1][CH3:30])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: O
Reactant: O=C([O-])O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-ene-11,20-dione (500 mg.) was dissolved in methanol (25 ml.) and to the stirred solution was added concentrated sulphuric acid (0.1 ml). The solution was stirred at room temperature for 15 minutes, then 10% potassium bicarbonate solution (5 ml.) was added, and the mixture was poured into water. The precipitate was extracted into chloroform, and the extract was dried over sodium sulphate and evaporated to an oil which was recrystallised from ethyl acetate/petrol to give title compound (370 mg.) as fine white crystals, m.p. 159°-163° , [α]D + 82.0° .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([NH2:25])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[P+]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]#[N:25])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(C(N)=O)CCC2c2ccc(F)cc2)cc1
Agent: O=[P+]
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Yield: 82.4 %

Procedure:
A stirred mixture of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid amide (1.15 g, 3.17 mmol) and phosphorus oxide chloride (8 ml) was heated for 5 min under reflux conditions. Aqueous work-up and crystallization from ethyl acetate/hexane yielded the title compound as a light brown solid (0.9 g, yield 82%), m.p. 128° C. and MS: m/e=344 (M+).
Reaction SMILES: [CH:1]1([CH:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(#N)C>[Br-:14].[NH2:23][C:24]1[CH:29]=[CH:28][N+:27]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH:7]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccncc1
Reactant: BrCc1ccc(OC(C2CCCCC2)C2CCCCC2)cc1
Solvent: CC#N
Product: Nc1cc[n+](Cc2ccc(OC(C3CCCCC3)C3CCCCC3)cc2)cc1
Product: [Br-]

Procedure:
8-5 (183 mg, 0.5 mmol) and 4-aminopyridine 8-6 (47 mg, 0.5 mmol) were reacted in acetonitrile (4 ml) as in Example 1. Recovered white solid 8-7. mp: 248°-249° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(-c2cccc3cccnc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(-c2cccc3cccnc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 8-(3-methoxyphenyl)quinoline (900 mg, 3.83 mmol) in CH2Cl2 (50 ml) was added BBr3 (2.4 g, 14 mmol) at 0° C. The mixture was stirred for 2 h at 0° C. then until the reaction was completed. The mixture was added drop wise to iced water (50 mL), and then extracted with CH2Cl2 (2×20 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give a yellow solid which was used in next step without further purification. (720 mg, Yield 85%). LCMS (m/z): 222.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-(Trifluoromethyl)phenyl)-2-propanol (233 mg, 1.14 mmol), acetic acid (0.50 mL) and 20% palladium(II) hydroxide (120 mg) were combined in 2.0 mL of methanol and subjected to hydrogenation at 48 psi on a Parr shaker overnight. The mixture was centrifuged and the supernatant was filtered through 0.45 micron filter. The catalyst was washed with 3.0 mL of methanol followed by 2×3.0 mL of pentane. The combined filtrates were diluted with 20 mL of pentane and washed with 35 mL of saturated sodium bicarbonate. After extracting the aqueous layer with 2×20 mL of pentane, the combined organic layers were dried over sodium sulfate. The solvents were removed by distillation at atmospheric pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:11][C:12]2[CH:17]=[C:16]([N+:18]([O-])=[O:19])[C:15]([F:21])=[CH:14][C:13]=2[CH3:22])=[CH:4][N:3]=1.CCN(CC)CC.[C:30](Cl)(Cl)=[O:31].[OH2:34]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][N:11]([C:12]3[CH:17]=[C:16]([N+:18]([O-:19])=[O:34])[C:15]([F:21])=[CH:14][C:13]=3[CH3:22])[C:30](=[O:31])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Cl)ncc1CNc1cc([N+](=O)[O-])c(F)cc1C
Reactant: O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(F)c([N+](=O)[O-])cc1N1Cc2cnc(Cl)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36 %

Procedure:
To suspension 2-chloro-5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methylpyridin-4-amine (2.04 g, 6.28 mmol) in dioxane (30 mL) was added Et3N (3.50 mL, 25 mmol) and phosgene (20% solution in toluene, 6.90 mL, 12.6 mmol). The reaction mixture was stirred at RT for 2.5 h. Water 30 mL) was added and the mixture was extracted with EtOAc (2×70 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo. The residue was stirred with EtOAC for 15 min and the precipitate was collected by filtration and dried in vacuo to give 7-chloro-3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.785 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.11 (s, 1H), 7.61 (s, 1H), 7.15 (s, 1H), 4.94 (s, 1H), 4.61 (s, 1H), 3.26 (s, 3H), 2.22 (s, 3H); MS (ESI) m/z: 351.0 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]([CH3:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)O)(C)(C)C>ClCCl>[CH3:31][C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH2:15])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(O)NCCCN1CCC(C)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccccc2)CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butoxy{[3-(4-methyl-4-phenyl-1-piperdinyl)propyl]-amino}methanol (0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10% KOH solution and extracted with dichloromethane (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.340 g (98%) of 3-(4-methyl-4-phenyl-1-piperdinyl)propylamine which was used without further purification in the subsequent step.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([C:12](=[O:24])[C@H:13]([OH:23])[C@@H:14]([OH:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.CN(C=O)C>CC(O)(C)C.CS(C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:3][CH2:2][O:23][C@H:13]([C@@H:14]([OH:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]2=[O:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)N(CCCl)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(F)cc2)C1=O
Yield: 27.5 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 59-4 (1.62 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 59-5 (400 mg) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH:1]1([CH2:4][C:5]2[N:6]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: c1ccc2[nH]c(CC3CC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(CC4CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 92.9 %

Procedure:
Using 2-cyclopropylmethyl-1H-benzo[d]imidazole (72 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (175 mg, 93%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:24]2[C:31]([F:32])=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:33])[C:16](=[O:23])[C:17]#[C:18][Si](C)(C)C)[CH:12]=[CH:11][CH:10]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:24]2[C:31]([F:32])=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:33])[C:16](=[O:23])[C:17]#[CH:18])[CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1c(F)cc(C#N)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1c(F)cc(C#N)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a solution of 4-[1-[6-(2,4-difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-3,5-difluorobenzonitrile (from Step F above, 7.00 g, 15.02 mmol) in THF (200 mL) was added tetrabutylammonium fluoride hydrate (22.5 mL, 1.0 M in THF) at 0° C. After stirring at 0° C. for 10 min, the reaction was diluted with EtOAc (3×), washed with aqueous NH4Cl, H2O, brine, dried over MgSO4 and concentrated. The crude residue was purified using silica gel chromatography (hexanes/methylene chloride) to yield the title compound (5.31 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[NH2:18][C@@H:19]([CH2:21][OH:22])[CH3:20].[Cl-].[NH4+]>C(N(CC)CC)C>[NH2:17][C:4]1[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=[C:2]([NH:18][C@H:19]([CH3:20])[CH2:21][OH:22])[CH:3]=1
Reactant: Nc1cc(Cl)nc(SCc2ccccc2F)n1
Reactant: C[C@@H](N)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2F)n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of the product from example 4, step (b) (15 g), triethylamine (15 ml) and D-alaninol (10 g) was heated at 160° C. for 18 h. The reaction mixture was allowed to cool to room temperature and poured into aqueous ammonium chloride (11). The resultant white precipitate was purified by silica gel chromatography, eluting first with 1:1 DCM:ethyl acetate and then 3:1 DCM:methanol, giving the subtitled product as a yellow foam (10.7 g).
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[CH:10]=[O:11].Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)C>[CH3:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:14]=1)[CH:10]=[O:11]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No. 60549-26-0] in 20 ml of DMF, the reaction mixture was cooled to 0° C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)cc1Cl
Yield: 69.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([S:22][CH3:23])[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([S:22][CH3:23])[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1
Reactant: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Reactant: BrCCCCBr
Product: COc1ccc(OCCCCBr)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Yield: 80 %

Procedure:
3,4-Dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-2-methylthio-3-oxo-2H-1,4-benzothiazine (3.5 g, compound No. 8) and 1,4-dibromobutane (3.6 ml) are treated by the similar method as in Example 15 to give 3.9 g (80.0%) of the titled compound.