Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:21][C:22]1[CH:27]=[C:26]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:25]=[N:24][CH:23]=1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1cncc(Br)c1
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
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Temperature: 120 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (1.0 g, 3.66 mmol), prepared as described in Example 3a, was added 3,5-dibromopyridine (2.6 g, 11 mmol), 1,2-dimethoxyethane (10.0 mL), and 2 M aqueous sodium carbonate (4.00 mL, 8.0 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at, which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (2.0 g, 0.220 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0133 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 8.01 (t, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Reactant: OB(O)c1ccsc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chloro-thieno[2,3-b]pyrazine-6-carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)C12 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1 Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]3)=[S:21])[C:16]([F:28])=[CH:15][C:14]=2[Cl:29])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:29][C:14]1[C:13]([S:12][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:10][CH2:11]2)=[CH:18][C:17]([N:19]=[C:20]2[N:22]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:1](=[O:2])[S:21]2)=[C:16]([F:28])[CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
While stirring at a temperature of from 0° to +10° C., 5.7 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 3.7 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclopropanecarboxylic acid methyl ester and 4.6 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 4 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 3.7 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclopropylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7-one, having a melting point of +149° C.
Reaction SMILES: C([O-])(=O)C([O-])=O.[CH3:7][C:8]1[S:9][C:10]([CH3:20])=[CH:11][C:12]=1[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=O.Cl[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[Mg]>>[S:17]1[CH:18]=[CH:19][C:15]([C:13]([C:12]2[CH:11]=[C:10]([CH3:20])[S:9][C:8]=2[CH3:7])=[C:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:16]1
Reactant: CN1CCC(Cl)CC1
Reactant: Cc1cc(C(=O)c2ccsc2)c(C)s1
Agent: O=C([O-])C(=O)[O-]
Agent: [Mg]
Product: Cc1cc(C(=C2CCN(C)CC2)c2ccsc2)c(C)s1

Procedure:
The starting carbinol was obtained in a manner analogous to Example 1 (a), from 12.2 grams (0.055) mole) of (2,5-dimethyl-3-thienyl)-3-thienyl ketone, 14.7 grams (0.11 mole) of 4-chloro-N-methyl-piperidine and 2.67 grams (0.11 gram atom, of magnesium.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:20]([O:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:13])([CH3:14])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a stirred solution of intermediate 25, ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL) was added K2CO3 (2.07 g, 20 mmol). After stirring 48 h at ambient temperature, the reaction mixture was diluted with ether (100 mL), then washed with water (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give a yellow solid. Trituration with hexanes/ether (9: 1) afforded the title compound as an off-white solid (2.79 g, 78% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.48-7.45 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.33 (2H, q, J=7.3 Hz), 4.05-3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3 Hz). HRMS (M+H) calcd for C19H23N2O5: 359.1607; found: 359.1611. Anal calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.81; found: C, 63.63; H, 6.16; N, 7.78.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[CH:8]2)[CH3:2].[CH3:14][O:15]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[C:8]2[CH:14]=[O:15])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCc1cccc2cccc(O)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cccc2c(C=O)ccc(O)c12
Reaction time: 0.17 h

Procedure:
24.0 g of 8-ethyl-1-naphthol was dissolved in 200 ml of dichloromethane, in which 30.6 ml of titanium tetrachloride was gradually dropped under ice-cooling conditions. Thereafter, 20.3 ml of dichloromethyl methyl ether was gradually dropped under ice-cooling condition. After agitation for 10 minutes, 50 ml of water was gradually dropped under ice-cooling conditions. The reaction solution was extracted with ethyl acetate and the organic phase was washed with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant crystals were washed with a mixed solvent of chloroform and isopropyl ether (1:1) to obtain 15.9 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=1
Reactant: [O-][n+]1ccccc1C=Cc1ccccc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccccc2F)n1

Procedure:
Following the general method described in example 2b, 2-[2-(2-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a brown crystalline material. MS: m/e=224 (M+).
Reaction SMILES: COC(C1N(C)C2C(C=1)=CC(N)=CC=2)=O.C(OC(C1N(C)C2C(C=1)=CC(N)=CC=2)=O)C.C(OC([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH2:46])=[CH:41][CH:40]=2)=O)C.[CH3:47][N:48](C)[C:49](C1NC2C(C=1)=CC(N)=CC=2)=[O:50].COC(C1N(C)C2C(C=1)=CC=C(N)C=2)=O>>[CH3:47][NH:48][C:49]([N:38]1[C:39]2[C:44](=[CH:43][C:42]([NH2:46])=[CH:41][CH:40]=2)[CH2:45][CH2:37]1)=[O:50]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CN(C)C(=O)c1cc2cc(N)ccc2[nH]1
Agent: CCOC(=O)c1cc2cc(N)ccc2n1C
Agent: COC(=O)c1cc2cc(N)ccc2n1C
Agent: COC(=O)c1cc2ccc(N)cc2n1C
Product: CNC(=O)N1CCc2cc(N)ccc21

Procedure:
5-Amino-1-methyl-1H-indole-2-carboxylic acid methyl ester/5-Amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester (5.25) for Example 32, 47: Pharmagene Laboratories Limited Patent: WO2005/80367 A1; 2005/Boehringer Ingelheim (Canada) Ltd. Patent: US2003/236251 A1; 2003) 5-Amino-1H-indole-2-carboxylic acid ethyl ester (5.26) for Examples 6, 8, 10-12, 16, 26, 28, 30, 31, 33-44, 49, 50, 53, 58-61, 63, 65, 67-193, 197-214, 253-258, 260-262, 273-277, 283: Bayer Healthcare AG; WO2008/56768; A2; 2004) 5-Amino-1H-indole-2-carboxylic acid dimethylamide (5.27) for Example 219, 222, 232: Vertex Pharmaceuticals Incorporated Patent: WO2006/10008; A1; 2006) 6-Amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (5.28) for Examples 66, 265, 266-270: Banyu Pharmaceutical Co. Patent: WO2007/29847 A1; 2007
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([Cl:16])[N:12]=[C:13]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(Cl)nc(OCc2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Yield: 94.1 %

Procedure:
Next, 5.70 mL of dichloromethane solution containing 896.2 mg (3.50 m mol) of 6-benzyloxy-2,4-dichloro-1,3,5-triazine, 2.00 mL of dichloromethane, 365.0 mg (3.88 m mol) of phenol and 0.738 mL (4.23 m mol) of N,N-diisopropylethylamine was added to a 30 mL eggplant flask, and reacted at 0 degree under a nitrogen atmosphere for 6 hours. After the reaction, 20 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away, and the residue was recrystallized to obtain 1033.2 mg of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine (yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.BrN1C(=[O:19])CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH:9]=[O:19])=[CH:7][CH:8]=1
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C=O)nc1[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 3-methoxy-6-methyl-2-nitropyridine (S. Lindstrom, T. Ahmad and S. Grivas, Heterocycles (1994), 38(3), 529-540) (30 mmole) and N-bromosuccinimide (60 mmole) in CCl4 (50 ml) was refluxed under a 500 watt tungsten lamp for 16 hours, cooled, filtered and evaporated. A portion (2.4 g) of the crude product was mixed with sodium formate (1 g), water (1 ml) and ethanol (7 ml), refluxed for 24 hours, cooled and concentrated to low volume. The residue was partitioned between dichloromethane and water, the organic dried and evaporated. Chromatography gave the title compound (25%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:19]=[CH:18][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:22][CH:21]=2)/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
N-Propargylpyrrolidine (113 mg, 1.04 mmol) and diisopropylamine (0.339 mL, 2.42 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (300 mg, 0.515 mmol; prepared as described in example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added. The reaction mixture was stirred at ambient temperature for 21 h. Further portions of N-propargylpyrrolidine (113 mg, 1.04 mmol), diisopropylamine (0.339 mL, 2.42 mmol), copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added and reaction mixture was stirred at 50° C. for further 5 h and then evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.Cl[C:15]1[C:16]2[CH:23]=[C:22]([CH3:24])[O:21][C:17]=2[N:18]=[CH:19][N:20]=1>>[CH3:24][C:22]1[O:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:11][CH2:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[C:16]=2[CH:23]=1
Reactant: Cc1cc2c(Cl)ncnc2o1
Reactant: NCCc1cccc(C(F)(F)F)c1
Product: Cc1cc2c(NCCc3cccc(C(F)(F)F)c3)ncnc2o1
Temperature: 230 °C

Procedure:
A mixture of 1.9 g of 2-[3-(trifluoromethyl)phenyl]ethylamine and 1.6 g of 4-chloro-6-methylfuro[2,3-d]pyrimidine was heated for ten minutes at 230° C. The mixture was then cooled and the product extracted in ethyl acetate/water. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on a silica column using toluene and acetone as eluent. Yield 0.97 g. M.P. 119° C.
Reaction SMILES: FC(F)(F)COC(=O)OCC(F)(F)F.FC(F)(F)C[NH:18][C:19](=[O:38])[O:20][CH2:21][CH:22]1[CH:27]=[CH:26][CH2:25][CH:24]([CH2:28][O:29][C:30](=[O:37])[NH:31]CC(F)(F)F)[CH2:23]1>>[C:30](=[O:37])([O:29][CH2:28][CH:24]1[CH:25]=[CH:26][CH2:27][CH:22]([CH2:21][O:20][C:19](=[O:38])[NH2:18])[CH2:23]1)[NH2:31]
Reactant: O=C(NCC(F)(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)F)C1
Agent: O=C(OCC(F)(F)F)OCC(F)(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 93.2 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 37.1 g (0.1642 mol) of bis(2,2,2-trifluoroethyl)carbonate (to be referred to as “BTrFC” hereinafter) synthesized in the above Synthesis Example 2 in place of BTFC, and it was confirmed that tetrahydro-m-xylylene bis(2,2,2-trifluoroethyl carbamate) (to be referred to as H-XDC-2 hereinafter) was generated as the main product (H-XDA base yield 93.2%). Structural assignment of the product H-XDC-2 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-2, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: OCCOCCCl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCCl
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 2-(2-chloroethoxy)ethanol (3.9 g, 31 mmol) in dichloromethane (15 ml) kept at 0° C. was added triethylamine (6.2 g, 61 mmol). A solution of methanesulfonyl chloride (3.6 g, 31 mmol) in dichloromethane (15 ml) was carefully added keeping the temperature below 0° C. When addition was complete the reaction mixture was left overnight at room temperature and then diluted with dichloromethane (150 ml). The organic phase was washed with a 2 N hydrochloric acid solution (75 ml) and water (75 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 6.3 g of crude 2-(2-chloroethoxy)ethyl mesylate as an oil. A suspension of 5,6,11,12-tetrahydrodibenz[b,f]azocine (5.0 g, 20 mmol) in dry THF (75 ml) placed under an atmosphere of nitrogen was cooled to -68° C. A solution of n-butyl lithium in hexanes (19 ml, 49 mmol, 2.5 M) was added dropwise keeping the temperature below -60° C. When addition was complete stirring was continued at this temperature for 30 minutes and then the reaction mixture was left overnight at room temperature. The mesylate prepared above was dissolved in dry THF (50 ml) and added dropwise to the reaction mixture. When addition was complete the mixture was stirred at room temperature for 168 h. Ice was added (80 g) and the phases were separated. The aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic phases were washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give a residue which was submitted to column chromatography on silica gel using a mixture of ethyl acetate and n-heptane (2:3) as eluent. This afforded 2.5 g of 2-(2-(5,6,11,12-tetrahydrodibenz[b,f]azocin-12-yl)ethoxy)ethylchloride as an oil.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
p-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature and (S)-Glycidyl nosylate (1.71 g, 6.6 mmol) was added. The system was stirred for an additional 24 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent system to give (S)-Glycidyl p-nitrophenyl ether (99.6% ee, based on chiral HPLC with Chiralcel OD, m.p 78-9° C.) as a yellowish solid (1.21 g, 93% yield). The NMR values are the same as the literature values for the racemic mixture: 1H-NMR (CDCl3) δ 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38 (dd, 1H), 6.99 (dd, 2H), 8.2 (dd, 2H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:11][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=2[CH3:10])=[CH:21][CH:22]=1)[CH3:28]
Reactant: Cc1c(O)ccc(C=O)c1O
Reactant: CCOc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc(C=O)c(O)c2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzaldehyde (1.00 g, 6.57 mmol) in DMF (20 mL) were added potassium carbonate (1.36 g, 9.86 mmol) and 1-(chloromethyl)-4-ethoxybenzene (1.23 g, 7.23 mmol), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:2) to give the title compound (336 mg, yield 18%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][C:18]([OH:20])=[O:19]>CO>[CH3:1][C:2]1[N:7]=[C:17]([C:18]([OH:20])=[O:19])[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cccn2)c(C#N)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
6-Methyl-3-(1H-pyrazol-1-yl)picolinonitrile (0.60 g, 3.26 mmol) and NaOH (1.37 g, 34.2 mmol) were dissolved in methanol (3 mL) and stirred at reflux overnight. The reaction was cooled to rt, diluted with more methanol (5 mL), and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a clear oil (0.62 g, 94%). MS (ESI) 204 (M+H).
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Cl>CO.Cl>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][O:3][C:2]1[CH:9]=[CH:8][C:6]([O:7][CH2:15][CH2:14][CH2:13][N:12]([CH3:17])[CH3:11])=[CH:5][CH:4]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C)CCCOc1ccc(OCCCN(C)C)cc1
Yield: 10.7 %

Procedure:
First, to a solution of 2.3 g of metallic sodium dissolved in 35 ml of absolute methanol, a solution of 2.2 g of hydroquinon in 15 ml of absolute methanol and a solution of 7.9 g of 3-dimethylaminopropyl chloride hydrochloride in 10 ml absolute methanol were added, and the mixture was heated to reflux for 5 hours. After the reaction was completed, the mixture was evaporated under a reduced pressure, and after adding water to the resulting residue, alkalized with 10% sodium hydroxide, salted-out with sodium chloride and extracted with 100 ml of chloroform, the extract was washed with a saturated sodium chloride, and dried over magnesium sulfate. The solvent was removed under a reduced pressure to obtain a reddish liquid, which was dissolved in 1N hydrochloric acid, the solution was washed with chloroform, alkalized with 1N sodium hydroxide and extracted with 100 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate, and the solvent was evaporated off under a reduced pressure to obtain 0.60 g of a desired compound as a reddish brown liquid.