Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: Cc1nn2c(-c3cccc(Cl)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: COc1ccc(B(O)O)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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(Cl)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
(S)-(1-(7-(3-Chlorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (30 mg), 4-methoxyphenylboronic acid (15 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (21 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>CC#N.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccccn2)CC1
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnc3ccccn23)CC1
Yield: 59.5 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)-4-(2-(2-pyridinyl)hydrazino)carbonyl-piperidine (320 mg, 1.0 mmol) and dichlorotriphenylphosphorane (666 mg, 2.1 mmol) in CH3CN (10 mL) was added Et3N (0.42 mL, 3.0 mmol). After refluxing for 2h, the solution was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration followed by flash chromatography eluting with 100% EtOAc, then 10% MeOH/CH2Cl2 afforded the title compound (180 mg) as a foamy solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 2.05˜2.11 (m, 4H), 3.03 (br s, 2H), 3.24 (m, 1H), 4.25 (br d, J=11.7 Hz, 1H), 6.86 (dt, J=6.9, 0.9 Hz, 1H), 7.25 (m, 1H), 7.78 (dt, J=9.4, 1.2 Hz, 1H), 7.95 (dt, J=6.8, 1.1 Hz, 1H), 7.79 (dd, J=7.3, 0.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1.Br[C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:12]2[CH:13]=[C:7]3[CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9][N:8]3[N:11]=2)[C:17](=[O:25])[N:18]([CH3:24])[C:19]=1[CH3:23]
Reactant: COCCN1CCn2nc(N)cc2C1
Reactant: Cc1c(Br)cc(Br)c(=O)n1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCCN1CCn2nc(Nc3cc(Br)c(C)n(C)c3=O)cc2C1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 327b (392 mg, 2.0 mmol), 327d (562 mg, 2.0 mmol), cesium carbonate (1.30 g, 4.0 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the suspension for 10 minutes, xantphos (115 mg, 0.20 mmol) and tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.10 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×15 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 327e (490 mg, 62%) as a yellow solid. MS-ESI: [M+H]+ 396.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:14]=2[CH3:23])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to the general procedure 3 described hereinabove. 2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.45 ml, 0.91 mmol) was added, and the mixture stirred for 15 min at −75° C. Iodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=326.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].C(Cl)(Cl)Cl.CS(ON=C(C#N)C(OCC)=O)(=O)=O>C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and L-leucine ethyl ester hydrochloride (1.0 g) are suspended into chloroform (10 ml), and therein is dissolved triethylamine (1.40 ml). To the solution is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred at room temperature for 16 hours. After reaction, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 1 N aqueous sodium hydrogen carbonate, water, 1 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the resulting residue is crystallized from petroleum ether to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (0.8 g), melting point: 65°-67° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>C(N(CC)CC)C.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.[Cu](I)I>[N+:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1)([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cncc(Br)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 159.3 %

Procedure:
To a suspension of 3-bromo-5-nitropyridine (1.0 g, 4.90 mmol), Pd(Ph3P)4 (0.57 g, 0.49 mmol), and copper iodide (0.19 g, 0.98 mmol) in triethylamine (30 mL) was added ethynyltrimethylsilane (1.0 mL, 7.35 mmol) and the reaction was purged with N2. The mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with saturated solutions of NaHCO3 and NaCl. The organic layer was concentrated to afford the crude product (1.72 g) as a light brown solid: ESI MS m/z 221 [C10H12N2O2Si+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16](Cl)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26](=[O:32])[N:27]([CH2:29][CH2:30][NH2:31])[CH3:28])([CH3:24])([CH3:23])[CH3:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(#N)C>[C:21]([O:25][C:26](=[O:32])[N:27]([CH2:29][CH2:30][NH:31][CH:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)[CH3:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCNC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21)C(=O)OC(C)(C)C
Yield: 46.2 %

Procedure:
6-Benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 1.95 mmol), (2-Amino-ethyl)-methyl-carbamic acid tert-butyl ester (0.512 g, 2.925 mmol), sodium iodide (0.1 g) and potassium carbonate (0.5 g) were added to 50 mL of acetonitrile, and the reaction mixture was refluxed for 120 hours. The reaction mixture was cooled and diluted with 200 mL of water. The aqueous mix was extracted twice with 200 mL of EtOAc, and the combined organic layers were washed with water, brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the resulting oil was eluted through silica gel (medium pressure chromatography) eluting with EtOAc/Hexanes 20%/80%. Removal of solvent under reduced pressure afforded 0.4 g (0.9 mmol, 46%) of [2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester as an oil. MS: 446 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(OC)(OC)OC.[CH2:18]([N:21]([CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH3:20].[BH4-].[Na+]>CO.O>[CH2:27]([N:21]([CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:28][CH3:29]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: O
Product: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3.94 g (0.03 mol, 1.0 equivalent) of 4-cyanobenzaldehyde was charged in a 300 ml four-necked flask, and dissolved in 60 ml of methanol. 9.55 g (0.09 mol, 3.0 equivalents) of trimethyl orthoformate was added dropwise therein at room temperature, and the mixture was then cooled to −20° C. 5.17 g (0.03 mol, 1.0 equivalent) of 4-dipropylaminobutylamine (4) was added dropwise therein, the mixture was stirred for one hour and further stirred at room temperature for three hours. After confirming the disappearance of the raw material, the mixture was again cooled to −20° C. 1.36 g (0.036 mol, 1.2 equivalents) of sodium borohydride was added dropwise therein, and the mixture was stirred for two hours. The reaction solution was added into 250 ml of water and extracted with 120 ml of chloroform. The chloroform layer was washed with 150 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 8.58 g of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) as a colorless oily substance (yield: 99%, GC: 96.7%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A solution of 2-chloro-3-nitropyridine (21.05 g, 132.7 mmol) in DMF (100 mL) was treated with 2-tert-butylphenol (23.5 mL, 152.6 mmol) and cesium carbonate (129.8 g, 398.3 mmol). The mixture was heated at 80° C. for 30 h. The reaction was cooled to rt, and the mixture was poured in water (1 L) with stirring. The yellow precipitate formed was filtered and washed with water, and recrystallized from ethanol to afford 1a as beige crystals (32.83 g, 90%). 1H NMR (400 MHz, CD3OD) δ ppm 1.34 (s, 9H), 6.93 (m, 1H), 7.22 (m, 3H), 7.47 (m, 1H), 8.31 (dd, J=4.82, 1.75 Hz, 1H), 8.46 (dd, J=7.89, 1.75 Hz, 1H).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:51][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[Cl-].[NH4+]>C1COCC1.O>[C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 52.5 %

Procedure:
To a clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 91A, 560 mg, 0.829 mmol) in anhydrous THF (20 mL) was added 1 M THF solution of lithium bis(trimethylsilyl)amide (4 mL, 4.00 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 60 min. before half the amount of the required iodomethane (0.25 mL, 4.00 mmol) was added. The mixture was stirred at 0° C. for 20 min. before the rest of the iodomethane was added. The mixture was stirred at 0° C. for an additional 50 min. and saturated aqueous ammonium chloride solution (5 mL) and water (2 mL) were added. The mixture was extracted with ethyl acetate (10 mL and then 2×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (24 g silica gel column, 5→50% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (300 mg, 0.435 mmol, 52.5% yield) as a glassy solid. The compound had an LC/MS M+1=690.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]C(=O)OC(C)(C)C)[CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[I:29]I.S(=O)(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:29]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: CN(C)CCN(C)C
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1nccc(Cl)c1I
Reaction time: 0.5 h

Procedure:
A solution of 10 g of the publicly known compound tert-butyl N-(4-chloro-2-pyridyl)carbamate, 16.6 ml of N,N,N′,N′-tetramethylethylenediamine and 200 ml of tetrahydrofuran was cooled to −75° C., and then 42 ml of n-butyllithium (2.6M solution in hexane) was added dropwise over a period of 30 minutes while stirring. After stirring for 1 hour at −75° C., a solution of 28 g of iodine in 28 ml of tetrahydrofuran was added dropwise over a period of 30 minutes. After completion of the dropwise addition, stirring was continued for another 30 minutes at −75° C., and then the mixture was returned to room temperature, aqueous sodium bisulfate was added and extraction was performed with ethyl acetate. NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=3:1). The solvent was distilled off under reduced pressure, 48% HBr water was added to the residue, and the mixture was stirred at 100° C. for 5 minutes. After adding ice water and 5 N sodium hydroxide water to the reaction solution, the precipitated solid was filtered out to obtain 7.4 g of a light yellow solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.[Cl:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1.CCOC(C)=O>[Cl:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:37][S:34]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30]1)(=[O:35])=[O:36]
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(Cl)CCCCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C(CCCCCl)CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of LDA (51 mmol, prepared by slow addition of n-butyl lithium (20.4 ml, 2.5M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g, 51 mmol) in THF (30 ml) at −78° C.) at −78° C. was added a solution of 1-(4-fluorophenyl)-4-(methanesulfonyl)-piperazine (6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 h at −78° C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at −78° C. for 1 h and at room temperature for 18 h. The solution was diluted with EtOAc and washed with sat. NH4Cl and brine and dried over MgSO4. Chromatography of the residue on silica gel (eluant:EtOAc—CH2Cl2—petroleum ether (15:35:50)) afforded 1-(6-chloro-2-hexanone-1-sulfonyl)-4-(4-fluorophenyl)piperazine (5.22 g, 60%) as white crystals: MS (ESI): 399 (MNa+).
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C1(S(Cl)(=O)=O)C=CC=CC=1.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:4]=1[N+:1]([O-:3])=[O:2])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)OC(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (1.104 mmol) of 2-nitro-3-methyl benzoic acid was dissolved in 16 ml of pyridine. 468 mg (2.208 mmol) of benzene sulfonyl chloride was added thereto and stirred at room temperature for 2 hours. 329 mg (4.146 mmol) of t-butanol was added thereto and stirred at room temperature for 15 hours. The reaction mixture was extracted with dichloromethane and pyridine was removed by using 2N hydrochloric acid. The organic layer was then neutralized with sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The resulting mixture was concentrated under reduced pressure. The concentrated product was then purified by the column chromatography (ethylacetate:hexane=1:30) to obtain 2-nitro-3-methyl benzoic acid t-butyl ester (Intermediate compound 43, 194 mg, Yield of the first step: 74%). 190 mg (0.800 mmol) of the first intermediate compound 43 as a starting material was subjected to the third step in the reaction of Example 1 to obtain 3-bromomethyl-2-nitrobenzoic acid t-butyl ester (Intermediate compound 44, 160 mg, Yield of the second step: 63%). 154 mg (0.487 mmol) of the intermediate compound 44 was dissolved in 7 ml of dichloromethane, and trifluoroacetic acid was added thereto. The mixture was stirred for 6 hours. When the reaction was completed, the resulting mixture was concentrated under reduced pressure and 3-bromomethyl-2-nitrobenzoic acid (Intermediate compound 45, 121 mg, Yield of the third step: 96%) was obtained. The intermediate compound 45 as a starting material was subjected to the fourth through sixth steps in the reaction of Example 3 to obtain the title compound 14 (83 mg, Yield of the sixth step: 14%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[Li+].[B-](CC)(CC)CC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(Br)c1Cl
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc(Br)c1Cl
Reaction time: 16 h

Procedure:
To a solution of methyl 3-bromo-2-chlorobenzoate (1.9 g, 7.6 mmol) in THF (30 mL) was added Super Hydride (23 mL, 23 mmol) at 0° C. The reaction was allowed to stir for 16 hours. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, and purified by MPLC to provide (3-bromo-2-chlorophenyl)methanol. LC-MS (IE, m/z): 205 [M-17]+;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCCCF
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCCF)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20 mmol) in THF (140 mL) were 3-fluoropropan-1-ol (1.67 mL, 22.3 mmol), triphenylphosphine (7.97 g, 30.4 mmol) and diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) added. The mixture was stirred at r.t. for two days. More 3-fluoropropanol (0.5 mL) was added and the mixture was heated to 45° C. After 2 h the mixture was concentrated, and the crude product was purified by flash chromatography using 0-20% EtOAc in heptane as eluent, affording 3.42 g (81% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.12-2.26 (m, 2H), 2.68-2.76 (m, 2H), 3.04-3.12 (m, 2H), 4.14 (t, 2H), 4.61 (t, 1H), 4.70 (t, 1H), 7.17-7.22 (m, 2H), 7.38 (d, 1H); MS (EI) m/z 208 M.