Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]([Br:29])=[CH:17][N:16]=2)[S:12][CH:13]=1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:22]([O:21][C:20]1[C:15]([NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[N:10]=2)=[N:16][CH:17]=[C:18]([Br:29])[CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)NNC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(CCc2csc(Nc3ncc(Br)cc3OCc3ccccc3)n2)o1
Temperature: 50 °C
Reaction time: 72 h
Yield: 28.2 %

Procedure:
The crude N′-acetyl-3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.339 g, 0.691 mmol) was added acetonitrile (25 mL), POCl3 (0.380 ml, 4.15 mmol) and the mixture heated at 50° C. overnight. Additional POCl3 (0.5 mL) was added and the reaction was stirred for 3 days 50° C. Additional 0.5 ml POCl3 (0.5 mL) was added and the reaction was stirred at 50° C. for an additional 18 hours. The reaction was then concentrated to dryness, diluted with water, extracted with DCM, dried over Na2SO4, filtered, concentrated to a residue and purified by prep HPLC and then on a silica gel column, eluting with 75% EtOAc/Hexanes, to give 3-(benzyloxy)-5-bromo-N-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-yl)pyridin-2-amine (0.092 g, 28% yield) as a white solid. 1H NMR (DMSO-d6) δ 2.44 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 3.17 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.73 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 10.31 (s, 1H); Mass Spectrum (apci) 472 (M+H).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>CCOCC>[CH2:12]([NH:14][C:15]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: NC1CCCc2ccccc21
Solvent: CCOCC
Product: CCNC(=O)NC1CCCc2ccccc21

Procedure:
To a solution containing 7.4 grams (0.05 mole) of 1,2,3,4-tetrahydro-1-naphthylamine in 150 ml. anhydrous ether is added dropwise with stirring 3.6 grams (0.05 mole) ethyl isocyanate in 10 ml. ether. After the addition, the mixture is heated under reflux for 3 hours, the mixture cooled, and the solid collected by filtration. Recrystallization of the crude product from aqueous methanol gives analytically pure 1-ethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 178°C. to 179°C. Other aprotic solvents such as acetone, tetrahydrofuran and benzene may be used as solvents for this reaction. Temperatures employed for the reaction are in the range of 0°C. to 100°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH2:29][Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl-:30].[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH2:29][P+:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(CCl)c1)CCC2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c1)CCC2
Product: [Cl-]
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A suspension of 4-(4-benzyloxy-3-chloromethylphenoxy)-5-methyl-7-nitroindane (2.04 g) and triphenylphosphine (1.39 g) in toluene (50 mL) was heated under reflux for 12 hours. The reaction mixture was allowed to cool to room temperature. Precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.50 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[C@@H:20]2[CH2:21][NH:22][CH2:23][C@@H:19]2[CH2:18][N:17]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:22]2[CH2:21][C@@H:20]3[CH2:16][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][C@@H:19]3[CH2:23]2)[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Brc1cncc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(OCc4ccccc4)c3)C[C@@H]2C1

Procedure:
3-(Benzyloxy)-5-bromopyridine and the product from Example 1C were processed as described in Example 53B to provide the title compound. MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: BrCC1C=[CH:6][S:5]N=1.C(N)[CH2:9][NH2:10].[S:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][NH2:21])=[N:13]1.[N-]=C=S>>[CH3:9][NH:10][C:6]([NH:21][CH2:20][CH2:19][NH:18][CH2:17][C:14]1[CH:15]=[CH:16][S:12][N:13]=1)=[S:5]
Reactant: NCCN
Reactant: BrCc1ccsn1
Reactant: NCCNCc1ccsn1
Agent: [N-]=C=S
Product: CNC(=S)NCCNCc1ccsn1

Procedure:
Reaction of 3-bromomethylisothiazole with ethylenediamine by the procedure of Example 34 and reaction of the resulting N-(3-isothiazolylmethyl)ethylenediamine with methyl (isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-methyl-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. This intermediate is reacted with lead cyanamide by the procedure of Example 3(b) to give N-cyano-N'-[2-(3-isothiazolylmethylamino)ethyl]-N"-mathylguanidine. Hydrolysis of the last prepared compound by the procedure of Example 3(e) gives N-[2-(3-isothiazolylmethylamino)ethyl]-N'-methylguanidine dihydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]([C:19]2[CH:24]=C[CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11]C[CH2:9][C:4]21OCCO2.[CH2:25]=O.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:34]([OH:36])[CH3:35]>>[C:13]1([C:12]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:25][CH:24]=3)[CH:3]3[CH:4]([CH2:9][NH:1][CH2:2]3)[C:34](=[O:36])[CH2:35][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCO
Reactant: C=O
Reactant: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reaction time: 48 h

Procedure:
A solution of (RS)-6-aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (1 g) in ethanol (2 cc) is added to a solution, brought to reflux, of paraformaldehyde (0.09 g) in 2% strength aqueous sulphuric acid solution (5 cc), and heating to reflux is continued for 48 hours. The reaction mixture is then cooled to +5° C., alkalinized with 4N aqueous sodium hydroxide solution and extracted with dichloromethane (3×50 cc), and the organic phases are combined, washed with distilled water (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in acetone (8 cc), and this solution is acidified with 3.6N ethereal hydrogen chloride (2 cc) and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 2.5 cm, height 35 cm), eluting with a mixture of dichloromethane and methanol (85:15) by volume) and collecting 15-cc fractions. Fraction 9 is concentrated to dryness under reduced pressure (2.7 kPa) and dissolved in water (10 cc), this aqueous solution is alkalinized at +5° C. with 4N aqueous sodium hydroxide solution and extracted with dichloromethane (3×30 cc), and the organic phases are combined, washed with distilled water (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. (3aRS,7aRS)-7,7-Diphenylperhydro-4-isoindolone (0.07 g) is obtained in the form of a white meringue-like product.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCCC2)=C[CH:14]=1.BrC1C=CC(C2CCCC=2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc(C2CCCC2)cc1
Agent: Brc1ccc(C2=CCCC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 720 mg of a mixture of 1-bromo-4-cyclopentyl-benzene and 1-bromo-4-cyclopent-1-enyl-benzene (˜3.2 mmol), 2.2 ml of a 1.6 molar solution of n-BuLi in hexane (3.52 mmol) and 492 μl of DMF (6.40 mmol). 4-Cyclopentyl-benzaldehyde was isolated by flash column chromatography (5:95 EtOAc/c-hexane) as a yellow liquid (165 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ 1.53-1.91 (m, 6H), 2.11 (m, 2H), 3.07 (quint, J=8.5 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1Cl
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
1.5 g (5.14 mmol) of ethyl[(Z)-1-(2-chloro-4-fluorophenyl)-2-cyanoethenyl]carbamate (Example 36A) and 952 mg (5.14 mmol) of 1-(propan-2-yl)piperidine-4-carbohydrazide (Example 38A) were dissolved in 27 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 3 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The resulting precipitate was filtered off, washed with a little water and then dried under high vacuum. This gave 1.25 g (61% of theory) of the product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[C:1]([N:21]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[O:13])[C:15]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:16]1=2)(=[O:3])[CH3:2]
Reactant: Cc1cccc2c1C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cccc(C)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (423 mg, 1.62 mmol) followed by titanium isopropoxide (645 mg, 2.27 mmol) to 6-Methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (423 mg, 1.62 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (6.7 mL) and sodium borohydride (92 mg, 2.43 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-6-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (27 mg, 3%). Add acetic anhydride (0.037 mL, 0.39 mmol) dropwise to a solution of the amine (27 mg, 0.055 mmol) and pyridine (0.038 mL, 0.43 mmol) in dichloromethane (0.5 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (28 mg, 96%); MS (ES+): 531 (M+H).
Reaction SMILES: [NH:1]([C:8](=[O:43])[C:9]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33]C(=O)OC(C)(C)C)=[O:25])=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:9]([F:10])([C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:43])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:42][CH:41]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22.9 %

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate (11 mg, 0.019 mmol) in CH2Cl2 (3 mL) at room temperature was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature 45 min and concentrated. Purification by reverse phase HPLC (10% to 80% MeCN in water) gave 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-2-fluoro-N,N′-diphenylmalonamide (2.1 mg, TFA salt, 19%) as a white solid: 1H NMR (600 MHz, CD3OD) δ 8.13 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.64-7.62 (m, 4H), 7.41-7.35 (m, 8H), 7.18 (t, J=7.6 Hz, 2H); ESIMS calcd 483.2 (M++H), found 483.1 (M++H). General Procedure for the Synthesis of Non-Symmetrical Malonamide Benzamides
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH2:3][C:2]2=O.N1CCCC1.[O-][S:16]([O-])(=O)=O.[Mg+2].[S].[N:22]#[C:23][NH2:24]>C1CCCCC1>[S:16]1[C:3]2[CH2:4][CH:5]3[O:8][CH:1]([C:2]=2[N:22]=[C:23]1[NH2:24])[CH:7]=[CH:6]3
Reactant: O=C1CCC2C=CC1O2
Reactant: O=S(=O)([O-])[O-]
Reactant: N#CN
Agent: [Mg+2]
Agent: [S]
Solvent: C1CCCCC1
Solvent: C1CCNC1
Product: Nc1nc2c(s1)CC1C=CC2O1
Temperature: 100 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
To 8-oxabicyclo[3.2.1]oct-6-en-2-one (prepared as described in Vogel et al. Tetrahedron 1993, 49 (8), 1649-1664) (0.5 g, 4.0 mmol) in cyclohexane (3 mL) in a sealable tube was added pyrrolidine (1.7 mL, 20.1 mmol) followed by MgSO4 (4.8 g, 40.3 mmol). The tube was sealed and the mixture was warmed to 100° C. and stirred for 16 hours. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 mL methanol, sulfur (0.13 g, 4.0 mmol) was added and the mixture stirred for 20 min. Cyanamide (0.17 g, 4.0 mmol) was then added and the mixture stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (SiO2, 50% hexanes in ethyl acetate) to give the title compound (90 mg, 0.5 mmol, 12% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.30 (d, J=16.3 Hz, 1H) 3.21 (ddd, J=16.4, 6.0, 1.0 Hz, 1H) 4.64-4.77 (m, 2H) 5.12 (dd, J=5.9, 1.9 Hz, 1H) 5.25-5.29 (m, J=1.9, 1.9 Hz, 1H) 6.00 (dd, J=5.9, 1.9 Hz, 1H) 6.63 (dd, J=5.6, 1.5 Hz, 1H); MS (DCI/NH3) m/z 181 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc(-c2cccc(I)c2)o1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(-c2cccc(I)c2)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
5-(3-Iodophenyl)-1,3,4-oxadiazol-2(3H)-one (778 mg, 2.70 mmol) obtained in Step 1 was dissolved in DMF (14 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (840 mg, 4.05 mmol) and methyl iodide (0.20 mL, 3.24 mmol). The mixture was stirred after adding water, and the precipitated solid was filtered off and dried to give 5-(3-iodophenyl)-3-methyl-1,3,4-oxadiazol-2 (3H)-one (736 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[B:20]([OH:23])[OH:21]
Reactant: Brc1ccc2oc3ccccc3c2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -40 °C
Yield: 71.7 %

Procedure:
Under an argon atmosphere, 400 mL of anhydrous THF were added to 24.7 g (100 mmol) of 2-bromodibenzofuran (Intermediate 1-3), and then 63 mL (100 mmol) of a solution of n-butyllithium in hexane having a concentration of 1.6 M were added to the mixture during the stirring of the mixture at −40° C. The reaction solution was stirred for 1 hour while being heated to 0° C. The reaction solution was cooled to −78° C. again, and then a solution of 26.0 g (250 mmol) of trimethyl borate in 50 mL of dry THF was dropped to the solution. The reaction solution was stirred at room temperature for 5 hours. 200 milliliters of 1N hydrochloric acid were added to the solution, and then the mixture was stirred for 1 hour. After that, the aqueous layer was removed. The organic layer was dried with magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene. Thus, 15.2 g of dibenzofuran-2-boronic acid were obtained (in 72% yield). The resultant was identified as Intermediate 1-4 by FD-MS analysis because a main peak having a ratio m/z of 212 was obtained with respect to C12H9BO3=212.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=[N:3]1.O.NN>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncnc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (11.27 g, 25.70 mmol, 1 eq.) in 500 ml of THF was added hydrazine hydrate (6.43 g, 128.52 mmol, 5 eq.). The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc and the organics were combined, dried over MgSO4 and concentrated to give 6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (7.85 g, 99%) as a clear viscous oil.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:13])=[CH:4][CH:5]=1)[OH:12])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](O)c1ccc(C(F)F)nc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(C(F)F)nc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of (R)-1-(6-(difluoromethyl)pyridin-3-yl)ethane-1,2-diol (2.5 g, 13.2 mmol) in dry CH2Cl2 at room temperature were added tert-butyldimethylsilyl chloride (2.19 g, 14.5 mmol) and imidazole (0.99 g, 14.5 mmol). The resulting reaction mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 20% EtOAc/pet. ether) to afford the title compound (3g, 75% yield). MS: 304 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.63 (s, 1H), 7.89 (d, 1H, J=8.2 Hz), 7.63 (d, 1H, J=8.2 Hz), 6.64 (t, 1H, J=55.4 Hz), 4.82-4.86 (m, 1H), 3.82 (dd, 1H, J=10.1, 3.7 Hz), 3.58 (dd, 1H, J=10.1, 7.8 Hz), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7]C(O)=[CH:4][CH:3]=1)O.B(F)(F)F.[CH3:13][CH2:14][O:15][CH2:16][CH3:17].O1CCOCC1>C(OCC)C>[O:15]1[C:16]2[C:8](=[CH:1][CH:3]=[CH:4][CH:17]=2)[CH2:7][CH2:13][CH2:14]1
Reactant: CCOCC
Reactant: Oc1ccc(O)cc1
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of hydroquinone 1 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) in an organic solvent, preferaby dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes, at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL). The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 3.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=1)=[O:3]
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cccc(OCc2ccccc2)c1
Product: Cl

Procedure:
3-Benzyloxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 3-benzyloxybenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.254 g, 65% overall); νmax (nujol)/cm−1 3320, 2684, 2587, 1716, 1694, 1599, 1415, and 1312; δH (400 MHz, DMSO-d6) 10.02 (1H, br), 9.27 (1H, br), 7.45–7.28 (6H, m), 7.01–6.94 (3H, m), 5.11 (2H, s), 5.09 (2H, s), 4.33 (2H, m), 3.15 (2H, d, J 13.2 Hz), 3.07 (2H, m), and 1.31 (6H, d, J 7.6 Hz).