Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[S:8][C:7]=2[CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.Cl.C(=O)(O)[O-].[Na+]>ClCCl.O.C1COCC1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=3)=[O:12])=[C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[S:8][C:7]=2[CH:30]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN(C)C)cc3)c(C3CCCC3)sc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)c2c(C3CCCC3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
35 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone was dissolved in 5 ml of dichloromethane, 65 mg of aluminum chloride and 0.03 ml of ethanethiol were added, and the mixture was stirred at room temperature for 2 hours. 0.3 ml of THF, 0.075 ml of 20% hydrochloric acid and 0.3 ml of water were added to the reaction mixture, a saturated aqueous sodium bicarbonate solution was added to make the mixture alkaline, and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resultant crude product was purified by TLC (developing solvent, chloroform:methanol=19:1) to obtain 21 mg of (6-hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[S:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(OCC)(=O)C>[CH2:17]([NH:21][C:7]([C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:9])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: Cc1cc(C(=O)O)sn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCNC(=O)c1cc(C)ns1
Reaction time: 0.5 h

Procedure:
3-Methyl-5-isothiazolecarboxylic acid (2.3 g) was dissolved in 40 ml of ethyl acetate. After 2 g of triethylamine were added, the resultant mixture was cooled over an ice-water bath and, at 5°-10° C., 1.5 g of n-butylamine were gradually added dropwise. After completion of the dropwise addition, stirring was continued for 30 minutes. The reaction mixture was washed successively with an aqueous solution of sodium hydrogencarbonate and then with water. After dried over sodium sulfate, the solvent was distilled off so that 2.60 g of N-n-butyl-3-methyl-5-isothiazolecarboxylic acid amide were obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]2[C:20](=O)[C:19]3[C:6](=[CH:7][C:8]4[C:9](=O)[C:10]5[C:15]([C:16](=O)[C:17]=4[CH:18]=3)=[CH:14][C:13]([Cl:26])=[CH:12][CH:11]=5)[C:5](=O)[C:4]=2[CH:3]=1.[BH4-].[Na+].CO.Cl>COCCOCCOC.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]2[C:4](=[CH:5][C:6]3[C:19]([CH:20]=2)=[CH:18][C:17]2[C:8](=[CH:9][C:10]4[C:15]([CH:16]=2)=[CH:14][C:13]([Cl:26])=[CH:12][CH:11]=4)[CH:7]=3)[CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2c(=O)c2cc3c(=O)c4ccc(Cl)cc4c(=O)c3cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOCCOC
Product: Clc1ccc2cc3cc4cc5cc(Cl)ccc5cc4cc3cc2c1
Temperature: 23 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
A mixture of 2.0 grams (5.9 mmol, leq) of 2,9-dichloropentacene-5,7,12,14-tetrone and 3.0 g (322 mmol, 54 eq) of sodium borohydride in 46 mL of 2-methoxyethylether was stirred at 23° C. in a nitrogen atmosphere for 14 hours. To this reaction mixture was added 23 mL of methanol in a dropwise fashion to keep the reaction temperature below 50° C. A solution of 18 grams (96 mmol, 16 eq) of stannous chloride in 19.7 grams of water and 7.3 grams of 12M hydrochloric acid was added at such a rate as to keep the reaction temperature between 23° C. and 40° C. The mixture was stirred for an additional 30 minutes. The reaction mixture was filtered and the residue washed with 46 mL of 12M hydrochloric acid followed by 120 mL of acetone and 40 mL of THF. The solid was dried in air to give 0.95 grams of the desired product. IR KBr 1618 cm−1, 906 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)=O>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)=[O:6]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: O=Cc1ccc(OCC(=O)O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3 g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3×), brine, and dried over MgSO4. The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford {4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-yloxy}acetic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.[I-].[Zn+2].[I-]>[CH2:11]([O:10][C:6]([CH:7]1[CH2:8][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2)=[O:9])[CH3:12]
Reactant: c1ccoc1
Reactant: C=CC(=O)OCC
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC2C=CC1O2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Furan (2.04 ml, 28 mmol), ethyl acrylate (2.06 ml, 20 mmol) and zinc iodide (1.92 g, 6 mmol) were placed in a sealed tube and the mixture was heated at 40° C. for 2 days. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). 10% Aqueous sodium thiosulfate solution (20 ml) was added, and the mixture was stirred at room temperature for 30 min. The organic layer was partitioned, washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. The components having a low boiling point, such as the solvent and the like, were distilled away. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10 (volume ratio)) to give 2-ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene as a mixture of exo form:endo form=7:3 (1.75 g, 10.4 mmol, yield 52.0%).
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[NH2:2].O.C(=O)([O-])O.[Na+].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>O1CCCC1.C(OCC)(=O)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:2][NH:1][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:25]
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccco1)OCc1ccccc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
Benzyl hydrazinecarboxylate (1.66 g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL) and added sodium hydrogen carbonate (1.68 g) thereto. Under ice cooling, furan-2-carbonyl chloride (1.30 g, 10 mmol) was gradually added, followed by stirring for 1 hour. After completion of the reaction, to the reaction solution was added 300 ml of ethyl acetate, followed by washing with saturated ammonium chloride solution and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 5 ml of ethyl acetate was dissolved in the resulting residue, followed by gradually adding hexane (100 ml) to afford 2.30 g of the title compound as a solid (yield 88.4%).
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15]([O-])([O-])=[O:16].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CO.[Cu]I>[NH2:1][C:2]1[C:9]([O:16][CH3:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cc(C#N)c(C(F)(F)F)cc1N

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (312 mg, 1.0 mmol), CuI (I) (20 mg, 0.1 mmol), Cs2CO3 (652 mg, 2.0 mmol) and 1,10-phenanthroline (36 mg, 0.2 mmol) were mixed in methanol (20 ml). The reaction mixture was refluxed overnight and then the solvent was removed under vacuum. Upon separation on silica gel (100% CH2Cl2), the tile compound was obtained as a colorless liquid.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[N:27]=[C:26]2[NH:28][C:29]([CH2:31][CH3:32])=[N:30][C:25]2=[C:24]([CH3:33])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:21][C:22]1[N:27]=[C:26]2[N:28]([CH2:2][C:3]3[CH:20]=[CH:19][C:6]4/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]5[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=5[CH2:10][CH2:11][C:5]=4[CH:4]=3)[C:29]([CH2:31][CH3:32])=[N:30][C:25]2=[C:24]([CH3:33])[CH:23]=1
Reactant: CCc1nc2c(C)cc(Cl)nc2[nH]1
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CO)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(Cl)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
[step 1] (E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (120 mg, 0.46 mmol) and 5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (117 mg, 0.60 mmol) were dissolved in THF (6.6 mL) and the solution was added with polymer supported triphenylphosphine (469 mg, 0.92 mmol) and di-t-butyl azodicarboxylate (211 mg, 0.92 mmol) at 0° C., followed by stirring at room temperature for 2 hr. The mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give (E)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (90 mg, 45%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]#[N:17])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1)(C)(C)C.[ClH:24].[CH2:25]([OH:27])[CH3:26]>>[ClH:24].[ClH:24].[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[NH:17])[O:27][CH2:25][CH3:26])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC#N)ccc1-n1cccn1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Nc1ccc(-n2cccn2)c(CN)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 61 %

Procedure:
A mixture of the compound (243 mg) obtained in Example 4a and saturated HCl-ethanol (10 ml) was stirred at room temperature for 29 hours. The reaction mixture was concentrated at reduced pressure and the resulting residue was recrystallized from ethanol-ethyl acetate to give the titled compound (yield, 61%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][B-:5]([F:8])([F:7])[F:6].C(O[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16])C.C(OCC)C>C(Cl)Cl>[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:1][N:2]([CH3:3])[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16]
Reactant: CNC
Reactant: CCOC(=O)C(=CC=[N+](C)C)OCC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=CC=[N+](C)C)N(C)C

Procedure:
A solution of dimethylamine (233 cc) in methylene chloride is added in the course of 1 hour 20 minutes, at a temperature of approximately 20° C., to a solution of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (1,007 g) in methylene chloride. Anhydrous ethyl ether (2,000 cc) is then run slowly into the reaction medium, and the crystalline product is then separated off by filtration and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of approximately 20° C. N-(3-Dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (925 g), m.p. 102° C., is thereby obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: NCCNCc1ncccn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1ncccn1

Procedure:
Treating N-(2-pyrimidylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate, then concentrating and separating by column chromatography by the procedure of Example 40 (a) (ii) gives the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[NH2:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:39])[CH3:40])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)=[CH:15][CH:14]=2
Reactant: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Ethyl 2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give ethyl 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate hydrochloride (0.13 g, 92.9%) as crystals.
Reaction SMILES: [C:1]1([C:17]2C=C[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH:16]2[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]2)[CH2:10]1)=[O:8].C(OC(N1CCC2C(NC2)C1)=O)(C)(C)C.[S:38]1C=CC=C1C1C=CC=CC=1C(Cl)=O.C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[C@@H:16]12[N:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:17]3[S:38][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:10][C@@H:11]1[CH2:12][CH2:13][NH:14][CH2:15]2
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Reactant: O=C(Cl)c1ccccc1-c1cccs1
Agent: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: O=C(c1ccccc1-c1cccs1)N1C[C@@H]2CCNC[C@@H]21
Yield: 66.7 %

Procedure:
Intermediate 7 was prepared in a manner analogous to Intermediate 3, substituting (1R,6S) 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 2-thiophen-2-yl-benzoyl chloride for biphenyl-2-carbonyl chloride in Step A. The final compound was concentrated and the residue was purified on HPLC to provide the title compound (150 mg, 66.7%). MS (ESI) mass calcd. for C17H18N2OS, 298.4; m/z found, 299.2. [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([I:24])[CH:17]=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[C:18]([I:24])[CH:17]=1
Reactant: BrCc1ccc(Br)cc1I
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccc(Br)cc2I)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Lithium diisopropylamide (3.34 mL, 6.68 mmol), was added dropwise to a solution of cyclobutanecarbonitrile (0.417 g, 5.14 mmol) in THF (20 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 30 min, then was a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239, 2.51 g, 6.68 mmol) in THF (8 mL) slowly added dropwise and the reaction was allowed to reach r.t. The mixture was stirred for another 3 h and then quenched with water. The reaction mixture was partitioned between water and EtOAc, the organic layer was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetae 12:1) to afford the title compound (1.71 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.34 (m, 4 H), 2.47-2.58 (m, 2 H), 3.18-3.23 (m, 2 H), 7.29 (s, 1 H), 7.49 (dd, 1 H), 8.03 (d, 1 H); GC MS (EI) m/z 375 M+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>CS(C)=O>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][S:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: C1CSCCN1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Solvent: CS(C)=O
Product: COc1cc(N2CCSCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 170 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) in DMSO (2 mL) was added thiomorpholine (0.29 mL, 2.85 mmol) and the reaction mixture was stirred for 5 h at 170° C. After cooling to ambient temperature it was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (164 mg, 66%) as an off-white solid. MS: m/e=435.3 [M+H]+.
Reaction SMILES: Cl.C([N:9]1[CH:13]=[C:12]([CH2:14][CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[N:11]=[CH:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH:16]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=2)[CH2:15][CH2:14][C:12]2[N:11]=[CH:10][NH:9][CH:13]=2)=[CH:22][CH:21]=1)#[N:24]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=CCc2cn(Cc3ccccc3)cn2)c2ccc(C#N)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C(CCc2c[nH]cn2)c2ccc(C#N)cc2)cc1

Procedure:
1 eqv. of 1-benzyl-4-[3,3-bis(4-cyanophenyl)-2-propenyl]-1H-imidazole hydrochloride is dissolved in ethanol (40 ml) and a catalytic aamount of 10% Pd/C is added. The reaction mixture is stirred at 40° C. in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by column chromatography methylene chloride-methanol (9:1) as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[N:27]1([CH2:32][C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:31]=[CH:30][N:29]=[CH:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:27]1([CH2:32][C@@H:33]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cc2c(O)ccc3c2CCCC3=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 96 %

Procedure:
Using the method in Example 154, this compound was prepared from methyl 4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate (1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) as a solid-foam, 2.78 g, 96% yield; mp 105° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O6S.H2O:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH3:38])[C:23](=[O:37])[C:24]3[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[N:31][C:25]=3[N:26]([CH2:29][CH3:30])[C:27]=2[N:28]=1.[C:39]1([OH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH3:38])[C:23](=[O:37])[C:24]3[CH:34]=[C:33]([CH2:35][O:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:32]=[N:31][C:25]=3[N:26]([CH2:29][CH3:30])[C:27]=2[N:28]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCN1c2ncc(COc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 78 %

Procedure:
Using a procedure analogous to that described in Example 98, except sodium bis(trimethylsilyl)amide was employed as the base instead of potassium tert-butoxide, the title compound, m.p. 140°-141° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and phenol. The yield was 78% of theory.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C>CCOC(C)=O>[OH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2O)o1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2O)o1
Yield: 10.4 %

Procedure:
The title compound was prepared from 2-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenol (44 mg, 0.094 mmol) following General Procedure D. Preparative thin layer chromatography (30% EtOAc) yielded the title compound as a white solid (3.4 mg, 12%): 1H NMR (CDCl3, 500 MHz) δ 7.94-7.93 (m, 1H), 7.82 (br s, 1H), 7.38-7.34 (m, 4H), 7.26-7.25 (m, 3H), 7.12 (t, 1H, J=15.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 3.18 (t, 2H, J=7.5 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.89-1.83 (m, 2H), 1.75-1.69 (m, 2H), 1.54-1.46 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 188.8, 153.4, 151.7, 143.1, 131.3, 128.8, 128.7, 127.7, 127.5, 126.0, 121.7, 116.9, 114.5, 39.4, 36.3, 31.7, 29.5, 29.4, 24.5; MALDI-FTMS m/z 350.1751 (M+H+, C22H24NO3, requires 350.1751).