Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>C(OCC)C.[Cu]I>[CH2:12]([CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3]1)[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Agent: [Cu]I
Solvent: CCOCC
Product: CCC1Cc2ccccc2O1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl lithium (1.6M in diethyl ether, 313 mL, 500 mmol) was added to a solution of copper (I) iodide (47.6 g, 250 mmol) in diethyl ether (750 mL) at −70° C. The solution was then allowed to warm to −10° C. and was stirred for 30 minutes. The mixture was then added to a solution of 2,3-dihydro-1-benzofuran-2-ylmethyl4-methylbenzenesulfonate (preparation 97) (15.2 g, 50 mmol) in diethyl ether (500 mL) and the reaction mixture was stirred at −40° C. for 1 hour and at room temperature for 2 hours. The mixture was then cooled to −70° C. and quenched with 10% ammonium chloride solution (750 mL) and 2M hydrochloric acid (50 mL), diluted with 0.88 ammonia (100 mL) and then stirred for 18 hours. The reaction mixture was extracted with diethyl ether (3×500 mL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil in 98% yield, 7.25 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25]([N:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[N:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]23)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: O=C=NC1CCCCC1
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)NC1CCCCC1)c1ccccc12

Procedure:
The subject compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and cyclohexyl isocyanate according to the method of Example 10. The confirmatory elemental analysis for the product, mp 114°-116° C., is shown in Table III.
Reaction SMILES: [NH3:1].[C:2](#[N:5])[CH:3]=[CH2:4]>O>[C:2]([CH2:3][CH2:4][NH:1][CH2:4][CH2:3][C:2]#[N:5])#[N:5]
Reactant: C=CC#N
Reactant: N
Solvent: O
Product: N#CCCNCCC#N
Reaction time: 10 h

Procedure:
The reaction takes place in a tube reactor which has an internal diameter of 36 mm and a length of 70 cm. At the lower end of the reactor there is a glass frit G 4, manufactured by the Schott Company, Mainz. It is designated 160 D and has a 30 mm diameter. The glass frit functions as a distribution device. The tube has a total volume of 700 ml. and the effective reaction volume (the space used during the reaction) equals 500 ml. 9 liters of gaseous ammonia are fed into the reactor per hour. The gas flows through the glass frit and reacts with the acrylonitrile. In order to monitor the gas conversion, the amount of unreacted gas is determined using a gas meter. 52 ml of acrylonitrile and 3.8 ml of water are pumped hourly into the upper end of the reactor at a rate which corresponds to a space velocity of 0.1 hr-1. After 10 hours of residence time, the reaction mixture is removed at a point above the distribution device located at the lower end of the tube reactor. The yield of bis-(2-cyanoethyl)-amine obtained is 91 %.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[O:20][C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:18][CH:17]=1)CCC>CN(C=O)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>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:19]1[O:20][C:16]([N:3]2[CH:2]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:17][CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Ic1n[nH]c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccc(C4OCCO4)o3)cc2c1
Reaction time: 0.25 h

Procedure:
10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1978, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh3)4 is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1,3-dioxolane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.
Reaction SMILES: [Zn](CC)[CH2:2]C.[CH2:6]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[CH2:22])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(I)I>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19]2([CH2:2][CH2:22]2)[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C1CCC(C(=O)OCc2ccccc2)CC1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: ICI
Product: O=C(OCc1ccccc1)C1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
Et2Zn (1.08 M solution in hexane, 5.23 ml, 5.65 mmol) was added to a solution of 4-methylene-cyclohexanecarboxylic acid benzyl ester (86.3 mg, 375 μmol) in toluene (1.4 ml), and the mixture was stirred at room temperature for 30 minutes. CH2I2 (500 μl, 6.22 mmol) was added to the reaction mixture at 0° C., and the mixture was stirred at 60° C. for 28 hours. Thereafter, Et2Zn (1.08 M solution in hexane, 2.60 ml, 2.22 mmol) and CH2I2 (260 μl, 3.23 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for four days. Further, Et2Zn (1.08 M solution in hexane, 2.60 ml, 2.22 mmol) and CH2I2 (500 μl, 6.22 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for one day. The reaction mixture was quenched by adding a 1% aqueous HCl solution and diluted with ethyl acetate and Et2O. The organic layer was then washed with a 1% aqueous HCl solution, a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to give spiro[2.5]octane-6-carboxylic acid benzyl ester (70.6 mg, 77%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH3:19])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[CH2:18]([C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:19]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-ethyl-1H-pyrazol-5(4H)-one and 4-acetamidothiophenol using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (t, J=7.45 Hz, 3H) 2.06-2.16 (s, 3H) 2.17-2.25 (m, 2H) 6.63 (s, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.78-7.89 (m, 4H) 8.08 (d, J=8.34 Hz, 1H) 10.32 (s, 1H); ESI-MS: m/z calc'd for C22H20N4O2S 404.13. found 405.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[N:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Product: Cc1ccnc(-c2sc(N=CN(C)C)nc2C)c1

Procedure:
A solution of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)thiazole (300 mg) in N,N-dimethylformamide dimethyl acetal (1.5 ml) was stirred at ambient temperature for 14 hours and evaporated under reduced pressure. The residue was triturated with 2-propanol (1 ml) and diisopropyl ether, and the solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N,N-dimethyl-N′-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-formamidine (268 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=CNc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CNc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Reaction time: 1.25 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)-formamide (26 g, 0.143 mol) in DMF (180 mL) is added potassium carbonate (22 g, 0.159-mol), followed by benzyl bromide (27 g, 0.158 mol) at 60° C. The mixture is stirred for 1.25 h. The mixture is diluted with water. The precipitated solid is separated by filtration and washed with 1N HCl, water and hexanes, and air dried for 18 h to afford N-(2-benzyloxy-5-nitrophenyl)-formamide as a white solid: (M−H)−=271.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C1C=NC2N(O)N=NC=2C=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>O1CCOCC1>[CH3:27][O:26][N:25]([CH3:24])[C:10]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1c[nH]c2ncccc12
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a solution of 7-azaindole-3-carboxylic acid (324 mg, 2.00 mmol) in dioxane (10 mL) was added HOAt (300 mg, 2.20 mmol), N,O-Dimethylhydroxylamine hydrochloride (214 mg, 2.00 mmol) and EDC (422 mg, 2.20 mmol). The mixture was stirred at rt for 15 minutes then DIPEA (853 mg, 6.60 mmol) added slowly over 5 minutes. The reaction was then stirred at rt for an additional 18 hrs. The reaction was then poured into 25% ammonium chloride solution (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated to a brown oil. This oil was purified via column chromatography (SiO2, EtOAc) to afford the title compound as a viscous clear oil which solidified on standing. Yield=86%
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21](S(=O)(=O)N(C)C)[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:37]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]([CH3:37])[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Ethyl (E)-4-[2-(5,6,7,8 -tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-N,N-dimethylsulfamoyl-2-imidazolecarboxylate (Compound 4, 70 mg, 0.18 mmol) was dissolved in acetone (10 mL) at room temperature and treated with methyl iodide (0.5 mL) and K2CO3 (350 mg). The suspension was stirred for 30 min, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (35 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)C1CCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCC1
Temperature: 25 °C
Reaction time: 42 h
Yield: 71.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), cyclobutanecarboxylic acid (218 mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP—Cl (203 mg, 2.17 mmol). The reaction was stirred at room temperature for 42 hours. The reaction mixture was then treated with 2M LiOH.H2O (2 mL) and stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction mixture, and the solid formed was filtered, washed with additional water, and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide (193 mg, 71% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (br s, 1H), 9.33 (s, 1H), 8.33 (d, 1H), 7.57 (s, 1H), 3.29-3.24 (m, 1H), 2.25-2.18 (m, 2H), 2.15-2.08 (m, 2H), 1.98-1.88 (m, 1H), 1.86-1.78 (m, 1H); LCMS (APCI+) m/z 311.9, 314.0 (M+H)+, Retention time=2.96 minutes (Method 2).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (880.2 mg, 1.916 mmol) was cooled down with an ice bath. Phosphorus oxychloride (2.938 g, 1.786 mL, 19.16 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at 0° C. and then allowed to warm up to rt and stirred at room temperature for 18 hours. The reaction mixture was quenched by slow addition onto ice. After 1 hour of stirring, the mixture was extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a pale orange solid. The solid was triturated further in EtOAc and filtered off (715.4 mg, 78% yield)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 2-[(4-hydroxy-3-nitrophenyl)carbonyl]benzoic acid (9.7 g, 30 mmol) in DMF (100 mL) was added cesium carbonate (9.8 g, 30 mmol) and benzyl bromide (3.6 mL, 30 mmol). The reaction mixture was stirred at rt for 4 h. Water, 10% citric acid, and ethyl acetate were added, and then the phases were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (50% hexanes:50% ethyl acetate). The product-containing fractions were combined and concentrated. Impurities were removed from the solid residue by trituration with ether. The desired phenylmethyl 2-[(4-hydroxy-3-nitrophenyl)carbonyl]benzoate was obtained as powdery yellow solid (6.17 g, 16.3 mmol, 54% yield. 1H NMR (400 MHz, CDCl3): 10.89 (s, 1H), 8.25 (d, 1H), 8.16 (dd, 1H), 7.91 (dd, 1H), 7.69 (m, 1H), 7.62 (m, 1H), 7.35 (m, 1H), 7.27-7.23 (m, 3H), 7.20-7.17 (m, 2H), 7.10 (d, 1H), 5.13 (s, 2H); MS (EI) for C21H15NO6: 400 (MNa+).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[C:17]([O:30][CH2:31][C:32](=[O:34])[NH2:33])[CH:16]=2)=[CH:6][CH:5]=1.[C:37](OC1C=CC=CC=1)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:1]=[N:2][CH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:26])[CH3:27])=[O:20])=[C:17]([O:30][CH2:31][C:32](=[O:34])[NH2:33])[CH:16]=2)=[CH:6][CH:5]=1)(=[O:39])[CH3:38]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1OCC(N)=O)C(C)C
Reactant: CC(=O)Oc1ccccc1
Solvent: ClCCl
Product: CC(=O)N=NCc1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OCC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 0.47 g (1.0 mmol) of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide in 10 ml of methylene chloride is added 0.14 g (1.0 mmol) of phenyl acetate. The mixture is stirred at room temperature for 4 hours and then poured onto a silica gel column and eluted with ethyl acetate, and then 10% methanol/ethyl acetate to give 4-[5-[4[(acetylimino)aminomethyl]-phenoxy]-pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide as a foam; CHN calculated for C29H40N4O8.0.5H2O:
Reaction SMILES: N.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=3[C:36](O)=[O:37])=[CH:30][CH:31]=2)[CH:26]=[N:25]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=3[C:36]([NH2:3])=[O:37])=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: O=C(O)c1ccccc1Nc1ccc2[nH]ncc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
A 28%-aqueous ammonia solution (57.6 mg, 0.948 mmol), 1-hydroxybenzotriazole (58 mg, 0.379 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (73 mg, 0.379 mmol) were added in that order to a solution of 2-(1H-indazol-5-ylamino)benzoic acid (80.0 mg, 0.316 mmol) in N,N-dimethylformamide (0.5 ml), and the resulting mixture was stirred at room temperature for 20 hours. A 5% aqueous sodium hydrogencarbonate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate/toluene/tetrahydrofuran (2/2/1). The organic phase was washed with a 5% aqueous sodium hydrogencarbonate solution and then a 5%-aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase dried was concentrated under reduced pressure and the resulting crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=50/1 to 20/1) to obtain 2-(1H-indazol-5-ylamino)benzamide (66 mg, 83%).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[C:5](=[O:10])[CH2:6]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(O)CN2CCNCC2=O)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 1-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (49 mg, 0.17 mmol) and 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (64 mg, 0.34 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 150° C. for 2 hours. LC showed formation of the product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[S:41])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
Dissolve 0.50 g (0.12 m mole) of 8-chloro-11-[1-(1-(3-pyridyl)methylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine (Example 2 of Table 2) and 0.5 g (0.12 m mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at room temperature and 18 hours at 80° C., under nitrogen. Filter the reaction mixture and concentrate under vacuo. Dissolve the residue in 50 mL of 1N HCl and extract with 200 mL of CH2Cl2. The water layer was neutralized with Na2CO3 and extracted with CH2 Cl2. The organic layer was dried over MgSO4 and concentrated under vacuo giving the product as a white solid, mp=92°-93° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[H][H]>N1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([CH:22]=[CH2:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: [H][H]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: C=C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Shake 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) in pyridine (20 cc.) containing a 2% palladium-calcium carbonate catalyst (150 mg.) with hydrogen at atmospheric pressure until one molecular equivalent of hydrogen has been absorbed. Recrystallise the product twice from ether-hexane and dry for 4 hours at 65°/.005 mm. to yield the title compound, m.p. 108°-111°; ultraviolet absorption peak at 240 (ε15,200); infrared absorption peak at 10.9μ.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.[NH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[N:18][OH:19])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Solvent: CN(C)C=O
Product: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1

Procedure:
20 mg (0.06 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzaldehyde were stirred with 20 μL (0.33 mmol) of hydroxylamine solution (50% in water) in 2 mL f DMF at 80° C. for 1 h. The reaction mixture was purified by chromatography (reversed phase).