Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:20])[C@@H:12]([OH:19])[C@@H:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=2[O:2]1.[N:21]1([C:27]([NH:29][C:30]2([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:19][C@@H:12]([C@@H:13]([NH:18][C:36]([C:30]1([NH:29][C:27]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:37])[CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:20]
Reactant: CCCC[C@H](N)[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 90 %

Procedure:
In anhydrous dichloromethane were dissolved 344 mg (1.23 mmol) of (2S,3S)-N-[(3,4-methylenedioxy)phenyl]-3-amino-2-hydroxyheptanamide, 315 mg (1.23 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 233 mg (1.48 mmol) of 1-hydroxybenzotriazole, and then, under nitrogen stream, 284 mg (1.48 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the above mixture at 0° C. Thereafter, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, and the resulting mixture was washed successively with water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 574 mg (Yield: 90%) of the desired compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1.[N:31]1[CH:36]=CC=C[CH:32]=1.CS(OS(C)(=O)=O)(=O)=O.CNC>C1COCC1>[CH3:32][N:31]([CH3:36])[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cccc2ccccc12
Reactant: c1ccncc1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1cc(C2=C(c3cccc4ccccc34)C(=O)NC2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of Compound 3 (25 mg, 0.063 mmol) in THF (5 mL) was added pyridine (24.9 mg, 0.315 mmol). The mixture was stirred at room temperature for 15 min and then methanesulfonic anhydride (43.9 mg, 0.25 mmol) was added and the mixture was heated to 50° C. for 2 h. TLC and mass spectra shown the formation of Compound 4a. To the crude product was added excess 1.0 M solution of dimethylamine in THF (1 mL). The mixture was heated from 50 to 65° C. overnight. The solvent was concentrated in vacuo. The crude product was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated NaHCO3, brine, and evaporated in vacuo to give a crude product (50 mg). The crude product was separated by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, from 98:2:0.2 to 95:5:0.5) to give 6 mg (22%) of Compound 4 as a yellow solid. 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.08 (dd, J=1.5, 4.7 Hz, 1H), 7.94 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.54 (m, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.28 (m, 1H), 6.44 (dd, J=4.7, 8.1 Hz, 1H), 6.26 (dd, J=1.5, 8.0 Hz, 1H), 4.37 (t, J=7.1 Hz, 2H), 2.29 (t, J=7.0 Hz, 2H), 2.25 (s, 6H), 2.07 (m, 2H). ES-MS m/z 425 (MH+).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=1)=O)C1C=CC=CC=1.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:9][OH:8])=[N:12]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)c1nn(Cc2ccccc2)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a stirring solution of 735 mg (2.15 mmol) of 1-Benzyl-1H-indazole-3-carboxylic acid benzyl ester, prepared as in Intermediate 14, in 15 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 5.4 mL (5.4 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 4 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 448 mg of the title compound as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ7.80 (d, 1H), 7.40-7.08 (m, 8H), 5.50 (s, 2H), 5.04 (d, 2H), 2.24 (m, 1H); Rf =0.50 in hexane/EtOAc 1/1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3C3CCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([N:18]2[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:19]2=[S:20])[CH:17]=1
Reactant: C#CCNCC(=O)OCC
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (7.0 g), 5-chloro-2-methylphenylisothiocyanate (9.2 g), triethylamine (5.0 g), and methylene chloride (100 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (50 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from EtOAc afforded the title compound (5.1 g) as a yellow solid, m.p. 131°-134° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.90; H, 3.77; N, 9.92. Mass spectrum (EI, M.+) m/z 278.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1>CN(C)C=O>[C:85]([O:84][C:82]([N:79]1[CH2:78][CH2:77][CH:76]([NH:75][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([F:31])[CH:24]=2)[CH2:81][CH2:80]1)=[O:83])([CH3:88])([CH3:87])[CH3:86]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a mixture of 0.10 g (0.23 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 6 mL of dimethylformamide was added 0.0499 g (0.37 mmole) of 1-hydroxybenzotriazole, 0.1349 g (0.356 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.0615 g (1.378 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0728 g (0.349 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0906 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-229) as a white solid.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (0.198 g) with 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride (0.404 g) in dichloromethane in the presence of N,N-diisopropylethylamine (0.155 g) gives the product as a solid.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24](Cl)[CH3:25])#[N:21].O>CN(C)C=O>[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24]([O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:8]2[O:9][C:5]3[CH:4]=[C:3]([Cl:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:16][CH:15]=1)[CH3:25])#[N:21]
Reactant: CC(Cl)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Reactant: Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2.70 Grams of a potassium salt of 4-(6-chloro-2-benzoxazolyloxy)phenol and 2.48 g of 1-cyano-1-(2,4-dichlorophenyl)-3-chloro-2-butanone were refluxed in 50 ml of N,N-dimethylformamide under heat at 100° C. for 4 hours. The reaction mixture was added to water, and after the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 2.05 g of a compound No. 176 which was a light yellow solid (melting point 93°-94° C.). The yield was 46.9%. The compound No. 176 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH3+:13])=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH:13][C:35]([NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:36])=[CH:3]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: [NH3+]CC(=O)c1c[nH]c2ccccc12
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC(=O)c1c[nH]c2ccccc12)Nc1cccc2ccccc12
Reaction time: 1 h
Yield: 87 %

Procedure:
[2-(3-indolyl)-2-oxoethyl]ammonium bromide (2.00 g, 7.84) was suspended in dry THF (20 ml). Ethyldiisopropylamine (1.40 ml, 7.84 mmol) was added followed by 1-naphthyl-isocyanate (1.13 ml, 7.84 ml). After stirring for 1 hour the formed precipitate was removed by filtration and washed with THF followed by water to give the sub-title product (2.33 g, 87%) as a white solid after drying.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:20][C:21]([OH:40])([CH2:26][C:27]([C:30]2[C:38]3[O:37][CH2:36][CH2:35][C:34]=3[CH:33]=[C:32]([Cl:39])[CH:31]=2)([CH3:29])[CH3:28])[C:22]([F:25])([F:24])[F:23])(=O)=O)C=CC=CC=1>CO.[OH-].[Na+].[Cl-].[Na+].O>[Br:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([CH2:20][C:21]([OH:40])([CH2:26][C:27]([C:30]1[C:38]3[O:37][CH2:36][CH2:35][C:34]=3[CH:33]=[C:32]([Cl:39])[CH:31]=1)([CH3:29])[CH3:28])[C:22]([F:25])([F:23])[F:24])=[CH:12]2
Reactant: CC(C)(CC(O)(Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CC(O)(Cc1cc2cc(Br)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 18 h
Yield: 63.1 %

Procedure:
A mixture of 2-(1-benzenesulfonyl-5-bromo-1H-indol-2-ylmethyl)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol (30 mg, 0.046 mmol) in 5 mL of methanol and 5 mL of 10% aqueous sodium hydroxide solution was warmed at reflux. After 18 hours, the mixture was diluted with brine and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of brine, three 5 mL portions of saturated aqueous ammonium chloride solution, 5 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (1 mm, silica gel, ethyl acetate-hexanes (3:7)) to afford 15 mg (63% yield) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(I)cc(C(=O)Cl)cc1C#N
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(I)cc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (317 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.70 mL) and 3-cyano-5-iodo-4-methoxybenzoyl chloride (527 mg) were added to the solution, and then the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (435 mg) as a yellow oily substance.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH:6]=[N:5]2.[CH2:24]([NH:26][CH2:27][CH2:28][NH:29]C(=O)C1C=CN=C(F)C=1)[CH3:25]>>[CH2:24]([NH:26][CH2:27][CH2:28][NH:29][C:12]([C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1)=[O:14])[CH3:25]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc2cc(I)ccc2n1
Reactant: CCNCCNC(=O)c1ccnc(F)c1
Product: CCNCCNC(=O)c1cnc2cc(I)ccc2n1
Yield: 92 %

Procedure:
This compound was prepared, starting from compound 24 (0.35 g, 0.83 mmol), according to the procedure developed for compound 36. Reaction time at room temperature: 28 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 54 (0.27 g, 0.76 mmol) as a beige solid. Yield 92%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.28; 1H NMR (200 MHz, CDCl3) δ 1.18 (t, 3H, J=7.1 Hz), 1.57 (se, 1H), 2.76 (q, 2H, J=7.1 Hz), 2.97 (t, 2H, J=6.1 Hz), 3.68 (q, 2H, J=6.0 Hz), 7.83 (d, 1H, J=8.8 Hz), 8.08 (dd, 1H, J=1.9, 8.8 Hz), 8.34 (m, 1H), 8.60 (d, 1H, J=1.9 Hz), 9.65 (s, 1H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Hf+4:5].[Li][Li].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=CC=1>>[CH2:12]1[C-:11]=[CH:14][CH:8]=[CH:13]1.[CH2:12]1[C-:11]=[CH:14][CH:8]=[CH:13]1.[Cl-:1].[Cl-:1].[Hf+4:5]
Reactant: Cc1ccccc1
Agent: [Hf+4]
Agent: [Cl-]
Agent: [Li][Li]
Product: [C-]1=CC=CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.81 g (5.6 mmol) of hafnium tetrachloride are added to a suspension, cooled to -78° C., of 2.00 g (5.64 mmol) of the dilithium salt (Example 4) in 150 ml of toluene. The orange suspension in allowed to warm to room temperature, and is stirred for a further 2 days in order to complete the reaction. Insoluble constituents are then filtered off via a frit, and the orange-red filtrate is evaporated to dryness on an oil pump 30 ml of pentane are added to the orange-red residue, and the mixture is stirred vigorously overnight. Removal of the solvent in vacuo gives the hafnocene dichloride as beige powder in a crude product yield of 700 mg (24%). The 1H-NMR spectrum of the crude product shows only one diastereomer.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:16]1([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=2)[CH:24]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][N:2]([CH:10]1[CH2:11][CH2:12][N:13]([CH2:24][C:23]2[CH:26]=[CH:27][N:28]=[C:21]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:22]=2)[CH2:14][CH2:15]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccnc(N3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
tert-Butyl methyl(piperidin-4-yl)carbamate (2.333 mmol, 1 eq) and 2-(pyrrolidin-1-yl)-isonicotinaldehyde (2.66 mmol, 1.14 eq) were dissolved in dichloromethane (15 ml), and acetic acid (5.459 mmol, 2.34 eq) and sodium triacetoxyborohydride (3.266 mmol, 1.4 eq) were added. The reaction mixture was stirred for 48 h at RT. When the reaction was complete (TLC monitoring), sat. sodium hydrogen carbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1). Yield: 64%.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[C:39](=O)[C:38]=2[CH:49]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3/[C:39](=[CH:7]\[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:38]=2[CH:49]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC/C=C1/c2cc(Br)ccc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122 mmole of n-butyl lithium in hexane, and 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (12.7 g., 43.8 mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure of Example I, Step b. This provided an E/Z (1:6) isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of pure Z-isomer as its hydrochloride salt, melting range 91°-100° C. and 2.16 g. of an E/Z (1:4) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 6.94-7.46 (m, 7H, aromatic), 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH2O), 3.07 (m, 4H, NCH2CH2), 2.75 (s, 6H, NMe2).
Reaction SMILES: CS(C)=O.C(=O)([O-])O.[K+].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>CC1(C)N(O)C(C)(C)CC(O)C1.O>[C:16]([O:20][CH2:11][CH2:12][CH2:13][C:14]#[N:15])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)O
Reactant: N#CCCCBr
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(=O)OCCCC#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a 200 mL three-necked flask, 33 g of dimethyl sulfoxide, 33 g of water, 14.8 g of potassium hydrogencarbonate, 10 g of 4-bromobutyronitrile, and 10 mg of 4-hydroxy TEMPO (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical) were added. Thereafter, 9.8 g of acrylic acid were added thereto dropwise. Then, the contents of the flask were heated to 80° C., and stirred at 80° C. for 4 hours. The resulting reaction liquid was cooled to room temperature. After cooling, the reaction liquid was washed with water, and was purified by column chromatography, to obtain 9 g of 3-cyanopropyl acrylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1>>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials piperidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-piperidin-1-ylbenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 1.60 (m, 6H), 2.30 (s, 3H), 2.82 (m, 1H), 3.52 (m, 4H), 7.02 (m, 2H), 7.27 (d, 1H), 7.55 (d, 1H), 7.96 (s, 1H), 8.02 (d, 1H), 8.39 (s, 1H), 9.95 (s, 1H); Mass Spectrum: M+H+ 423.