Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[N+:10]([C:6]1[C:5]2[O:13][CH:2]([CH2:3][OH:19])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1cccc2c1OC(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Br)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)[OH:18]>O>[Br:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][C:6](=[O:18])[C:7]=1[CH2:8][CH3:9]
Reactant: O=S(=O)(O)O
Reactant: CCc1c(Br)nc(-c2ccccc2)nc1Br
Solvent: O
Product: CCc1c(Br)nc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To 8.29 g (26.1 mmol) of crude 4,6-dibromo-5-ethyl-2-phenylpyrimidine was added a mixture of 4 mL of water and 15 mL of concentrated sulfuric acid. The mixture was stirred for 18 h and poured onto 200 g of crushed ice. After the ice had melted the precipitate was collected by filtration and dried under vacuum to afford 7.21 g (99%) of crude 6-bromo-5-ethyl-2-phenyl-4(3H)-pyrimidinone. 1H-NMR (d6-DMSO) δ 1.10(3H,t), 2.55(2H,q), 7.55(3H,m), 8.10(2H,m).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C1COCC1>[N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CN=[N+]=[N-])cc(N(C)S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 130 mg (0.475 mmol) of methyl 3-(hydroxymethyl)-5-(N-methylmethylsulfonamido)benzoate in 7 mL of toluene and 4 mL of THF was added 120 μL of diphenyl phosphoryl azide (DPPA). The solution was cooled to 0° C. and 86 μL (0.568 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) was added. The ice bath was removed, and stirring was continued with warming to room temperature. After about 16 h, the solution was diluted with EtOAc and H2O, and 1N HCl was added to a pH=8. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (50% EtOAc/hexanes) to give 151 mg of methyl 3-(azidomethyl)-5-(N-methylmethylsulfonamido)benzoate as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
10.0 g (corresponding to 80.0 mmol) of 2-bromoethanol and 10.9 g (corresponding to 160 mmol) of imidazole were dissolved in 100 mL of N,N-dimethylformamide (DMF), and cooled to 0° C. Then, 12.1 g (corresponding to 80.0 mmol) of t-butyldimethylchlorosilane (TBDMSCl) was added thereto. After the reaction mixture was stirred at room temperature for 3 hours, a saturated aqueous sodium hydrogencarbonate solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure (120° C., 100 mmHg), to obtain 14.5 g (corresponding to 60.6 mmol) of 1-bromo-2-(t-butyldimethylsiloxy)ethane (FIG. 9, Step 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([NH:35]C(=O)OC(C)(C)C)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:43])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([NH2:35])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:43])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 86.8 %

Procedure:
tert-Butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (1 eq, 243 mg, 0.380 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-50% CMA 80/ethyl acetate to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (178 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.64-1.95 (m, 2H) 2.10-2.29 (m, 5H) 3.50-3.66 (m, 1H) 3.70-3.88 (m, 1H) 4.03-4.19 (m, 1H) 4.42 (d, J=13.28 Hz, 1H) 7.04-7.10 (m, 2H) 7.13-7.20 (m, 1H) 7.20-7.40 (m, 6H) 7.40-7.50 (m, 3H).
Reaction SMILES: CS(O[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=O)=O.[Cl-:17].[Li+].O>CN(C)C=O>[Cl:17][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(CCCCC)OS(C)(=O)=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(Cl)CCCCC
Temperature: 15 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Thirty grams (0.12 mol) of 6-methanesulfonyloxyundecane was dissolved in 150 mL of N,N-dimethylformamide and 15.3 g (0.36 mol) of anhydrous lithium chloride was added to the solution under cooling with ice. The mixture was warmed to 50˜55° C. and stirred for 3 hours. Thereafter, the mixture was cooled to 15° C. and 300 mL of cold water was added. The reaction mixture was extracted three times with 150 mL of hexane and the organic layer was sequentially washed with 150 mL of water and 150 mL of a saturated aqueous solution of sodium chloride and thereafter dried over 6 g of anhydrous magnesium sulfate. After filtering off the anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 22.2 g (97.1% in yield) of 6-chloroundecane.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(Cl)Cl.O>[C:22]([C:20]1[C:19]2[N:24]=[N:25][N:26]([CH3:27])[C:18]=2[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[C:11]([C:28]([F:30])([F:29])[F:31])[CH:12]=2)[N:21]=1)#[N:23]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.5 %

Procedure:
Acetyl chloride (18.3 mg) was added to a mixture of 6-(4-(3-aminopropoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (100 mg) and triethylamine (294 μl) in DCM (2 ml). The mixture was stirred at room temperature for 2 hours then diluted with water, the organic layer was separated, dried over magnesium sulphate, and solvent was removed under reduced pressure. The residue was purified by HPLC to give the expected product (4.4 mg). 1H NMR (CD3OD) δ: 8.56 (s, 1H), 8.38-8.45 (m, 2H), 7.33 (d, 1H), 4.45 (s, 3H), 4.23 (t, 2H), 3.40 (t, 2H), 2.05 (quin, 2H), 1.95 (s, 3H). MS m/z 419 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>CC(CC(C)C)=O.O>[OH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 60 °C
Reaction time: 20 h

Procedure:
20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 l methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60° C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60° C. The reaction mixture is cooled to 25° C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50%) and 60 l water at 25° C. The methylisobutylketone is largely distilled off in vacuo, and the residue is dissolved in 80 l methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[F:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:2]([O:3][CH3:4])[CH3:1])=[O:11])=[CH:8][C:7]=1[F:15]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,O-Dimethylhydroxylamine (2.45 g, 25.1 mmol) was added to an ambient temperature solution of 4-bromo-3-fluorobenzoic acid (5 g, 22.8 mmol), EDC (5.25 g, 27.4 mmol), HOBt (4.2 g, 27.4 mmol) and NMM (12.55 mL, 114.2 mmol) in methylene chloride (50 mL). After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 40-80% ethyl acetate/hexane afforded 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][NH:21][CH:22]1[CH:30]=[CH:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:25]4[CH2:24][CH:23]5[CH:27]([CH2:28][CH:29]=[CH:30][CH:22]5[NH:21][CH3:20])[CH2:26]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CNC1C=CCC2CNCC21
Solvent: CC#N
Product: CNC1C=CCC2CN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC21
Yield: 100.4 %

Procedure:
282 mg (1 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are stirred in 3 ml of acetonitrile with 310 mg (2 mmol) of 4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindole at room temperature for 1 hour. The undissolved solid is filtered off with suction, washed with water and acetonitrile and dried at 120° C. under a high vacuum. 0.4 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained as a crude product, which is dissolved in 5 ml of half-concentrated hydrochloric acid under the influence of heat. The hydrochloride is precipitated by addition of ethanol, filtered off with suction and dried at 120° C. under a high vacuum.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[S:25][CH:24]=[CH:23][N:19]2[C:20](=[O:22])[CH:21]=1)[CH:2]([CH3:4])[CH3:3].[I:26]N1C(=O)CCC1=O>C(#N)C>[I:26][C:21]1[C:20](=[O:22])[N:19]2[CH:23]=[CH:24][S:25][C:18]2=[N:17][C:16]=1/[CH:15]=[CH:14]/[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C

Procedure:
A solution of Step 1 intermediate (600 mg, 1.683 mmol) was treated with N-iodosuccinimide (416 g, 1.851 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford 600 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.05 (d, J=6.9 Hz, 6H), 2.04-2.08 (m, 1H), 3.71 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 7.10-7.12 (m, 2H), 7.27-7.30 (m, 1H), 7.48-7.53 (m, 2H), 7.96 (d, J=4.8 Hz, 1H), 8.17 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 483.16 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:20]=O>C(O)=O>[CH3:20][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=O
Reactant: CCCCCCC(C)NCCCCc1ccccc1
Solvent: O=CO
Product: CCCCCCC(C)N(C)CCCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with dibroane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([NH:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:43])[CH3:37])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)CCCN
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1
Product: CN(C)CCCNc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)ccc2Cl)c1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in the sixth paragraph of the portion of Note a) immediately above which is concerned with the preparation of starting materials, 4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with 3-dimethylaminopropylamine to give 4chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide in 76% yield; NMR Spectrum: (DMSOd6) 1.62-1.74 (m, 2H). 2.12 (s, 6H), 2.27 (t, 2H), 3.08-3.13 (m, 4H), 3.18-3.22 (m, 2H), 3.69-3.74 (m, 4H), 6.58 (d, 1H), 6.67 (m, 2H), 7.15-7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H), 7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+599.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=474.4.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[NH:33][CH:34]=[CH:35][C:25]=3[C:24]=2[CH:23]=1)=O)(C)(C)C.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]>ClC(Cl)C>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[NH:33][CH:34]=[CH:35][C:25]=3[C:24]=2[CH:23]=1.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 100 mg (0.22 mmol) of 8-(2-tert-butoxycarbonylaminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 2 mL of dichloroethane. The solution is stirred at room temperature for 30 minutes then the solvents are evaporated. The residue is triturated with diisopropyl ether then the solid is filtered and washed with dichloromethane. It is taken up in 2 mL of dichloromethane then triethylamine is added to release the amine. Water is added and the compound is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated. The solid is triturated with water to give 35 mg (45%) of 8-(2-aminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: C=O.[CH:3](O)=O.[F:6][C:7]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])O.[Na+]>O>[F:6][C:7]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH3:3])[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCC2CCCNC2)c(F)c1
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCCC(COc2ccc([N+](=O)[O-])cc2F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
38% aqueous formaldehyde (1.00 ml) and formic acid (1.00 ml) were added to 3-(2-fluoro-4-nitrophenoxymethyl)piperidine (compound of Reference Example 53; 0.300 g, 1.18 mmol), and the mixture was stirred at 90° C. for 1 hour. The reaction mixture was adjusted to pH=8 by addition of saturated aqueous sodium hydrogencarbonate, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel to give the title compound (0.275 g, 87%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:14][C:15]1[N:16]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:17]=[CH:18][N:19]=1
Reactant: N#Cc1ccc(OCCCCl)cc1
Reactant: Cc1ncc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCOc1ccc(C#N)cc1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
There were dissolved, in 20 ml of dry N,N-dimethylformamide, 1.797 g of 4-(3-chloropropoxy)benzonitrile, 985 mg of 2-methylimidazole and 1 765 g of a 90% potassium t-butoxide, then the resulting solution was stirred at room temperature for 4.5 hours, poured into ice water, the resulting precipitates were filtered off and washed with water. The precipitates were recrystallized from a mixed solution of ethanol and water to give 1.682 g (yield 69.7%) of 4-[3-(2-methylimidazol-1-yl) propoxy]benzonitrile.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][CH:17]([OH:21])[CH2:18][C:19]#[N:20].C(=O)(O)[O-].[Na+]>C(O)C>[C:19]([CH2:18][CH:17]([OH:21])[CH2:16][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)#[N:20]
Reactant: N#CCC(O)CCl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CC(O)CC#N)CC1
Temperature: 90 °C
Reaction time: 19 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl 1,4-diazepane-1-carboxylate (4.65 g, 23.2 mmol) and 4-chloro-3-hydroxybutanenitrile (2.0 g, 17 mmol) in ethanol (40 mL) was added sodium bicarbonate (2.1 g, 25 mmol). The mixture was stirred at 90° C. for 19 hours. After cooling to room temperature, ethanol was evaporated. The remaining mixture was diluted with ethyl acetate and washed with water and brine. The organic was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0% to 10% methanol/DCM) to give the desired product as yellow oil (3.2 g, 68%). LCMS calculated for C14H26N3O3(M+H)+: m/z=284.1.