Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.[NH3:39]>C(Cl)(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:39])=[O:28]
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (1.04 g, 2.42 mmol) in anhydrous chloroform (50 mL) was added oxalyl chloride (0.50 mL, 5.7 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (36 mL), cooled to 0° C. and 7 M methanolic ammonia (5.20 mL, 36.3 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with acetone/dichloromethane (1/9), followed by recrystallization from dichloromethane/diethyl ether to afford 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (1.03 g, 99%) as a colorless solid: mp 130-135° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.71-7.69 (m, 1H), 7.48-7.39 (m, 2H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.76-6.74 (m, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 6.10 (br s, 1H), 5.71 (br s, 1H), 5.14-5.09 (m, 1H), 4.95-4.81 (m, 2H), 4.67-4.64 (m, 1H), 4.19-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 168.7, 155.3, 144.7, 141.8, 138.4, 136.5, 134.0, 132.1, 130.8, 129.4, 128.9, 126.8, 126.5, 124.0, 123.7, 120.9, 111.4, 109.2, 99.5, 80.0, 64.5, 63.9, 58.1, 43.8; MS (ES+) m/z 428.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc(F)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(F)cc1C=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a mixture of 0.500 g (3.57 mmole) of 5-fluoro-2-hydroxy-benzaldehyde, 0.694 g (6.4 mmole) of triethylamine, and 5 mL of dichloromethane at 0 degrees was added dropwise, 0.444 g (3.90 mmole) of methanesulfonyl chloride. Stirring was continued for 15 minutes. The mixture was diluted with 30 mL of dichloromethane and washed with 20 mL of saturated ammonium chloride solution, 20 mL of water, 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.760 g of methanesulfonic acid 4-fluoro-2-formyl-phenyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](S)C1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 937 mg, 2.77 mmol), (R)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (prepared in STEP C of Example 18, c.a. 3.60 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80.1 mg, 0.138 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.1 mg, 0.0690 mmol) and N,N-diisopropylethylamine (725 microL, 4.15 mmol) in 1,4-dioxane (15 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (802 mg, 63% mmol) as a pale orange gum.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[CH2:4][CH2:3]1.O>[OH-].[Na+].CO>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCN(C)c4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCC(NC(=O)Nc2cccc3[nH]ncc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in example 95B was dissolved in 2 mls of 5N NaOH in methanol and stirred for 2 hours at ambient temperature. Water was added to the reaction mixture and the precipitate was collected. The precipitated compound was redissolved in 10% methanol in dichloromethane and purified by flash chromatography on silica using a gradient from dichloromethane to 20% methanol in dichloromethane with a few drops of NH4OH as the solvents to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.99 (s, 1H) 8.53 (s, 1H) 8.01 (s, 1H) 7.70 (d, J=7.46 Hz, 1H) 7.21 (t, J=7.97 Hz, 1H) 7.11-7.17 (m, 2H) 7.07 (t, J=8.48 Hz, 1H) 6.58-6.72 (m, 3H) 4.76-4.85 (m, 1 H) 3.15-3.29 (m, 2H) 2.89 (s, 3H) 1.99 (s, 2H). MS (DCI/NH3) m/z 322.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15].Cl>CCOCC.O1CCCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]([OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
A solution of 2-bromoanisole (50 g, 0,267 mol) in ether is added portionwise to a mixture of magnesium (7.1 g, 0,293 mol) in ether. After the addition is complete, the reaction mixture is heated at reflux for 1 hour, diluted with ether, cooled to 0° C., treated with a solution of 2-chloro-5-nitrobenzaldehyde (39 g, 0.210 mol) in tetrahydrofuran, warmed to room temperature and diluted with an ice/water mixture. After acidifying the aqueous mixture with hydrochloric acid (pH2-pH3), the organic phase is separated and the aqueous phase is extracted with ether. The extracts are combined, washed sequentially with 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown gum.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=[C:8]1[S-:18].[K+].CI>CN(C)C=O>[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=[C:8]1[S:18][CH3:2]
Reactant: C1CCOC1
Reactant: Cn1c([S-])nc2c(c1=O)CCCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2c(c(=O)n1C)CCCC2
Temperature: 25 °C

Procedure:
To a mixture of 10 ml of tetrahydrofuran and 5 ml of dimethylformamide, 340 mg of potassium 3-methyl-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-2-thiolate was added, followed by addition of 210 mg of methyl iodide and an overnight's stirring at room temperature. The solution was concentrated, to which chloroform was added, followed by washing with saturated brine and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 310 mg (quantitative) of 3-methyl-2-methylthio-5,6,7,8-tetrahydro-3H-quinazolin-4-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, benzylamine (1.58 g, 0.0147 mole) was added and the reaction was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated, to give a solid. The solid was recrystallized from isopropyl alcohol, collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. overnight to give 3.43 g (65%) of title compound, mp 200°-200.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)=[O:18]
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and (3S)-1-benzylpyrrolidin-3-ylamine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50:1, changing to 20:80:1, by volume, hexane:ethyl acetate:0.88 aqueous ammonia solution, in 10% increments. The product was further purified by recrystallisation from ethyl acetate:hexane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].O>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CNc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
In 30 ml of DMF was dissolved 2.12 g (13.8 mmol) of 4-amino-2-hydroxybenzoic acid, and 3.0 g (13.8 mmol) of geranyl bromide was added thereto. After the mixture was stirred at room temperature for 4 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography and recrystallized from ethyl acetate/hexane to obtain 0.30 g (yield: 7.6%) of N-{(2E)-3,7-dimethylocta-2,6-dienyl}-4-amino-2-hydroxybenzoic acid represented by the following structural formula (hereinafter referred to as compound 47) as white crystals. The analytical results are shown below. ##STR68##
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24](O)[CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:24][CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., triethylamine (0.131 ml, 0.942 mmol) and methanesulfonyl chloride (0.0665 ml, 0.856 mmol) were added to a solution of 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (204 mg, 0.544 mmol) in methylene chloride (10 ml). After stirring at 0° C. for 1 hour, the reaction mixture was diluted with methylene chloride, washed successively with a saturated aqueous ammonium chloride solution, water and brine, dried over MgSO4, and then concentrated. The residue was dissolved in tetrahydrofuran (5 ml). After cooling the solution to 0° C., potassium hexamethyldisilazide (a 0.5M toluene solution, 1.30 ml, 0.650 mmol) was added thereto. The resulting mixture was stirred at 0° C. for 3 hours, and saturated ammonium chloride was added thereto. The resulting mixture was extracted with ethyl acetate, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (15% ethyl acetate-hexane). The resulting solid was recrystallized from hexane, whereby the title compound (33.0 mg, 17%) was obtained as colorless needle crystals.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1([C:31](O)=[O:32])[CH2:30][O:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([C:27]5([CH3:26])[CH2:30][O:29][CH2:28]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC1(C(=O)O)COC1
Agent: Cl
Product: CC1(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)COC1

Procedure:
The title compound, white solid (13.6 mg, 37.3%), MS (ISP) m/z=429.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 0.085 mmol) and 3-methyl-oxetane-3-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1.[C:21]([O:25][C:26](NCC1CN(C(C2C=CC=CC=2)C2C=CC=CC=2)C1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NCCC1CN(C(c2ccccc2)c2ccccc2)C1
Product: CC(C)(C)OC(=O)NCCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from 3-aminoethyl-1-benzhydryl azetidine according the procedure for 3-(N-tert-butyloxycarbonylaminomethyl)-1-benzhydryl azetidine, in a yield of 6.5 g (95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1>CN(C=O)C.C(N(CC)CC)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:20]2[N:19]([C:17]([CH:14]3[CH2:13][CH2:12][CH:11]([CH2:10][NH:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:16][CH2:15]3)=[O:18])[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]=2[CH:30]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CN)CC1)C2
Reactant: CCCCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCNCC1CCC(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (2.05 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=458.4
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[C:10]([Cl:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:40]=[N+:41]=[N-:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:40]=[N+:41]=[N-:42])[CH3:15])=[C:10]([Cl:17])[CH:9]=1
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl

Procedure:
To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0° C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, N.Y.) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26].C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[N:6]=[C:5]2[O:4][C:3]([C:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[C:10]2=[CH:9][C:8]=1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Product: O=C(CO)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the general acylating procedure described in Example 18, the product of Example 157 was reacted with acetoxyacetyl chloride and then subjected to the general ester hydrolysis procedure described in Example 25 to afford the title compound. HPLC/MS: 518.0 (M+1), 520.0 (M+3); Rt=3.52 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1>>[N+:1]([C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:6]([F:15])([F:5])[F:14])[CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Product: O=c1[nH]cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 75 h

Procedure:
To 0.95 l. of stirred fuming nitric acid was added 29 g. of 5-trifluoromethyl-2-pyridone over 1 hour, and stirring was continued for 75 hours. The fuming nitric acid was evaporated and the residue was triturated with acetone. The acetone was evaporated to about 60 ml. and the precipitate was collected on a filter and washed with a 5:1 mixture of methylene chloride:acetone and dried and used directly in the next step.
Reaction SMILES: Br[CH:2]([CH:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:3](=[O:12])[CH2:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])(=O)C.[K+]>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[O:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3](=[O:12])[CH:2]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(Br)C(Br)c1ccccc1OC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)cc(-c2ccccc2OC)o1
Reaction time: 8 h

Procedure:
A solution of ethyl 5,6-dibromo-2,4-dioxo-6-(2-methoxyphenyl)hexanoate (9.5 g) and potassium acetate (10.0 g) in absolute ethanol (100 ml) was heated under reflux for 5 hours and then allowed to stand at room temperature overnight. The mixture was evaporated and the resulting brown residue dissolved in water (150 ml) and diethyl ether (150 ml). The ethereal solution was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulphate, filtered and evaporated to give a tan coloured solid. Recrystallisation from ethanol-water yielded the title product as pale yellow needles (mp 78°-81° C.).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[N+](C1C=CC([O:34][C:35](=O)[C@H:36]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=CC=1)([O-])=O.CN(C)C=O>C(OCC)C>[ClH:1].[CH2:41]([O:40][C:38]([NH:37][C@H:36]([C:35]([NH:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:34])[CH2:48][CH:49]([CH3:50])[CH3:51])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of L-arginyl-L-prolyl-glycinamide hydrochloride (from de-protection of 21.2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-glycinamide hydrochloride), 17 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenyl ester and 85 ml. of dimethylformamide is allowed to stand at 25° C. for 48 hours, warmed to 50° C. for 10 minutes and let stand for six hours at 25° C. The solution is poured slowly into 800 ml. of stirred dry diethyl ether. The sticky solid is separated by decanting, dissolved in 50 ml. of methanol with warming and the solution poured into 500 ml. of stirred ether. The solid is separated and dried at 40° C. under reduced pressure. It is dissolved in 50 ml. of methanol and 450 ml. of chloroform and chromatographed over a column of 170 g. of silica gel (prepared in 10% methanol in chloroform) and eluted with 10 to 20% methanol in chloroform. The desired fractions, as shown by thin layer chromatography, are combined and evaporated to dryness at 40° C. under reduced pressure and the residue is dissolved in 50 ml. of methanol and 25 ml. of ethyl acetate and the solution is dropped slowly into 350 ml. of stirred dry ether. The solid is separated and dried at 40° C. under reduced pressure to give Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride; 11.6 g.; [α]D23 -51.6° (c 1.0, methanol); ultraviolet in methanol λmax 257 E11 3.24.