Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:33]([F:36])([F:35])[F:34])=[C:16]([CH2:20][O:21][CH:22]4[CH2:25][N:24]([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.ClCC1C=CC(C2C(C(F)(F)F)=C(COC3C[N:55](C(NC(C)(C)C)=O)[CH2:54]3)C=CC=2)=CC=1.CN1CCNCC1>>[CH3:54][N:55]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15]([C:33]([F:35])([F:34])[F:36])=[C:16]([CH2:20][O:21][CH:22]4[CH2:23][N:24]([C:26]([NH:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25]4)[CH:17]=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CN4CCOCC4)cc3)c2C(F)(F)F)C1
Agent: CN1CCNCC1
Product: CN1CCN(Cc2ccc(-c3cccc(COC4CN(C(=O)NC(C)(C)C)C4)c3C(F)(F)F)cc2)CC1
Yield: 67 %

Procedure:
3-[4-(4-methyl-piperazin-1-ylmethyl)phenyl-2-(trifluoromethyl)phenyl]methoxy-N-(tert-butyl)azetidine-1-carboxamide (211) was prepared using the procedure given in Example 146 for compound 196, starting from compound 195 and N-methylpiperazine. Purification through an SCX-2 cartridge afforded the title compound as a white solid (32 mg, 67% yield).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[CH:10]=1)(=[O:8])C>O.O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:2])[CH:18]=[CH:17]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a solution of sodium hypochlorite (62 ml, 5.25% in water (w/w), 3.6 g, 48.18 mmol) and sodium hydroxide (6.4 g, 160.6 mmol) in 50 ml of water was added a solution of 2-acetyl-6-bromonaphthalene (Compound L) 4 g, (16.06 mmol) in 50 ml of 1,4-dioxane. The yellow solution was heated to 70° C. in an oil bath for 2 hours, cooled to ambient temperature, and extracted with ethyl ether (2×50 ml). The aqueous layers were diluted with NaHSO3 solution (until KI indicator solution remained colorless) and then acidified (pH<2) with 1N sulfuric acid to give a white precipitate. The mixture was extracted with ethyl ether, and the combined organic phase washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give 3.54 g (88%) of the title compound as a solid. 1H NMR (DMSO-d6): δ 8.63 (1H, br s), 8.32 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.00-8.05 (2H, m), 7.74 (1H, dd, J=2.0, 8.8 Hz).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(Cl)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(Cl)C(Cl)=O)C=CC=CC=1.N1CCOCC1.[NH:46]1[CH:50]=[CH:49][N:48]=[CH:47]1>C(#N)C>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:47]2[NH:46][CH:50]=[CH:49][N:48]=2)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: O=C(N1CCOCC1)C(Cl)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1COCCN1
Product: O=C(N1CCOCC1)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
A mixture of 15.5 g of diphenylchloroacetic acid morpholide, m.p. 113° C (prepared from diphenylchloroacetyl chloride and morpholine in accordance with the procedure described in Ber. 41, 3593) and 11g of imidazole in 100 ml of acetonitrile is heated at reflux for 18 hours. The solvent is removed by distillation in vacuo and, after addition of 70 ml of water, the residue is extracted with methylene chloride. The extracts are dried and the solvent is removed by distillation to yield diphenyl-imidazolylacetic acid morpholide which is further purified by recrystallization from methanol. The hydrochloride salt, m.p. 118° C, is obtained by treating an ethyl acetate solution of the free base with an ethereal solution of hydrogen chloride.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:17]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:17][CH2:18][CH2:19][O:20]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: CC1(CCCC=O)C(OCc2ccccc2)CCCC12OCCO2
Solvent: CCOCC
Product: CC(O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Methyllithium (63.3 ml, 0.0918 mol, 1.45 M in ether) is added dropwise to a solution of the aldehyde (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane (25.4 g, 0.0765 mol) in ether (1000 ml) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hours at ambient temperature. The mixture is then poured into a cold saturated sodium chloride solution (500 ml). The ether phase is separated and the aqueous phase is extracted with ether (3×100 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (27.1 g) is chromatographed on SilicAR CC-7 (300 g, Millinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane as a colorless oil (25.8 g, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250 mL 3 neck flask with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following was added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethyl-piperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of ethyl acetate. The mixture was heated slowly to reflux. After overnight reflux, the mixture was cooled to ambient temperature, after which 60 mL of deionized water was added. The aqueous layer was separated and discarded. The organic layer was extracted with 4N hydrochloride (3 aliquots of 20 mL). The combined acid extracts were heated to reflux. After 1 hour at reflux, HPLC indicated the saponification to be 609 complete. After 4 hours, the reaction was near 100% complete. The mixture was cooled to 0° C.-5° C. and stirred. The resulting crystals were filtered, rinsed with acetone and dried.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]1[CH2:13][O:12][S:9](=[O:11])(=[O:10])[CH2:8][CH2:7]1>O1CCCC1>[C:1]([NH:5][CH2:13][CH2:6][CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S1(=O)CCCCO1
Solvent: C1CCOC1
Product: CC(C)(C)NCCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-butylamine (1.0 mL, 9.5 mmol) in tetrahydrofuran (4 mL) was added 1,4-butane sultone (1.36 g, 10.0 mmol) at room temperature. The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. Yield: 690 mg (34%). 1H NMR (D2O, 500 MHz) δ ppm 2.92 (t, 2H, J=7.1 Hz), 2.82 (t, 2H, J=7.1 Hz), 1.68 (m, 4H), 1.22 (s, 9H). 13C (D2O, 125 MHz) δ ppm 57.07, 50.30, 40.95, 25.28, 24.96, 21.62. ES-MS 210 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]2=[N:13][N:14]=[C:15]([CH3:16])[N:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:16][C:15]1[N:4]2[N:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[CH:10]4[CH2:12][CH:7]([C:6]=3[C:5]2=[N:13][N:14]=1)[CH2:8][CH2:9]4
Reactant: Cc1nnc2c3c(c(Cl)nn12)C1CCC3C1
Reactant: C1COCCN1
Product: Cc1nnc2c3c(c(N4CCOCC4)nn12)C1CCC3C1
Yield: 80.6 %

Procedure:
The 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine (4.5 grams, 0.019 mol) was mixed with 25 milliliters of morpholine and the mixture heated at boiling under reflux for eight hours. The reaction mixture was concentrated and partitioned between methylene chloride and water. The organic layer was collected, dried over sodium sulfate and evaporated to dryness to yield 4.4 grams (80.6% yield) of 7,8,9,10-tetrahydro-3-methyl-6-(4-morpholinyl)-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After recrystallization from benzene-hexane the product was found to melt at 166°-168° C. Infrared analysis and nuclear magnetic resonance analysis confirmed the assigned structure, as did elemental analysis. Calculated for C15H19N5O: C, 63.14; H, 6.71; N, 24.55. Found: C, 63.20; H, 6.71; N, 24.32.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7].O.[OH-].[Li+:32].Cl>C1COCC1.O>[Li+:32].[CH:26]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[C:6]([NH:5][CH2:4][C:3]([O-:29])=[O:2])=[O:7])=[CH:13][CH:14]=1)([CH3:27])[CH3:28]
Reactant: COC(=O)CNC(=O)c1cccc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)NCC(=O)[O-])c2c1)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of N-[7-(triisopropylsilyloxy)naphthalene-1-carbonyl]glycine methyl ester, as described above in Step C, (175 mg, 0.42 mmol) in 4:1 THF/water (5 mL) at ambient temperature was added lithium hydroxide monohydrate (18 mg, 0.44 mmol). After 30 min, the solution was adjusted to pH 7 with 1.0 N hydrochloric acid and concentrated in vacuo. The residue was concentrated from toluene in vacuo (3×10 mL) to give the titled product.
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].Cl[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>CO.O.CO>[N+:16]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[S:1][S:1][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])([O-:18])=[O:17]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [S-2]
Agent: [Na+]
Agent: [S]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(SSc2ccc(C(=O)OC)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A solution of sodium sulfide.nanohydrate (1.15 g, 4.9 mmol) in methanol-water (ca. 10 mL, 1:1) is warmed on a hot plate. To this solution is added elemental sulfur (150 mg, 4.6 mmol). Heating is continued for 15 min before the solution is poured into a separate solution of 1.0 g (4.6 mmol) of methyl 4-chloro-3-nitrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48, 837.) in MeOH (5.0 mL). The mixture is stirred for 30 min, followed by cooling in a refrigerator overnight. The solid precipitate is filtered, washed with water and methanol, and dried in vacuo at 50° C. to afford 650 mg (65%) of dimethyl 4,4′-dithio-bis-(3-nitrobenzoate) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.0, 8.2, 7.9, 4.0.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1ccnc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 55.3 %

Procedure:
5.0 gm (0.016 mol) of 4-hydroxy-2-methyl-2H-naphtho[ 2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.2 gm (0.02 mol) of 2-amino-4-methylpyridine in 220 ml of xylene analogous to Example 10, and yielded 3.5 gm (58% of theory) of 4-hydroxy-2-methyl-N-(4-methyl-2-pyridyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 221° C (decomp.; from ethyl acetate).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:48]([OH:50])=O)[CH2:46][OH:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:51]([O:55][C:56](=[O:61])[NH:57][CH2:58][CH2:59][NH2:60])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([CH2:46][OH:47])[C:48]([NH:60][CH2:59][CH2:58][NH:57][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:61])=[O:50])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.05 g (2.759 mmol) of HATU and 648.3 mg (5.016 mmol) of N,N-diisopropylethylamine are added to a solution of 600 mg (2.5 mmol) of N-[(benzyloxy)carbonyl]-L-serine in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 442.0 mg (2.76 mmol) of tert-butyl(2-aminoethyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.C(N(CC)CC)C.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a stirred solution of 1-bromo-3-(bromomethyl)benzene (677 mg, 2.71 mmol) in THF (10 ml) was added triethylamine (380 μL, 2.71 mmol), followed by tert-butyl piperazine-1-carboxylate (504 mg, 2.71 mmol). The mixture was allowed to stir at RT for one hour. The solvent was evaporated and the residue was purified with a silica gel column eluting with 1:10 EtOAc/hexanes to give the title compound as an oil (888 mg, 2.49 mmol, 92%). [M+H] calc'd for C16H24BrN2O2, 355; found, 355.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=O)=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH3:30].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CCOCC>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:30])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOCC
Solvent: c1ccccc1
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
A solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in abs. benzene is saturated with ammonia. After cooling of the solution to 0°, an addition is made portionwise, with a light flow of ammonia gas and in the course of 45 minutes, of 14.0 g (0.030 mole) of lead tetraacetate. The reaction mixture is then stirred for a further 24 hours at 25°; it is subsequently diluted with ether and filtered through kieselguhr. The filtrate is washed with 1N hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed through silica gel with the use of ethyl acetate as eluant. The fractions containing the desired nitrile [Rf = 0.63 in the eluant system ethyl acetate/isopropanol (7:1)] are combined, and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].C(N(CC)C(C)C)(C)C.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CNCCCN(C)C
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)N(C)CCCN(C)C

Procedure:
A mixture of 3.89 g. (0.0335 mol) of N,N,N'-trimethyl-1,3-propylenediamine and 4.33 g. (0.0335 mol) of N,N-diisopropylethylamine in 50 mL chloroform was added to 7.33 g. (0.0335 mol) of lauroyl chloride dropwise, on an icebath, and was then reacted for another two hours at room temperature. 75 mL of aqueous sodium bicarbonate was then added to this reaction mixture, and the chloroform layer was separated and washed with 125 mL aqueous sodium bicarbonate followed by 100 mL water. The chloroform layer was then dried (MgSO4) filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[C:4]([N+:25]([O-:27])=[O:26])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN(CCc1ccc(F)cc1[N+](=O)[O-])S(=O)(=O)c1csc2c1CCCC2=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-ethyl]-methyl-amide (the compound of Preparation Example 41) (222 mg) was dissolved in a concentrated sulfuric acid (1.5 mL), potassium nitrate (74 mg) was added in small amounts on an ice bath. After stirring for 45 minutes, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and dried with anhydrous magnesium sulfate. Spots for two products were identified by silica gel TLC (hexane/ethyl acetate=1:1). The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), fractions with a high RF value were collected, and the title compound (78 mg) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1c(Cl)cc(Cl)cc1Cl
Yield: 51 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4,6-trichlorobenzenesulfonyl chloride (15.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 51% yield (10.7 mg). MS (ESI+) calcd mass for C13H8Cl3N5O2S 402.946428, found 402.946218.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].CN(C)C=O.C(N(CC)CC)C.[N+](C1C=CC([O:44][C:45]([N:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:45]([N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][CH2:48]1)=[O:44])(=[O:12])=[O:11]
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of N-(6-Aminohexyl) -2-trifluoromethylbenzene sulfonamide Hydrochloride( 0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3, 4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.C(O/[CH:16]=[C:17](/[C:23](=O)[C:24]([F:27])([F:26])[F:25])\[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]([C:24]([F:27])([F:26])[F:25])=[N:2][NH:3][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 146.66 mmol) in ethanol (500 mL) at −20° C. was added DIPEA (45.3 mL, 266.66 mmol) followed by stirring at this temperature for 10 minutes. Ethyl (2Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (Preparation 113, 32 g, 133.33 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and diluted with EtOAc. The organic solution was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30% EtOAc in hexane to afford the title compound (13 g) that was taken directly on to the next step.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(O)C>CC(C)=O>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1OC
Yield: 77.6 %

Procedure:
The compound was prepared according to general procedure E with vanillin (5.3 mmol) in dry acetone (20 ml), anhydrous K2CO3 (6.8 mmol), and ethylbromoacetate (6.3 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 980 mg of pure compound were obtained (78% yield). 1H NMR (250 MHz, CDCl3): δ 1.23 (m, 3H), 3.88 (s, 3H), 4.21 (m, 2H), 4.78 (s, 2H), 6.90 (m, 1H), 7.38 (m 2H), 9.80 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 13.9, 55.7, 61.2, 65.6, 109.8, 112.3, 125.7, 130.8, 149.7, 152.4, 167.9, 190.6 MS (ESI): m/z 253.0 [M+H]+.