Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[CH:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N2CCN(C(C)C)CC2)ccc([N+](=O)[O-])c1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To the solution of 2-chloro-4-fluoro-3-methyl-1-nitrobenzene (12.5 g, 64.8 mmol, 1.2 equiv.) and isopropylpiperazine (10.8 g, 53.98 mmol, 1 equiv.) in 90 mL of anhydrous DMSO was added powdered K2CO3 (37 g, 269 mmol, 5 equiv.). The mixture was stirred at 40-50° C. overnight before it was poured into 200 mL of ice-water. The precipitates were collected and purified via chromatography on SiO2 to afford 1-(3-chloro-2-methyl-4-nitrophenyl)-4-(1-methylethyl)piperazine as a yellow solid (12.7 g, 79% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.95-1.05 (d, J=6.53 Hz, 6H), 2.31 (s, 3H), 2.60-2.72 (m, 5H), 2.89-2.95 (m, 4H), 6.87 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:13][C:12]2=[O:27])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[NH4+].[Cl-]>[Fe].CCO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]2=[O:27])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1N
Yield: 99 %

Procedure:
A solution of 1-(3-methyl-4-nitrophenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.46 g, 1.2 mmol) in 9:1 EtOH/H2O (20 mL) was treated with iron powder (0.62 g, 11.1 mmol) and NH4Cl (33 mg, 0.61 mmol), and the resulting suspension was heated at reflux for 18 h. The reaction mixture was filtered, while hot, through Celite® with portions of CH2Cl2 (2×25 mL) and MeOH (2×25 mL). The filtrates were combined and made basic with 1 N NaOH (10 mL). The solution was extracted with CH2Cl2 (2×40 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated to provide the title compound (0.409 g, 100%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.68 (d, J=7.0 Hz, 1H), 6.96 (s, 1H), 6.92 (dd, J=8.5, 2.0 Hz, 1H), 6.80 (d, J=1.5 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.63 (dd, J=7.0, 2.0 Hz, 1H), 5.11 (s, 2H), 2.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7](O)[C:3]=1[C:4]([OH:6])=[O:5].C(Br)C>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nccc(O)c1C(=O)O
Solvent: CCBr
Product: Nc1ncccc1C(=O)O

Procedure:
By substituting 2-amino-4-ethoxynicotinic acid (prepared by reaction of the 2-amino-4-hydroxynicotinic acid with ethyl bromide in accordance with the procedure of Yale and Pluscec, supra.) for the 2-aminonicotinic acid in Example 4, there is obtained the named compound.
Reaction SMILES: [CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28]C)[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C@H:14]([CH2:15]5)[C@@:5]4(CC2)[CH2:4]1.C(Cl)(Cl)(Cl)Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:46]1COC[CH2:47]1>>[CH:25]1([CH2:24][N:13]2[CH2:12][CH2:11][C@@:10]34[C:17]5[C:16]6[CH2:15][C@@H:14]2[C@H:5]3[CH2:4][C@H:3]([C@:2]([OH:34])([C:30]([CH3:32])([CH3:33])[CH3:31])[CH3:1])[C@H:8]([OH:28])[C@@H:9]4[O:23][C:18]=5[C:19]([OH:22])=[C:20]2[CH2:47][CH2:46][C:21]2=6)[CH2:27][CH2:26]1
Reactant: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of buprenorphine (1) (10.0 g, 21.58 mMol) in CCl4 (21.7 ml, 224.5 mMol) and THF (200 ml) was added at 0° C. LiAlH4 (320 ml, 1.0 M, 320 mMol) in THF. The reaction mixture was heated to 55° C. for 24 h. The resulting reaction mixture was cooled to 0° C. and the reaction was quenched by slow, portion-wise addition of Na2SO4·10H2O (103 g), followed by addition of EtOAc (400 ml). After 20 minutes agitation, the resulting slurry was filtered through the pre-packed Solka Floc-40 (18 g). The resulting wet cake was washed thoroughly with EtOAc (2×100 ml). The combined filtrate was concentrated to dryness, affording 13.5 g of crude compound 2 which was subsequently purified by column chromatography on silica gel to afford 6.03 g of compound 2 (62.2% yield) as a white solid with a purity of >99%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccnc1
Solvent: ClCCl
Product: O=C(OCc1cccnc1)n1ccnc1
Yield: 83.3 %

Procedure:
A solution of (pyridin-3-yl)methanol (2 g, 18.32 mmol) and di(1H-imidazol-1-yl)methanone (5.94 g, 36.65 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (3.1 g, 84%). LC/MS: m/z 204.1 (M+H)+ at 0.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) d 8.74 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 1H), 7.44 (s, 1H), 7.38 (m, 1H), 7.09 (s, 1H), 5.46 (s, 2H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:12])=[O:11]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 65 %

Procedure:
To a solution of 5.0 g (7.8×10-3 mol) of 2-(3-thienyl)-ethanol (Aldrich Chemical) in 10 ml of dry, freshly distilled pyridine was added 3.62 ml (1.2 equiv.) of methanesulfonyl chloride in 20 ml of pyridine at 5°-10° C. The addition was carried out gradually, over a period of about 15-20 min. The reaction mixture was stirred overnight at room temperature and was quenched by pouring into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic extracts were extracted once with 10% hydrochloric acid, followed by water and drying over Na2SO4. Evaporation of the solvent afforded 5.3 g of a light brown oil (65% yield), and tlc (CHCl3) showed a single spot. Chromatographic purification on silica gel afforded a light yellow oil. Nmr (CDCl3, δ rel TMS) 2.9s, 3H; 3.1t, 2H; 4.4t, 2H; 7.0-7.4m, 3H. Ir (neat, ν, cm-1) 3100w, 2930w, 29202, 1415w, 1355s, 1335s, 1245w, 1173s, 1080w, 1055w, 970s, 955s, 903m, 850m, 825w, 795s, 775s, 740w. MS, 206.0.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27]CC)=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].B(Br)(Br)Br.C(C1C(=O)N(C(NCC2C3C(=CC(OC)=C(S(=O)(=O)N)C=3)OCC2)=O)CC=1C)C>C(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:27])=[C:20]([S:23](=[O:25])(=[O:26])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Agent: BrB(Br)Br
Agent: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(N)(=O)=O)cc32)C1=O
Solvent: ClCCl
Product: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(O)c(S(N)(=O)=O)cc32)C1=O
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Preparation of the starting compound 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-ethoxychroman ##STR54## 9.5 ml (0.1 mol) of boron tribromide are added dropwise to a solution of 10.6 g (0.025 mol of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-methoxychroman in 75 ml of methylene chloride cooled to -10° C. After standing overnight at 20° C., the excess boron tribromide is destroyed after cooling to -10° C. by cautious dropwise addition of methanol. The mixture is then introduced into ice/water and extracted several times with methylene chloride. The combined methylene chloride extracts are dried, evaporated and recrystallized from methanol. 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-hydroxychroman of melting point 175° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][OH:14].[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C#CCO)c(Cl)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCO)c(Cl)c1
Reaction time: 12 h

Procedure:
A suspension of 1.25 g (6.808 mmol) 3-(2-chloro-4-nitro-phenyl)-prop-2-yn-1-ol and 1.00 g Raney nickel in 50 mL THF was hydrogenated for 12 h at RT and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated down i. vac.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](N)=[N:6][CH:7]=1.N([O-])=O.[Na+].[NH4+].[OH-].[BrH:18]>>[I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Br:18])=[N:6][CH:7]=1
Reactant: Nc1ncc(I)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(I)cnc1Br
Reaction time: 8 h
Yield: 23 %

Procedure:
5-iodo-3-nitro-2-aminopyridine (5.6 g, 21.1 mmol) and concentrated HBr (60 mL) were stirred at room temperature for ten minutes. Sodium nitrite (11.7 g, 170 mmol) was then slowly added followed by CuBr (3.9 g, 27.2 mmol). Stirring continued overnight. The mixture was poured into 1:1 NH4OH:H2O, extracted with ethyl acetate, dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography using 9:1 hexane:ethyl acetate to yield 5-iodo-3-nitro-2-bromopyridine (1.618 g, 23%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28](=[O:35])[NH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O.C(#N)C>ClCCl>[N:6]1([C:4]([C:3]2[CH:20]=[C:21]([CH:22]=[CH:23][C:2]=2[F:1])[CH2:24][C:25]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28](=[O:35])[NH:27][N:26]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c3CCCC4)ccc2F)CC1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F)N1CCCNCC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 5A (330 mg) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid (8 mL). The solution was warmed to ambient temperature, and acetonitrile was added. The mixture was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether and filtered to give the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ 1.70-1.76 (m, 4H), 2.02-2.11 (m, 2H), 2.52 (d, J=27.5 Hz, 4H), 3.32-3.36 (m, 2H), 3.40-3.46 (m, 2H), 3.51 (t, J=6.1 Hz, 2H), 3.95-4.01 (m, 2H), 4.06 (s, 2H), 7.19 (t, J=9.0 Hz, 1H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:34])=[C:17](F)[C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:35]([NH:42][C:17]1[C:18]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]3[CH:21]([CH3:25])[CH2:22][O:23][C:24]([C:19]=23)=[C:15]([C:12]2([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:14][CH2:13]2)[C:16]=1[F:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 200 mg of 10-(1-benzyloxycarbonylaminocyclopropyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. To the resulting solution was added 319 mg of benzylamine. The resulting mixture was stirred at 90°-100° C. for 4.5 hours. The reaction mixture was added to a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained and the resulting crystals were collected by filtration to obtain 110 mg (yield: 46.4%) of 8-benzylamino-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [Si]([O:8][CH:9]([C:20]([F:23])([F:22])[F:21])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:13])[CH3:12])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:23][C:20]([F:21])([F:22])[CH:9]([OH:8])[CH2:10][C:11]([CH3:12])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13]
Reactant: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(CC(O)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 550 mg (1.58 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]pyridine in 4.5 mL (4.5 mmol) of tetrabutylammonium fluoride (1.0 M solution in THF) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography to give 367 mg (99%) of 1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-ol as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.O.NN>C(O)C>[NH2:17][O:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 70 °C

Procedure:
A stirred suspension of 8-chloro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine (9.4 g., 0.02 mole) in absolute ethanol (100 ml.) was treated with hydrazine hydrate (1.45 ml.) and warmed, under nitrogen, at a bath temperature at 70° C. for 3 hours. The mixture was cooled in an ice bath and filtered. The solid was washed with ethanol and methylene chloride. The combined filtrate was concentrated in vacuo; the residue was mixed with water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in chloroform-ethyl-acetate and filtered through a small pad of silica gel. The filtrate was crystallized from methanol-ethylacetate to give 1-[(aminooxy)methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in three crops: 1.95 g. of melting point 190°-191.5° C.; 0.89 g. of melting point 183°-186° C.; 0.285 g. of melting point 183°-186° C. The analytical sample had a melting point 191°-192° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16]O)([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][N:41]2[C:37](=[O:47])[C:38]3[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:40]2=[O:42])([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1(CO)CCN(Cc2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC1(CN2C(=O)c3ccccc3C2=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of (1-benzyl-3-methoxymethylpyrrolidin-3-yl)methanol (Example A19, 1.71 g, 7.27 mmol), triphenylphosphine (2.16 g, 8.22 mmol), phthalimide (1.14 g, 7.73 mmol), and anhydrous tetrahydrofuran is cooled to 0° C. and treated with diethyl azodicarboxylate (1.62 g, 9.31 mmol). The resulting mixture is stirred at room temperature for 18 hours and concentrated under vacuum. The residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound, (0.58 g) as a solid. 1H NMR (200 MHz, CDCl3): δ 7.91-7.80 (m, 2H), 7.78-7.66 (m, 2H), 7.39-7.11 (m, 5H), 3.95-3.72 (m, 2H), 3.65-3.40 (m, 2H), 3.31 (s, 2H), 3.27 (s, 3H), 2.72-2.34 (m, 4H), 2.02-1.82 (m, 1H), 1.76-1.56 (m, 1H). MS ES: m/z 365 (MH+).
Reaction SMILES: [O:1]=[C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:25]([C:28]([C:38](=[O:40])[CH3:39])=[CH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)(=[O:27])[CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:25]([CH:28]([C:38](=[O:40])[CH3:39])[CH:29]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH:3]([C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:1])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:27])[CH3:26]
Reactant: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)C(C(C)=O)C(c1ccc(C#N)cc1)C(C(=O)Nc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (6.7 g, 19.2 mmol) (Example 3A) and 4-(2-acetyl-3-oxobut-1-en-1-yl)benzonitrile (4.2 g, 19.2 mmol) (Example 4A) in tetrahydrofuran (140 ml) is added tetrabutylammonium fluoride (9.9 ml of a 1 M solution in tetrahydrofuran). The reaction is stirred for 2 hours at room temperature, then concentrated in vacuo and chromatographed over silica gel 60 with cyclohexane/ethyl acetate mixtures as eluent. The product is isolated as a mixture of diastereomers.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9](/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:10].[Cl-].[NH4+]>CS(C)=O>[C:9](/[C:11](/[CH3:2])=[CH:12]/[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:10]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)c1cccc(/C=C/C#N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(/C=C(\C)C#N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.2 %

Procedure:
To a suspension of trimethylsulfoxonium iodide (2.88 g, 13.1 mmol) in dimethyl sulfoxide (10 mL) was added 60% sodium hydride (150 mg, 11.2 mmol), and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added methyl 3-[(1E)-2-cyanoethenyl]benzoate (700 mg, 3.74 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→85/15), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (205 mg, 27%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO[C:19](OC)([N:21]([CH3:23])[CH3:22])[CH3:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:19](/[N:21]([CH3:23])[CH3:22])\[CH3:20])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COC(C)(OC)N(C)C
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C

Procedure:
To a solution of 14.5 g. (0.10 m) of (p-fluorobenzoyl)acetonitrile in 100 ml. of chloroform, cooled in an ice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide dimethylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol®. The filtrate was evaporated and the oil thus obtained was dissolved in 50 ml. benzene to which petroleum ether was added until the solution became cloudy. The precipitate which formed upon cooling was collected. The solid was recrystallized twice from benzene-petroleum ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 90°-92° C.