Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=NO)o2)cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2ccc(C#N)o2)cc1
Temperature: 25 °C

Procedure:
A 500 ml three-necked flask equipped with stirrer, thermometer and reflux condenser was charged with 5-(p-methoxyphenyl)-2-furaldehyde oxime (28 g, 0.129 mole) and acetic anhydride (317 ml). This mixture was refluxed (138°) for 3 hours. After cooling to room temperature overnight, the green solution was poured into ice water (ca. 2l. ) with stirring. When the ice melted, the solid was collected by filtration, washed with water, and dried to give 26 g.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>CC(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cnn(C)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cnn(C)c2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (460 mg) was dissolved in 2-propanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound as colorless crystals (yield 285 mg, 72%).
Reaction SMILES: C(O[C:5]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1)=[C:6](C1C=CN=CC=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1(C)C=CC=CC=1.N12C[CH2:50][CH2:49][N:48]=[C:47]1[CH2:46][CH2:45][CH2:44]CC2>CCOCC>[CH2:30]([C:20]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:17](/[CH:5]=[C:6](\[CH2:44][C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCc1ncc(C(OC(C)=O)=C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 90 °C

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(4-pyridyl)propenoate (7.5 mmol), toluene (50 mL) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) (3.4 mL, 22.5 mmol) was heated at 90° C. for 18 hours under argon. The cooled mixture was diluted with ether, and washed with brine, dried and concentrated to 3.1 g (97%) of the title compound. NMR showed that the trans or E isomer was the primary product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[C:27]1([CH2:33][CH2:34]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH2:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[S:25]
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: BrCCc1ccccc1
Reactant: S=C=S
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1c2[nH]c3ccccc3c2C[C@@H](CO)N1C(=S)SCCc1ccccc1
Yield: 95 %

Procedure:
In the same manner as described in Example 34 by using (1RS, 3RS)-cis-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (1.08 g), triethylamine (0.7 ml), CS2 (0.3 ml), 2-phenylethyl bromide (0.93 g) and dimethylsulfoxide (5 ml), there is prepared the title compound (1.88 g, 95%) as pale yellow powder, NMR (CDCl3, δ): 3.65 (b, t, J=6.0 Hz, 2H, ##STR24## Mass m/e: 396 (M+), 258 (M+ -- ##STR25##
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].CS[C:7](=[N:11][C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[NH:8][C:9]#[N:10].C([N:21](CC)CC)C>C(O)C.O>[CH3:2][O:3][NH:4][N:8]([C:9]#[N:10])[C:7]([NH:11][C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[NH:21]
Reactant: CON
Reactant: CSC(=Nc1ccc(Cl)nc1)NC#N
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CONN(C#N)C(=N)Nc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 0.7 %

Procedure:
169.2 mg (20 mMol) O-methylhydroxylamine hydrochloride and 2.0 g (8.3 mMol) S-methyl-N-cyano-N′-(6-chloropyrid-3-yl)isothiourea are added to 50 ml ethanol and treated with 1.27 ml (9.1 mMol) triethylamine and 50.0 ml water. The reaction mixture is then stirred for ca. 18 hours at 60° C. under a protective gas (argon). At the end of the reaction the ethanol is distilled off under reduced pressure and the aqueous residue is extracted three times with chloroform. After drying the organic phase is evaporated to dryness under reduced pressure and the residue is purified by preparative HPLC. 13.5 mg (0.7%) N-methoxyamino-N′-(6-chloropyrid-3-yl)cyanoguanidine are obtained.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[O:3][C:4]1[CH:44]=[CH:43][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:46][C:2]([F:1])([F:45])[O:3][C:4]1[CH:44]=[CH:43][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a mixture of the compound (54 mg) obtained in Step 1 and ammonium formate (49 mg) in ethanol (2.0 ml) was added 10% palladium carbon (50 mg) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (49 mg) and 10% palladium carbon (50 mg) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate) to give the title compound (24 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](Cl)=[N:33]1)=O)(C)(C)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:34]4[C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[NH:32][N:33]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccccc21
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4n[nH]c5ccccc45)cc3CC[C@@H]12
Yield: 41.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-(t-butoxycarbonyl)-3-chloroindazole (116 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 60 mg (16%) of the title compound as an oil. FDMS: m/e=377.
Reaction SMILES: [Cl-].COC[P+:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC)(=[O:31])CCCC=CC.C(O)(=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOCC>[C:6]1([P:5](=[O:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=CCCCC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
Into a dry 100 ml round bottom 3-necked flask containing a stir bar is added dried methoxymethyltriphenylphosphonium chloride ((C6H5)3P+ --CH2OCH3Cl-) (12.9 g, 37.7 mmol) and 235 ml distilled toluene (stored over molecular sieves). The resulting suspension is stirred in an ice-bath, under argon, until cold and then a 1.55M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A bright red solution formed which is stirred at 0° C. for an additional 35 minutes. Thereafter, a solution of 4.8 g (18.8 mmol) of [1β,2α(5Z),3α,4β]-7-(3-formyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene is added by means of a dropping funnel over a 35 minute period with the ice-bath still in place. The reaction is then quenched by addition of 2.3 g (39 mmol) of acetic acid in 5 ml ether. The mixture is immediately poured into 200 ml saturated NH4Cl, and extracted with ether (4×200 ml). The combined ether phases are washed with NaCl saturated solution, and dried (MgSO4 anhydrous) and concentrated to yield a yellow oil in a white crystalline solid (triphenylphosphine oxide). This is washed with EtOAc and the material in the washings is purified by chromatography on an LPS-1 silica gel column. The fractions obtained are (A) [1α,2β(5Z), 3β,4α]-7-[[3-(2-oxo)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, (B) [1α,2β(5Z),3β,4α]-7-[3-(2-methoxy)ethendiyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, and (C) [1α,2β(5Z),3β,4α]-7-[[3-(2,2-dimethoxy)ethyl]-7-oxabicylo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15]([C:24]3[O:25][C:26]([CH2:30]O)=[C:27]([CH3:29])[N:28]=3)=[CH:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:32]([N:34](CC)[CH2:35][CH3:36])[CH3:33].C(NCC)C.Cl>ClCCl.O1CCCC1>[ClH:5].[CH:6]1([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15]([C:24]3[O:25][C:26]([CH2:30][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[C:27]([CH3:29])[N:28]=3)=[CH:14]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cccc2c(-c3nc(C)c(CO)o3)cn(CC3CCCCC3)c12
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1oc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (1M solution in diethyl ether; 5.8 ml, 5.8 mmol) was added dropwise to a mixture of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester and 1-cyclohexylmethyl-7-methoxy-3-(4-methyl-oxazol-2-yl)-1H-indole (1171 mg) dissolved in tetrahydrofuran (20 ml) under ice-methanol cooling. The resulting mixture was stirred for 20 minutes at 0° C., then diluted with diethyl ether (40 ml). Excess sodium sulfate decahydrate was added and the resulting mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of dicalite, washing with diethyl ether (100 ml) and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography eluting with 50% (v/v) ethyl acetate in n-heptane to afford [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)4-methyl-oxazol-5-yl]-methanol as a white solid (774 mg). Methane sulfonyl chloride (281 mg, 2.45 mmol) was added dropwise to a solution of [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-4-methyl-oxazol-5-yl]-methanol (724 mg, 2.04 mmol) dissolved in dichloromethane (40 ml) at −78° C. under nitrogen. Triethylamine (269 mg, 2.66 mmol) was added dropwise and the mixture allowed to warm to room temperature with stirring for 2 h. The mixture was then diluted with dichloromethane (100 ml), washed with saturated sodium carbonate solution (2×100 ml) and brine (100 ml). The organic extracts were dried over magnesium sulfate then concentrated in vacuo. A mixture of the resulting residue (100 mg, 0.23 mmol), diethylamine (169 mg, 2.30 mmol) and tetrahydrofuran (2 ml) was subjected to microwave irradiation at 150° C. for 15 minutes. The resulting mixture was concentrated in vacuo and purified by flash column chromatography, eluting with 2% ammonia in methanol/dichloromethane in 1:49 ratio, to afford a brown gum. The gum was dissolved in dichloromethane (0.5 ml), then hydrogen chloride (1M solution in diethyl ether; 0.5 ml) was added and the mixture concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt (32 mg). 1H NMR (400 MHz, CD3OD) δ 0.85-1.38 (6H, m), 1.46 (6H, t, J 7.5), 1.55-1.78 (4H, m), 1.88 (1H, m), 2.39 (3H, s), 3.34 (4H, q, J 7.6), 3.98 (3H, s), 4.34 (2H, d, J 6.9), 4.65 (2H, s), 6.88 (1H, d, J 8.2), 7.23 (1H, t, J 8.0), 7.74 (1H, d, J 8.0), 8.00 (1H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:32].O.[OH-].[Na+]>CC(O)=O>[Br:32][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)=[CH:25][CH:26]=1
Reactant: Br
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of {3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol from Step 1 (1.0 eq.) in AcOH (0.3M) was added HBr (48%; 9.5 eq.). The mixture was stirred at 80° C. for 12 h, cooled to rt, poured in cold water containing 10 eq. of NaOH and extracted with EtOAc. The organic extract was washed with saturated aqueous NaHCO3 (3×), brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:27]([O-:32])=[O:28])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added 2.8 g (0.022 mole) of cyclohexene-4-carboxylic acid, then dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. The mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 5% sodium hydroxide solution, water and saturated sodium chloride solution and dried. The extracts are then concentrated to provide a solid residue which is recrystallized from aqueous ethanol to provide yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 122°-127° C., which is shown to be identical to the product of Example 2 by its infrared spectrum.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](Br)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[N-:37]=[N+:38]=[N-:39].[Na+].CN(C)C=O>C1OCCOCCOCCOCCOC1.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([N:37]=[N+:38]=[N-:39])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(CC)C(N=[N+]=[N-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.05 g, prepared as described in Example 29), sodium azide (0.60 g), 15-Crown-5 (0.02 g), water (1.2 ml) and N,N-dimethylformamide (10 ml) was heated at 100° C. for five hours, cooled, poured into water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-azido-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.64 g, m.p. 82°-84° C.). NMR (CDCl3): δ1.3(6H,dt), 1.6-2.0(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 4.65(1H,t), 7.1(6H,m), 7.3(9H,m), 8.0(1H,s). M/S: MH+ 531.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].[NH3:12].CO.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[NH2:12][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CBr)ccc1F
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1cc(CN)ccc1F

Procedure:
A solution of 5-(bromomethyl)-2-fluorobenzonitrile (300 mg, 1.402 mmol) in 7M NH3/methanol (5 mL, 35.0 mmol) was stirred at room temp for 18 h. After the removing the solvent the resulting residue was stirred with Et2O/sat. Na2CO3. The aqueous layer was then separated and the organic layer dried (Na2SO4), filtered and concentrated to give a 3:1 mixture of the title compound, amine 5-(aminomethyl)-2-fluorobenzonitrile contaminated and 5,5′-azanediylbis(methylene)bis(2-fluorobenzonitrile). The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.48-7.66 (2 H, m), 7.07-7.21 (1 H, m), 3.89 (2 H, s).
Reaction SMILES: [CH3:1][NH2:2].ClC(Cl)(Cl)[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[CH:25][CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].C(N([CH2:44][CH3:45])CC)C.CS(C)=O>C(#N)C>[CH3:31][C:30]1[O:35][C:44]([CH3:45])=[CH:26][C:29]=1[CH2:1][NH:2][C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[CH:25][CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CN
Reactant: CCN(CC)CC
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cc(C)oc4C)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared according to the procedure of Example 2 starting from 2,5-dimethyl-3-furyl)methylamine (0.264 g, 2.1 mmole), 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.138 g, 2.1 mmole), triethylamine (0.470 g, 2.2 eq., 4.6 mmole) and dimethylsulfoxide (1.1 g, 5.0 eq., 10.5 mmole) in 20 mL of acetonitrile. Flash chromatography of the residue on silica Merck-60 using a gradient elution of 30 to 45% ethyl acetate in hexane gave a white powder (0.453 g). Further purification was achieved by prep HPLC, Primesphere C18, 2×25 cm column, 68% acetonitrile in water containing trifluoroacetic acid, 100 ml/min, 254 nm detection. The pure fractions were neutralized with ammonium hydroxide and evaporated to an amorphous solid (0.153 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=[O:4].ClCCl.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(N(CC)CC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]([C:23](=[O:24])[CH2:22][Cl:21])[NH:6]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2C(C(=O)CCl)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
To a mixture of 7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (Example 33 (a), 4.466 g, 18.9 mmol), dichloromethane (130 ml) and triethylamine (3.0 ml), cooled in an ice bath, was added dropwise chloroacetyl chloride (1.74 ml, 21.8 mmol). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction mixture was then washed with dilute hydrochloric acid and then with water. The organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to yield 2-chloroacetyl-7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (6.22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)[CH:18]=[CH:19][C:20](=[O:26])[CH:21]=[CH:22]N(C)C.Cl>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:22]=[CH:21][C:20](=[O:26])[CH:19]=[CH:18]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CN(C)C=CC(=O)C=CN(C)C
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro -3(2H)-pyridazinone (101 mg), 1,5-bis(dimethylamino)-1,4-pentadien-3-one (84 mg) and hydrochloric acid (1N, 0.5 ml) in water (1.5 ml) was stirred at room temperature for 4 hours. More hydrochloric acid (1N, 0.5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours and then under reflux for 4 hours to afford a quantity of red insoluble material. The hot aqueous solvent was decanted off from the insoluble material, was allowed to cool and was seeded to afford the title compound, 41 mg, m.p. 245-249° C.