Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]([C:24]2[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:22][CH3:23])[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([CH3:18])[C:12]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:43][NH2:44]>CS(C)=O.[Na+].[Cl-]>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12](=[C:13]([CH3:18])[CH:14]=1)[NH:44][N:43]=[C:9]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:40][CH:41]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Cl)cc(C)c1Cl)c1ccc(Cl)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(C)cc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of the major diastereomer of the product of Step A (271 mg, 0.439 mmol) in DMSO (25 mL) was added hydrazine hydrate (60 wt %, 0.90 mL, 11 mmol). The mixture was stirred at 100° C. for two days in a sealed tube. The mixture was diluted with saturated NaCl (aq) then extracted twice with ethyl acetate. The combined organic layers were then washed with 2 N HCl (aq), saturated NaHCO3 (aq), and saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the major diastereomer of the title compound as a solid. This diastereomer was resolved to provide enantiopure material by supercritical fluid chromatography on a ChiralPak OJ-H column (2 cm×25 cm) eluting with 50 mL/min of 20% (MeOH+0.1% Et2NH) and 80% CO2 at 35° C. and 100 bar. LC1 2.58 min. (M-tBu+H)+ 538.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11]([NH:41][C:38]2[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=2)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C)ccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.7 %

Procedure:
To a solution of 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline (152 mg, 0.454 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (168 mg, 0.681 mmol), and the mixture was stirred for 40 min at 0° C. DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4, and concentrated under reduced pressure. To the residue (154 mg) was added 5-methyl-1H-pyrazol-3-amine (132 mg, 1.36 mmol) in THF (4 mL), and the mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Varian Diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/5% ACN/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (62.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 12.08-12.20 (m, 1H), 10.53-10.66 (m, 1H), 8.66 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 7.93-8.03 (m, 2H), 7.66 (s, 1H), 7.48 (d, J=7.5 Hz, 1H), 5.99 (s, 1H), 2.51 (s, 4H), 2.18 (s, 3H). LCMS (ESI) m/z 386 (M+H)+.
Reaction SMILES: [PH3:1].[C:2]1([CH3:8])[CH:7]=[CH:6]C=CC=1>>[CH2:6]([P:1]([CH2:6][CH2:7][CH2:2][CH3:8])[CH2:8][CH2:2][CH2:7][CH3:6])[CH2:7][CH2:2][CH3:8]
Reactant: P
Reactant: Cc1ccccc1
Product: CCCCP(CCCC)CCCC

Procedure:
0.52 kg PH3 and 2.6 kg butene-(1) were reacted as described in Example 7 to give an about 50% solution of tri-n-butyl-phosphine in toluene. Introduced thereinto under slight overpressure were 16.2 kg butene-(1) and 2.82 kg PH3. The whole was heated to about 70° C. and initiator solution was metered thereinto. The exothermal reaction made the temperature increase to 106° C. and the pressure to 23 bars. Altogether 3 l initiator solution was added within 3 hours. The pressure was then found to have dropped to 5 bars (at 120° C.). The whole was allowed to cool, a specimen was taken and analyzed gas-chromatographically. It was an about 67% tributylphosphine solution in toluene, corresponding to a conversion rate of more than 95%, based on butene and PH3.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH3:2].CN(C)N>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([C:12]1[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[O:15][C:13]=1[CH3:14])=[O:16])[CH3:2]
Reactant: CCc1cccc(C)c1NC(=O)CC(C)=O
Agent: CN(C)N
Product: CCc1cccc(C)c1NC(=O)c1c(C)oc(C)cc1=O
Yield: 58 %

Procedure:
The title compound was prepared from N-(2-ethyl-6-methylphenyl)-3-oxo-butanamide and N,N-dimethylhydrazine in a manner similar to the method described in Example 2. (Yield: 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 100.5 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-{5-[4-(t-butoxycarbonyl-n-hexylamino)phenoxy]-2-nitrophenyl}-N-methylcarbamate (13.8 g), palladium on carbon (10%, 1.0 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (13.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:1]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][CH:7]=[C:6]4[CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[NH:27][C:22]=2[CH:21]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CN1CCC(c2c[nH]c3ccc(C=O)cc23)CC1
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccc(F)cc5[nH]4)cc23)CC1
Temperature: 155 °C
Reaction time: 24 h
Yield: 23.9 %

Procedure:
A solution of 5-formyl-3-(1-methylpiperidin-4-yl)-1H-indole (0.210 g, 0.90 mmol), and 4-fluoro-o-phenylenediamine (0.112 g, 0.90 mmol), in 15 mL of nitrobenzene was heated, with stirring, at 150-160° C. for 24 hours. An additional 0.5 equivalents of the diamine was added, and heating continued for an additional 24 hours. The solution was allowed to cool to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (dichloromethane:methanol 10:1.5) to give the title compound (0.075 g, 25%) as an amorphous tan solid. FDMS m/e=348 (M+). EA calculated for C21H21N4F.¾ H2O: C, 69.69; H, 6.27; N, 15.48. Found: C, 69.61; H, 6.19; N, 15.17.
Reaction SMILES: [CH2:1]([S:8][CH:9](N)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:12].B>C1(C)C=CC=CC=1.[Ru].ClC1CCC=CCCC=1Cl.[Co](Cl)Cl>[CH2:1]([S:8][CH2:9][CH2:10][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(N)SCc1ccccc1
Agent: Cl[Co]Cl
Agent: [Ru]
Agent: B
Solvent: Cc1ccccc1
Product: NCCSCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
This compound was prepared in situ as described above. In a typical experiment, benzylthio ethanamine (0.2 g, 1.2 mmol) was dissolved in toluene (5 ml) and the solution was then added to a suspension of dichloro 1,5-cyclooctadiene ruthenium polymer [RuCl2(COD)]n in toluene (5 ml). The mixture was then stirred under argon at 100° C. for 2 hours. The solvent volume was reduced in vacuo to approximately 3 ml and a solid was precipitated by adding ether (10 ml) to obtain a reddish brown product. The activities of these catalysts are low for the hydrolysis of ammonia borane. The reactions with cobalt(II)chloride (CoCl2) and chlorobis(cyclooctene)iridium(I)dimer [IrCl(COE)2]2 were performed similarly. The three catalysts prepared in the section (section b) were all tested for ammonia borane hydrolysis.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Br:14][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 142.3 %

Procedure:
To a solution of 10 g of methyl 4-hydroxymethylbenzoate and 80 g of carbon tetrabromide in 300 ml of diethyl ether was added 63.2 g of triphenylphosphine. The reaction was warmed to room temperature overnight, filtered through Celite® and concentrated to 87.2 g of a yellow oil. Chromatography on silica gel (95:5, hexane:ethyl acetate) afforded 19.62 g of a white solid, m.p. 52° to 55° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:19]3[CH:18]=[C:17]([CH3:28])[CH:22]=[CH:21][CH:20]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: Cc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-m-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=372.16.
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[C:28](=[O:35])([S:32][CH2:33][CH3:34])[O:29][CH2:30]Cl>CO.C(Cl)Cl>[CH2:33]([S:32][C:28]([O:29][CH2:30][O:7][C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH3:34]
Reactant: CC(C)(C)CC(=O)O
Reactant: CCSC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCSC(=O)OCOC(=O)CC(C)(C)C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of t-butylacetic acid (0.025 mol, 3 g) in methanol is added tetrabutylammonium hydroxide (1M/methanol, 25 ml). The mixture is stirred for 1 h and the solvent removed to a residue. The residue is dissolved in 150 ml of methylene chloride and 150 ml of water and a solution of O-chloromethyl S-ethyl carbonothioate (0.025 mol, 3.85 f) in 50 ml of methylene chloride added. The mixture is stirred at room temperature for 24 h. The methylene chloride layer is separated, washed with water, brine and dried over sodium sulfate. The solvent is removed under vacuo and the residue stirred in 300 ml of ether for 24 h. The resulting white solid is filtered, the solid discarded and the solvent removed from the filtrate to give 6 g of a crude oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]=[C:36]1[NH:41][C:40]2[CH:42]=[CH:43][C:44]([S:46](Cl)(=[O:48])=[O:47])=[CH:45][C:39]=2[C:38](=[O:50])[O:37]1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[S:46]([C:44]1[CH:43]=[CH:42][C:40]2[NH:41][C:36](=[O:35])[O:37][C:38](=[O:50])[C:39]=2[CH:45]=1)(=[O:47])=[O:48])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2c(=O)o1
Reactant: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Product: O=c1[nH]c2ccc(S(=O)(=O)N3C[C@H](SC(c4ccccc4)(c4ccccc4)c4ccccc4)C[C@H]3COCc3ccccc3)cc2c(=O)o1

Procedure:
In analogy: (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine and 2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-sulfonyl chloride [Ferrini et al. Eur. Pat. Appl. No. 800220] gave (2S,4R)-6-(2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione, MS: 689(M−H−), which was deprotected (following Method 3) to give (2S,4R)-6-(2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione, MS: 447 (M−H−).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.Cl.C(OCC)(=O)C>[CH2:16]([O:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cc2cc(F)c(F)cc2nc1Cl
Reactant: c1ccc(COCC[C@H]2CC[C@H]([C@H]3CCCN3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(CCOCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde (8.30 g, 36 mmol), trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine (10.5 g, 36 mmol), and potassium carbonate (7.60 g, 55 mmol) in toluene (90 mL) and water (12 mL) is stirred and refluxed for 4 hours. The reaction mixture is cooled to room temperature and then diluted with 1N HCl aq. and ethyl acetate. The organic layer is washed with sat. NaHCO3 aq., brine, dried over magnesium sulfate, filtered and concentrated to give 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinoline-3-carbaldehyde as yellow syrup, which is used without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
A solution of 7.5 ml (90 mmol) of methyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon 10 with 56.3 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 8.4 ml (80 mmol) of 4-fluorobenzaldehyde in 80 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 800 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(4-fluorophenyl)-4-hydroxy-2-butynoate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Li+].[Cl-]>C1(C)C=CC=CC=1>[CH2:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[CH:12]=[CH2:11]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(F)c1

Procedure:
A mixture of 4-bromo-2-fluorobenzonitrile (250 mg, 1.3 mmol), allyl-tributyl-stannane (500 mg, 1.5 mmol), LiCl (160 mg, 3.8 mmol) and Pd(PPh)4 (15 mg) in 5 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-2-fluorobenzonitrile. MS m/z: 162 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[CH:23]1([CH2:29][N:30]=[C:31]=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[CH:23]1([CH2:29][NH:30][C:31](=[O:32])[O:8][C:7]2[CH:6]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])[C:4]([F:22])=[CH:3][C:2]=2[Cl:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=C=NCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)NCC3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with cyclohexylmethyl isocyanate and triethylamine in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl cyclohexylmethylcarbamate, m.p. 132°-135° C.;
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:14]([C:25]#[N:26])=[CH:15][C:16]2[O:23][CH2:22][CH:21]=[CH:20][CH2:19][O:18][C:17]=2[CH:24]=1.NN.Cl>C1COCC1>[NH2:3][CH2:12][C:13]1[C:14]([C:25]#[N:26])=[CH:15][C:16]2[O:23][CH2:22][CH:21]=[CH:20][CH2:19][O:18][C:17]=2[CH:24]=1
Reactant: N#Cc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCC=CCO2
Agent: Cl
Agent: N#Cc1cc2c(cc1CN)OC/C=C\CO2
Agent: N#Cc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OC/C=C\CO2
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1CN)OCC=CCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The residue prepared in STEP A above (0.34 g, 0.98 mmol) and hydrazine (0.31 ml, 9.8 mmol) were dissolved in THF (34 ml) and stirred at room temperature for 5 h. 1N HCl (22 mL) was added and the resulting mixture stirred overnight. The resulting mixture was then concentrated in vacuo and the residue was triturated with water. The water triturations were combined and concentrated in vacuo. The resulting solid was partition between ethyl acetate (50 ml) and saturated sodium bicarbonate (10 mL). The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine (20 ml), dried (Na2SO4) and concentrated in vacuo to yield (Z)-9-(aminomethyl)-2,5-dihydrobenzo[b][1,4]dioxocine-8-carbonitrile as a residue.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=[O:2].C([OH:18])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]([OH:18])=[O:2])=[CH:12]2)=[CH:7][CH:8]=1)#[N:14]
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Reactant: CC(C)O
Agent: [Cr+3]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc2ccc(C(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (3.0 g) was dissolved in 50 ml of acetone. The solution was cooled to 0° C. with stirring, and a solution prepared by dissolving 10 g of chromium oxide (IV) in 11 ml of concentrated sulfuric acid and 50 ml of water was added until the mixture becomes orange yellow. The reaction solution was stirred at 0° C. for 90 minutes and then at room temperature for 45 minutes, followed by the addition of 2 ml of isopropyl alcohol. The reaction solution was evaporated, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with saturated sodium bicarbonate aqueous solution, the saturated sodium bicarbonate layer was adjusted to pH 1 by adding concentrated sulfuric acid, and the thus precipitated solid matter was collected by filtration to give 1.94 g of 7-cyano-2-naphthalenecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:10]
Reactant: Cc1cnccc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnccc1C(C)O
Temperature: 25 °C

Procedure:
3-Methylpyridine-4-carbaldehyde (310.6 mg, 1.00 mmol) in tetrahydrofuran (6 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 4.74 mL, 4.65 mmol) under −78° C., and the mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (310.6 mg).
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].N[C:24]1CN=C(C2C=CC=CC=2)C2C=C([N+]([O-])=O)C=CC=2N=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])([O-])OCC.C(Cl)(Cl)Cl>[N+:20]([C:17]1[CH:18]=[CH:19][C:5]2[N:4]3[CH:24]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 1 h

Procedure:
2-Hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine prepared from 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine in a similar manner to Example 7, is dissolved in a mixture of 20 parts by volume of ethyl orthoformate and 100 parts by volume of chloroform, followed by the addition of 10 parts of p-toluenesulfonic acid. The whole mixture is left standing at room temperature for 1 hour with occasional shaking. After completion of the reaction, the solution is washed with a saturated aqueous solution of sodium bicarbonate, then with water, and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with ethyl acetate, whereby 8-nitro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as crystals. Recrystallization from tetrahydrofuran yields pale yellow needles melting at 271° C to 272° C.