Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13](=[N:15]O)[C:10]2([CH2:12][CH2:11]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:15][CH:13]1[C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]1
Reactant: O=C1N(Cc2ccccc2)CC(=NO)C12CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC1CN(Cc2ccccc2)CC12CC2

Procedure:
In 80 ml of dry tetrahydrofuran was dissolved 490 mg of compound 5 followed by addition of 500 mg of lithium aluminum hydride and the mixture was refluxed for 8 hours. Then, at room temperature, 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added thereto in the order mentioned and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give 7-amino-5-benzyl-5-azaspiro[2.4]heptane (compound 6). This product was dissolved as it was, i.e., without purification, in 20 ml of ethanol and after addition of 10% palladium-on-carbon, catalytic hydrogenation was carried out at 4.5 kg/cm2 and 50° C. After 6 hours of reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure at a temperature not higher than room temperature. The above procedure gave title compound 7 as a crude product. This compound 7 was used, without purification, in various reactions.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][NH:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([NH:20][C@@H:21]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]([OH:26])[C:23](O)=[O:24])=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:27]([C@H:21]([NH:20][C:18]([C:16]1[NH:15][C:12]2=[CH:13][N:14]=[C:9]([Cl:8])[CH:10]=[C:11]2[CH:17]=1)=[O:19])[C@H:22]([OH:26])[C:23]([N:4]1[CH2:5][CH:6]([OH:7])[CH:2]([OH:1])[CH2:3]1)=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CC(O)C(O)C1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 12 h

Procedure:
cis-3,4-Dihydroxypyrrolidine (Preparation 23, 9 mg, 0.087 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14 mg, 0.091 mmol), DIPEA (31 μL, 0.18 mmol) and EDCI (18 mg, 0.094 mmol) in DMF (3 mL). After stirring for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with brine (50 mL) and drying (MgSO4) gave, after concentration, a residue which was purified by preparative LCMS to give the title compound as a colourless solid. m/z (ES+)=459.29 [M+H]+; RT=2.87 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-])=O)[C:12]=3[N:11]=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:19][C:18]1[C:12]2[N:11]=[C:10]([C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[NH:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCN(C(=O)c2nc3c([N+](=O)[O-])cccc3[nH]2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Yield: 90.6 %

Procedure:
To a solution of (4-methyl-piperazin-1-yl)-(4-nitro-1H-benzoimidazol-2-yl)-methanone (640 mg, 2.21 mmol) in 1:1 THF/ethanol (10 mL, with a few drops of ethyl acetate) was added 10% palladium on carbon (640 mg). The reaction mixture was placed under 1 atm hydrogen for 72 h. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel (40 g; 0-10% methanol/CH2Cl2) to afford 519 mg (91%) of the title compound. MS (ESI): mass calculated for C13H17N5O, 259.31; m/z found, 260.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 12.21-11.36 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.94-6.83 (m, 1H), 6.53 (d, J=7.8 Hz, 1H), 4.82-4.78 (m, 2H), 4.43-4.40 (m, 2H), 3.94-3.92 (m, 2H), 2.56-2.54 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(COC)OC>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15]1
Reactant: N#CC1(c2ccccc2F)CCC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COCCOC
Product: NCC1(c2ccccc2F)CCC1
Yield: 70.8 %

Procedure:
Add LiAlH4 (461 mg, 12.1 mmol) to a solution of 1-(2-fluoro-phenyl)-cyclobutanecarbonitrile (1.38 g, 7.88 mmol) in dimethoxyethane (30 mL). Stir the solution at reflux overnight then add aq. Satd Rochelle's salt solution (30 mL) and stir for an additional 1 h at RT. Extract the mixture with CH2Cl2 (3×30 mL). Combine the organic extracts and wash with additional aq satd Rochelle's salt solution (30 mL) and brine (30 mL). Dry, filter and concentrate the organic solution then purify the crude material by flash chromatography, using 20% MeOH/CH2Cl2, to give the title compound (1 g, 71%) as a white solid. MS (ES) 180.1 (M+1)+.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[F:12].[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].N1CCCCC1.Cl>C(O)C>[F:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[CH:3]=[O:13])[CH:8]=[C:19]1[S:15][C:16](=[O:21])[NH:17][C:18]1=[O:20]
Reactant: COC(OC)c1ccc(C=O)cc1F
Reactant: O=C1CSC(=O)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.9 %

Procedure:
To a mixture of 4-dimethoxymethyl-3-fluorobenzaldehyde obtained in Example 37 (1.12 g, 5.66 mmol) and 2,4-thiazolidindione (795 mg, 6.79 mmol) in ethanol (20 mL) was added piperidine (0.68 mL, 6.8 mmol), and the mixture was heated to reflux for 13 h. Hydrochloric acid (1 mol/L) was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (25 mL) and hydrchloric acid (1 mol/L; 5 mL), and the mixture was stirred at room temperature for 20 h. Water was added, and the precipitated products were collected by filtration to afford 3-fluoro-4-formylbenzylidene-2,4-thiazolidinedione (696 mg, 49%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[O:5][C:4](=[O:10])[CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:16]([O:9][CH2:8][C:6]1[O:5][C:4](=[O:10])[CH:3]=[C:2]([OH:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=c1cc(O)cc(CO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(=O)o1
Yield: 47 %

Procedure:
4-Hydroxy-6-hydroxymethylpyran-2-one (14.6 parts) was dissolved in dimethyl formamide (30 parts) at 20° C., imidazole (17.2 parts) was added and the temperature of the mixture cooled to 13° C. t-Butyldimethylsilyl chloride (17.1 parts) was then added in portions, the temperature was allowed to rise to 25° C. and maintained at 25°-30° C. by external cooling. The mixture was stirred for a further hour at 25°-30° C., before pouring into water (1100 parts) and stirring for 30 minutes until the product crystallised. The product was filtered off, washed with water (2×200 parts) and dried at 40° C./20 mm to give 6-t-butyldimethylsilyloxymethyl-4-hydroxy pyran-2-one (12.1 parts, 47%) m.pt 139°-141° C. Extraction of the filtrates with dichlorometane gave a further 7.0 parts, 27% of the product.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:22]([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)[CH2:21][CH2:20][N:19]1[CH2:35][C:36](O)=[O:37].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][C:36](=[O:37])[CH2:35][N:19]2[CH2:20][CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpropan-1-amine (0.0.21 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (t, J=5.4 Hz, 1H), 7.12-7.35 (m, 20H), 3.98 (t, J=7.8 Hz, 1H), 3.89 (s, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.94-3.01 (m, 2H), 2.72 (t, J=6.4 Hz, 2H), 2.13-2.21 (m, 2H); MS (DCI+) m/z 489 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([OH:37])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:41]1([O:47][C:48](Cl)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CO>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([O:37][C:48]([O:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[S:49])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1OC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
In an atmosphere of argon gas, 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (151 mg, 0.3 mmole) was dissolved into acetonitrile (5 ml), to which were then added 4-dimethylaminopyridine (75.1 mg, 0.62 mmole) and phenyloxythiocarbonyl chloride (57 μl, 0.33 mmole). After stirring the resulting mixture at room temperature for 24 hours. 0.1M aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water and then with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-(phenoxythiocarbonyloxy)cyclohexyl]-adenine (109 mg, Yield 56.8%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](C=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:21](OC)([O:24][CH3:25])[O:22][CH3:23].C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]([O:24][CH3:25])[O:22][CH3:23])=[CH:6][N:7]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(Br)nc1
Yield: 95.6 %

Procedure:
A solution of 6-bromopyridine-3-carbaldehyde (3.07 g, 16.5 mmol), p-toluenesulfonic acid (386 mg, 2.02 mmol) and trimethyl orthoformate (1.97 ml, 18 mmol) in MeOH (80 ml) was stirred at room temperature for 48 hours. The mixture was then brought to basic conditions with a 5% NaHCO3 solution and extracted twice with diethyl ether. The pooled organic phases were dried over Na2SO4 and evaporated to dryness to give 3.66 g of 2-bromo-5-dimethoxymethyl-pyridine as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:19])[N:13](CC#C)[C:14]=2[CH:15]=1)=[CH:10][C:9](Cl)=[CH:8][CH:7]=3>O1CCCC1.CCCCCC>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:19])[NH:13][C:14]=2[CH:15]=[CH:2][CH:3]=1
Reactant: C#CCn1c(=O)c2cc(Cl)ccc2c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c2ccccc12

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f]1,2,4]triazolo[4,3-a][1,4]diazepine with 3.8-dichloro 5-(2-propynyl)-6(5H)-phenanthridinone under the conditions used in Example 37, but at the end, the reaction mixture was heated for minutes at 90°-95°. The product was isolated by chromatography over the 50-fold amount of silica gel using tetrahydrofuran/hexane 4:1 for elution. Crystallization of the combined clean fractions from tetrahydrofuran/ethyl acetate gave colorless crystals of 3,8-dichloro-5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]1,4]diazepin-2-yl]-2-propynyl}-6(5H)-phenanthridinone with m.p. 218°-220°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65° C. for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS m/z [M+Na]+ 348.2.
Reaction SMILES: [CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[CH2:1]([N:4]1[CH2:5][C:6]([NH2:7])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:10]([CH2:9][OH:8])[CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CONC2(c2cccc(Br)c2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=CCN1CC(CO)C(N)(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A 22° C. solution of 5-allyl-6a-(3-bromophenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (40 g, 129.4 mmol) in acetic acid (400 mL) is treated with zinc dust (42.3 g, 646.8 mmol) in one portion. The reaction is stirred vigorously at room temperature for 1 hour. Ethyl acetate (400 mL) is added and the mixture is filtered through diatomaceous earth. The filtrate is evaporated and the residue dried under vacuum. The residue is partitioned in water (300 mL) and MTBE (300 mL). The pH is adjusted to 8 with sodium hydroxide 50% w/w and the organic layer is separated, dried over sodium sulfate, and filtered. The filtrate is evaporated and the residue dried under vacuum to give the title compound (41 g, 97%). ES/MS (m/e): 311 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])=[CH:16][CH:15]=1)[C:10](=[O:27])[CH2:9]3.Br>C(O)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]([N:24]([CH3:25])[CH3:26])[CH3:23])=[CH:18][CH:19]=1)[C:10](=[O:27])[CH:9]=3
Reactant: CC(COc1ccc(N2N=C3c4cc(F)ccc4CCC3CC2=O)cc1)N(C)C
Agent: Br
Solvent: CC(=O)O
Product: CC(COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1)N(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 116 g of 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and 1.2 l of acetic acid is added 116 ml of 30% hydrobromic acid--acetic acid. While the solution is heated to 50° C., a solution of 48 g of hydrobromic acid and 200 ml of acetic acid is added dropwise over the period of 30 minutes. After the completion of the dropwise addition, the mixture is stirred for further 30 minutes. The solvent is distilled off under reduced pressure. Water and ethyl acetate are added to the residue, and the mixture is rendered alkaline with potassium carbonate. The ethyl acetate layer is separated, washed with water and extracted with an aqueous solution of hydrochloric acid. The hydrochloric acid layer is rendered alkaline with potassium carbonate, and the resultant oily substance is dissolved in ethyl acetate, which is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. Ethanol and fumaric acid are added to the residue to convert it into its salt. The resultant crystals are collected by filtration and recrystallized from water--ethanol to give 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.fumarate, m.p. 178°-180° C.
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14](=[O:23])(=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1.[OH-].[Na+]>CO>[C:16]1([NH:15][S:14]([C:10]2[CH:9]=[C:8]([C:7]#[C:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2])[CH:13]=[CH:12][CH:11]=2)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of E-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid methyl ester (55a) (0.34 g, 1 mmol) in methanol (3 ml) 1N solution of sodium hydroxide (3 ml) was added and the mixture was stirred at ambient temperature for 3 hours. Methanol was removed under reduced pressure, to the residue water (5 ml) was added and the mixture was acidified with 3% HCl. The precipitate was filtered, washed with water, and dried to give the title compound (0.31 g, 95%) as white crystals. M.p. 188-190° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.36 (1H, d, J=15.8 Hz, CH); 6.92 (1H, d, J=15.8 Hz, CH); 7.01-7.36 (5H, m, C6H5); 7.38-7.89 (4H, m, C6H4); 10.32 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([N:9]1[CH:8]([CH3:21])[CH2:7][C:6]2[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:11]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:10]1)(=[O:25])[CH3:24]
Reactant: CC1Cc2cc(Cl)ccc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc2CC1C
Temperature: 0 °C
Yield: 88 %

Procedure:
0.72 g (2.2 mmoles) of 7-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine are stirred in 4 ml of acetic anhydride at 25° C. for 3 hours, then the reaction mixture is poured onto 20 ml of ice water, the crystalline product is filtered and washed with water several times. The crude product obtained is purified by suspending it in 4 ml of hot ethanol. After filtration and drying, 0.69 g (88%) of the title compound are obtained M.p.: 174°-175° C.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH3:22][O:23][CH:24]1[O:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>C(Cl)Cl>[CH3:22][O:23][CH:24]1[O:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1
Reactant: COC1CCC(O)CO1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC1CCC(=O)CO1
Reaction time: 8 h
Yield: 25.6 %

Procedure:
PDC (6.0 g, 28 mmol) was added to a solution of 6-methoxytetrahydro-2H-pyran-3-ol (2.0 g, 15 mmol) from step (394a) in methylene chloride (50 ml) at room temperature. The reaction was stirred overnight, filtered through silica gel and concentrated to give an oil. The product was distilled at 35° C. at 1000 mtorr pressure to give the 6-methoxydihydro-2H-pyran-3-(4H)-one (0.5 g, 25%) as an oil.
Reaction SMILES: C(CC(O)=O)#N.C12(CCCC1)C1C(=CC=CC=1)C(=O)C2.N1CCCCC1.[C:27]12([CH2:42][CH2:41][CH2:40][CH2:39]1)[C:35]1[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:29]([CH2:36][C:37]#[N:38])=[CH:28]2>CCCCCC.O.C1C=CC=CC=1>[C:27]12([CH2:42][CH2:41][CH2:40][CH2:39]1)[C:35]1[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:29](=[CH:36][C:37]#[N:38])[CH2:28]2
Reactant: N#CCC1=CC2(CCCC2)c2ccccc21
Agent: N#CCC(=O)O
Agent: O=C1CC2(CCCC2)c2ccccc21
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: N#CC=C1CC2(CCCC2)c2ccccc21

Procedure:
To a mixture of cyanoacetic acid (85 g; 1.0 moles) and spiro(cyclopentane-1,1'-indan)-3'-one (186 g; 1.0 moles) there is added piperidine (85.2 g; 1.0 moles) dropwise under agitation and cooling at such a rate that the temperature does not exceed 40°-60° C. After addition of benzene (300 ml) the mixture is refluxed for 24 hours with continuous separation of the water formed. Benzene and piperidine are distilled off under reduced pressure and the oil obtained is distilled in vacuum. At 130°-140° C./1 torr there is obtained a colourless oil consisting of the title nitrile as well as the isomer spiro(cyclopentane-1,1'-indene)-3'-ylacetonitrile and a small amount of unreacted ketone. The mixture is dissolved in hot hexane and cooled, and then spiro(cyclopentane-1,1'-indan)-3'-ylideneacetonitrile crystallizes as colourless crystals of mp 82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(I)cc1
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Yield: 97 %

Procedure:
1-bromo-4-iodobenzene was reacted with trimethylsilylacetylene via Sonogashira coupling reaction under the PdCl2(PPh3)2/CuI/TEA catalyst system to produce (4-bromophenylethynyl)trimethylsilane as a white solid, quantitatively. Specifically, 11.32 g (40 mmol) of 1-bromo-4-iodobenzene was placed in a round bottomed flask equipped with a septum and a stirring bar. The flask was put into a glove box and 281 mg (0.4 mmol) of dichlorobis-(triphenylphosphine)palladium(II) and 19 mg (0.1 mmol) of CuI were added. Afterward, 100 mL of dried triethylamine and 5.65 mL (40 mmol) of trimethylsilylacetylene were injected into the flask through syringes while stirring. The mixture was stirred at room temperature for 2 h. Precipitates were formed. The precipitates were filtered and washed with diethyl ether. The solutions were combined and the solvent was evaporated. The crude product was purified by a silica gel column chromatography using hexane as eluent. A white powdery product was obtained in 97% yield (9.82 g).