Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][CH:37]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])#[N:9]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][CH:37]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][C:17]=1[C:18]([OH:20])=[O:19])=[O:14])#[N:9]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
0.5 mL of trifluoroacetic acid was added to 0.5 mL of methylene chloride solution containing 10 mg of tert-butyl 2-(3-cyanobenzamido)-4-phenylbenzoate and stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 7.6 mg of 2-(3-cyanobenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O>CCO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=[CH:22][CH:23]=1
Reactant: COP(=O)(OC)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OC)OC
Agent: O=[Pt]=O
Solvent: CCO
Product: COP(=O)(OC)C(Cc1ccc(N)cc1)P(=O)(OC)OC
Reaction time: 14 h
Yield: 103.4 %

Procedure:
A mixture of 12 (1.01 g, 2.75 mmol) and PtO2 (0.035 g, 0.15 mmol) in EtOH (40 mL, 95%) was shaken in a PARR apparatus under 55 p.s.i of H2 for 14 hr. The catalyst was removed by filtration through glass fiber filter paper and the solvent was removed under reduced pressure to give 13 as a pale yellow solid (0.959 g, 103%) that was used without purification. 1H NMR (400 MHz, CDCl3) δ 2.62 (tt, J=6.3, 23.9, 1H), 3.12 (dt, J=6.3, 16.2, 2H), 3.70 (d, J=1.9, 6H), 3.73 (d, J=1.9, 6H), 6.61 (d, J=8.5, 2H), 7.04 (d, J=8.5, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:18]([NH:20]C(CCl)=O)=[O:19])[C@H:10]1[O:25][CH3:26])[CH3:8].[CH3:28][SH:29].[Na]>C(O)C>[C:18]([O:17][CH:11]1[CH2:12][CH2:13][C:14]([CH2:15][S:29][CH3:28])([OH:16])[CH:9]([C:6]2([CH3:8])[O:7][CH:5]2[CH2:4][CH:3]=[C:2]([CH3:27])[CH3:1])[CH:10]1[O:25][CH3:26])(=[O:19])[NH2:20]
Reactant: CS
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Agent: [Na]
Solvent: CCO
Product: COC1C(OC(N)=O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Yield: 70 %

Procedure:
To a solution of O-chloroacetylcarbamoyl fumagillol (209 mg) in ethanol (2 ml) was added a 15% aqueous solution of methanethiol.sodium salt (500 μl), and the mixture was stirred for one hour at room temperatures. The reaction mixture was concentrated, to which was added ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=2:1) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) -3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (136 mg: yield 70%) as colorless powder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](O)CC2)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cn3)CC2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of 200 mg (0.79 mmol) of trans-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone (Intermediate 4) in 1 ml of DMA, 42 mg (0.96 mmol) of sodium hydride was added at room temperature and stirred for 30 min. To the mixture, 220 mg (1.59 mmol) of 6-chloronicotinonitrile (commercially available) was added and stirred at 100° C. for 24 h. The mixture was poured into saturated NaHCO3 solution., extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with CH2Cl2 and methanol=from 98:2 to 95:5. The combined product fractions were evaporated to dryness to yield 33 mg (6%) of the title compound. MS (m/e): 357.1 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:22]([NH:34][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCCCCCCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and laurylamine were used to obtain N-Lauryl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2].C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1Nc2ccccc2N(C)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC1Nc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Methyl-3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene-acetic acid ethyl ester (1.1 g, 4.47 mmol) was suspended in 25 mL of MeOH/HOAc (2:1) at rt and sodium cyanoborohydride was added portionwise (281 mg, 4.47 mmol). The mixture became clear after five minutes and was continuously stirred at rt for 2 hours. The solvent was removed under reduced pressure. The crude residue was mixed with water (50 mL) and extracted with EtOAc (3×40 mL). The organic layers were combined, washed with water, brine and dried over MgSO4. After removal of the solvent, a pale brown oil was obtained as the desired pure product: 1H NMR (CDCl3) δ=6.97–6.94 (m, 3H), 6.74 (d, J=9.0 Hz, 1H), 4.28 (dd, J=3.0, 9.0 Hz, 1H), 4.23 (q, J=9.0 Hz, 2H), 3.37 (s, 3H), 3.11 (dd, J=3.0, 18.0 Hz, 1H), 2.68 (dd, J=9.0, 19.0 Hz, 1H), 1.28 (t, J=9.0 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-].[K+].CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:22]=[CH:23][C:24]=1[OH:25]>O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(OCC(=O)c2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of α-chloroacetophenone (4,64 g; 0.03 mol), anhydrous potassium fluoride and DMF (200 ml) is stirred for 15 minutes. Next, 3-(3-chloro-4-hydroxyphenyl)-1,1-dimethylurea (6.44 g; 0.03 mol) is added and the mixture stirred for 20 hours at room temperature and then for 24 hours at 80° C. The mixture is then drowned in water, and extracted with methylene chloride. The organic layer is separated, washed with water and filtered through a 5 cm pad of neutral alumina. The pad is washed with acetonitrile, filtrate and washings are combined and evaporated under vacuum to give a brown-yellow oil (7.0 g, 70.1%). This oil is purified by chromatographing on silica gel (eluent: methylene chloride) to afford the title compound: 6.75 g of a cream colored solid, m.p. 148°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15](OC)=[O:16])=[N:13][CH:14]=2)[CH2:6]1.[NH3:24]>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]([NH2:24])=[O:16])=[N:13][CH:14]=2)[CH2:6]1
Reactant: COC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To methyl 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carboxylate (0.080 g, 2.1 mmol) in MeOH was bubbled ammonia and the mixture was heated at 50° C. After 2 d, the methanol was evaporated followed by the addition of ether. The solid was filtered to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][N:18]=[C:15]3[CH2:16][CH2:17][N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[CH2:13][CH2:14]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(C#N)CC3)CC2)c(F)c1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(ON=C3CCN(c4ccc(S(C)(=O)=O)cc4F)CC3)CC2)n1
Reaction time: 1 h

Procedure:
68b (35 mg, 0.066 mmol) and 68a (8 mg, 0.08 mmol) were combined in ethyl acetate (1 mL) and 1N ZnCl2 (80 μL, 0.08 mmol) was added dropwise. After 1 h, the solvent was evaporated. 1 mL of ethanol and 0.5 mL of concentrated HCl were added and the mixture was heated to reflux. The solvent was removed and the crude mixture was purified on preparative HPLC to give 68-1: LC-MS 480.2 (MH+), tR=5.57 (Method 5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=[C:4]2[CH:3]=1.C[OH:16]>ClCCl>[F:13][C:11]([F:14])([F:12])[C:8]1[N:5]2[N:6]=[CH:7][C:2]([CH:1]=[O:16])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: CO
Reactant: Cc1cnn2c(C(F)(F)F)nnc2c1
Solvent: ClCCl
Product: O=Cc1cnn2c(C(F)(F)F)nnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A finely-ground powder of NaIO4 is added to a solution of 7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine x233 (0.52 g, 2.0 mmol) in absolute methanol (42 ml). The reaction mixture is stirred at room temperature for 1.5 h and diluted with an equal volume of dichloromethane. The mixture is filtered through the Celite layer, and the solvents are removed under reduced pressure. The residue (0.5 g) is purified by chromatography on silicagel (hexane/ethyl acetate 3/2) to yield 0.34 g of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde x235 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(Cl)c1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1c(Cl)cccc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 4.6 mmol) and N-tert-butyl-2-chloro-6-methyl-benzamide (1.5 g, 4.6 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N+:7]([O-])=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12].P(Cl)(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:15])[N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12]
Reactant: Cc1sc2c[n+]([O-])ccc2c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Cl)nccc2c1Br
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Bromo-2-methylthieno[2,3-c]pyridine-N-Oxide (0.500 g, 2.05 mmol) was dissolved in chloroform (10 mL) and treated with phosphorous oxychloride (0.955 ml, 10.2 mmol). The reaction was heated to 70° C. while stirring. After 3 hours, the volatiles were removed in vacuo and the residual phosphorous oxychloride was azeotroped with toluene. The resulting residue was taken up in DCM and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20-60% EtOAc in hexanes to give 3-bromo-7-chloro-2-methylthieno[2,3-c]pyridine as a yellow solid. MS (M+H)+ 263.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[F:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:19][C:20]=1[CH:21]=O.Cl>CN(C=O)C>[CH2:26]([O:25][C:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])=[C:15]([F:14])[CH:16]=1)=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
Sodium hydride (0.513 g of a 60% dispersion, 12.8 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (10 mL) and cooled to 0° C. Trimethyl phosphonoacetate (2.2 mL, 13.5 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0° C., a solution of benzyl 3-fluoro-4-formylphenylcarbamate (3.5 g, 12.8 mmol) in DMF (10 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCl and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, H2O, brine, and dried (MgSO4) filtered and concentrated. The resulting orange solid was washed sequentially with hexane and then 30% ethyl acetate-hexane to provide the title compound as a yellow-orange solid (2.7 g). The washings were concentrated and purified by column chromatography (0-30% ethyl acetate-hexane) to provide an additional 0.95 g of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]#[N:8])([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A solution of 3-nitro-4-hydroxybenzonitrile (10 g, 61 mmol) in a mixture of 40 mL of dimethylformamide and 100 mL of acetonitrile was stirred as anhydrous potassium carbonate (10.1 g, 73.2 mmol) and benzyl bromide (10.4 g, 61 mmol) were added. The reaction was heated at 60° C. for about 4 h. The reaction was filtered and the solid was washed with ethyl acetate. The filtrate was washed with water. The organic layers were washed with water and brine, dried and concentrated. The solid was recrystallized from acetone/hexane to give 14 g (90%) of 3-nitro-4-(benzyloxy)benzonitrile, as a white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(C(C)(C)C)ccc1C2
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate toluene 1:1). 1.9 g (70%) of (R)-1-(7-tert-butyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCO>[CH:5]1([CH:11]2[CH2:12][CH2:13][N:14]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:16]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=CC#N
Reactant: C1CCC(C2CCNCC2)CC1
Solvent: CCO
Product: N#CCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
Acrylonitrile (4.16 mL, 63.1 mmol, 2.50 equiv) was-added at 0° C. to a solution of 4-cyclohexylpiperidine (4.20 g, 25.3 mmol, 1.00 equiv) in EtOH (50 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 5.11 g (92%) of white solid, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH3:9])[NH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=O)[CH:19]=[CH:20]N(C)C>C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[N:3]2[N:4]=[C:5]([CH3:9])[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:20][CH:19]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Reactant: Cc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: Cc1nn2c(-c3cc(Cl)ccc3Cl)ccnc2c1C#N
Yield: 70.3 %

Procedure:
A mixture of 12.2 g of 3-amino-4-cyano-5-methyl-pyrazole and 24.4 g of 2',5'-dichloro-3-dimethylaminoacrylophenone in 250 ml of glacial acetic acid is heated on a steam bath for 4 hours. The mixture is cooled and filtered to give 21.28 g of 7-(2,5-dichlorophenyl)-2-methylpyrazolo(1,5-a)pyrimidine-3-carbonitrile as off-white crystals.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:28]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:29][CH3:30])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C(Cl)(=O)C(Cl)=O.[CH3:52][N:53](C=O)[CH3:54]>C(Cl)Cl>[CH3:52][N:53]([CH3:54])[C:25]([C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([CH2:14][N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:45])([F:44])[F:1])[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:16]([N:28]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:29][CH3:30])=[N:17]2)=[CH:22][CH:21]=1)=[O:27]
Reactant: CCN(CC1CCCC1)c1nc2cc(C(=O)O)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC1CCCC1)c1nc2cc(C(=O)N(C)C)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carboxilic acid (30 mg, 0.047 mmol), oxalyl chloride (10 ul), and catalytic amount of DMF in CH2Cl2 (2 mL) is stirred at room temperature for 3 hours and concentrated in vacuo. The residue is dissolved with THF and treated with 2M dimethylamine in THF, and the resulting THF mixture is stirred at room temperature for 3 hours. The mixture is quenched by 1N HCl and extracted with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carboxylic acid dimethylamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:6]2)#[N:2].O.[NH2:19][NH2:20]>C(O)(=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[CH:8]([CH2:14][C:15](=[O:17])[NH:19][N:20]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCC(CC(=O)O)C2=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)CCC1CC(=O)NN=C21

Procedure:
A solution of 6-cyano-1-oxo-1,2,3,4-tetrahydro-2-naphthyl acetic acid (5.0 g) in 50% hot aqueous acetic acid was treated with hydrazine hydrate (1.0 ml ) and heated under reflux for 2 hours. The precipitated solid was filtered off and washed with water to give 8-cyano-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (1.2 g; m.p. 292°-5°); ν(Nujol mull) 3500, 3225, 2225, 1685, 1615, and 1586; δ(DMSO-d6) 1.55 (1H,m,5-H), 2.14 (1H,m,5-H) 2.40 (2H,m,4-H), 2.78 (3H,m,4a,6-H), 7.65 (lH,m,9-H), 7.71 (lH, s, 7-H), 8.12 (1H,d,10-H), 11.04 (1H,s,NH).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([CH3:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:24])[CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:24])[CH2:16]2)[C@:19]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@H:21]([CH3:22])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 3α-hydroxy-2β-methyl-5α-pregnane-11,20-dione (1.04 g.) in dry methanol (150 ml) was stirred at 0°-5° during the dropwise addition of a solution of bromine (0.16 ml) in dry methanol (20 ml) over a period of 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to a white foam. Purification by preparative t.l.c. (ethyl acetate:benzene 1:2.5) gave the title compound (510 mg.), m.p. 140° dec.; [α]D + 133° (c 0.95).