Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH:23]([NH2:26])([CH3:25])[CH3:24].O>O1CCCC1>[CH:23]([NH:26][C:19](=[O:21])[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH3:22])([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)phenyl]-propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.59 g of isopropylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene to obtain 3.30 g of desired N-isopropyl-2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]-propionamide. The yield was 87%, and the melting point of this compound was from 203° to 204° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>C1COCC1>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:22])=[CH:23][CH:24]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (32.0 mg) obtained in Example 142 in THF (10 ml) were added pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. Pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) were added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give a mixture containing the title compound and the raw material (4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide. To a solution of the obtained 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide in THF were added triethylamine (0.055 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with the mixture containing the title compound, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.10 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].C>C(O)C>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(F)c1
Agent: C
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Yield: 71.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol and 2.55 ml (25.8 mmol) 3,4-difluoroaniline was heated to reflux under N2. Removed heat at 3.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and air dried. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 5.02 g of yellow solid: mass spectrum (electrospray m/e): M+H=327.1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:18])[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:50]COC)([C:46]([F:49])([F:48])[F:47])[C:42]([F:45])([F:44])[F:43])=[CH:37][C:36]=2/[CH:54]=[CH:55]\[CH3:56])[C@H:31]([CH3:57])[CH2:30]1)=[O:28].Cl.C(OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C.O>[F:48][C:46]([F:47])([F:49])[C:41]([C:38]1[CH:39]=[CH:40][C:35]([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:13]3[C:12](=[O:17])[C@:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=4)([CH3:18])[NH:15][C:14]3=[O:16])[CH2:30][CH:31]2[CH3:57])=[C:36](/[CH:54]=[CH:55]\[CH3:56])[CH:37]=1)([OH:50])[C:42]([F:45])([F:44])[F:43]
Reactant: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@H]1C
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)N[C@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
5-[4-(1-Methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (7.7 mg, 0.0311 mmol) was dissolved in N,N-dimethylformamide (500 μL), added potassium carbonate (8.6 mg, 0.0622 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, (R,Z)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)ethanone (17 mg, 0.0311 mmol) was added, and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained crude product was dissolved in ethyl acetate (1.0 mL), added a solution of 4N-hydrochloric acid-ethyl acetate (1.0 mg), and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and (R,Z)-3-(2-{4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]-3-methylpiperazin-1-yl}-2-oxoethyl)-5-[4-(1-methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (17.4 mg (yield 83%)) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Piperazine-1-carboxylic acid benzyl ester (500 mg) was dissolved in DCM (5 ml) and the mixture was cooled down to 0° C. Benzoyl chloride (290 μl) and NEt3 (379 μl) were added. The mixture was stirred for 48 h, diluted with DCM, washed with water, dried (Na2SO4) and evaporated off. After HV, 650 mg of the desired compound were obtained.
Reaction SMILES: OC([C:4]([F:7])([F:6])[F:5])=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:49]([CH3:51])[CH3:50])[C:14]([N:16]1[CH2:20][C@@H:19]([CH3:21])[CH2:18][C@H:17]1[C:22]1[NH:23][C:24]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35]4[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=4[O:44]C(F)(F)F)[CH:31]=3)[C:25]=2[N:26]=1)=[O:15])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:76]([O:80][C:81]([N:83]1[CH2:88][CH2:87][N:86]([C:89]2[CH:94]=[CH:93][C:92]([NH2:95])=[CH:91][N:90]=2)[C@H:85]([CH3:96])[CH2:84]1)=[O:82])([CH3:79])([CH3:78])[CH3:77].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:76]([O:80][C:81]([N:83]1[CH2:88][CH2:87][N:86]([C:89]2[CH:94]=[CH:93][C:92]([NH:95][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([C:30]4[CH:31]=[C:32]5[C:27](=[CH:28][CH:29]=4)[C:25]4[N:26]=[C:22]([C@@H:17]6[CH2:18][C@H:19]([CH3:21])[CH2:20][N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[CH:49]([CH3:50])[CH3:51])[NH:23][C:24]=4[CH:34]=[CH:33]5)=[C:36]([O:44][C:4]([F:5])([F:6])[F:7])[CH:37]=3)=[CH:91][N:90]=2)[C@H:85]([CH3:96])[CH2:84]1)=[O:82])([CH3:79])([CH3:77])[CH3:78]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(-c4ccc(C(=O)O)cc4OC(F)(F)F)ccc32)[nH]1)C(C)C
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(-c4ccc(C(=O)Nc5ccc(N6CCN(C(=O)OC(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)ccc32)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A solution of 4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoic acid TFA (136 mg, 0.19 mmol; Preparation 17) and HATU (86 mg, 0.23 mmol) in DMA (3 mL) was stirred for 10 min, then (R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (55 mg, 0.19 mmol), and DIPEA (98 μL, 0.56 mmol) were added. The resulting mixture was stirred at RT for 1 h, concentrated, and purified by silica gel chromatography (EtOAc/hexane 20 to 100%) to give the title intermediate (158 mg, 95% yield). (m/z): [M+H]+ calcd for C46H53F3N8O7 887.40 found 887.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (800 mg) obtained in Reference Example 1(2) is dissolved in chloroform (30 ml), and thereto are added morpholine (560 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.24 g) and triethylamine (650 mg) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=30/1) to give methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexanecarboxylate (897 mg). APCI-MS M/Z:256[M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1)=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Reaction time: 0.17 h
Yield: 31 %

Procedure:
4-Hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (0.86 g, 3.02 mmol) was dissolved in DMF (10 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 22 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 4-[5-(6-Hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 was obtained (0.43 g, 31% yield) as a pale yellow foam.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]1=[O:29])#[CH:21]>>[F:19][C:18]1[C:2]([C:21]#[C:20][C:22]2([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]2=[O:29])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC1(O)CCCN(C)C1=O
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: CN1CCCC(O)(C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)C1=O
Yield: 16 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A1) to give the titled compound as a white solid (20 mg, 16%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]([CH3:10])C=O.[F:11][CH:12]([F:20])[C:13]1[CH:17]=[C:16]([OH:18])N(C)[N:14]=1>O>[Cl:3][C:10]1[N:7]([CH3:6])[N:14]=[C:13]([CH:12]([F:20])[F:11])[C:17]=1[CH:16]=[O:18]
Reactant: Cn1nc(C(F)F)cc1O
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)F)c(C=O)c1Cl
Yield: 73.3 %

Procedure:
41.6 g (270.1 mmoles) of phosphorus oxychloride was added, with ice-cooling, to 7.9 g (108.0 mmoles) of N,N-dimethylformamide. Thereto was added, at room temperature, 8.0 g (54.0 mmoles) of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol. The mixture was refluxed for 4 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water, a 5% aqueous sodium hydroxide solution and water in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 7.7 g (yield: 73.3%) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde as white crystals.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4]O[N+:6]=2[O-])[CH:2]=1.[N:11]#[C:12][NH2:13].[Na].[Na]>CO.O>[NH2:13][C:12]1[N:11]=[N:6][C:7]2[CH:8]=[CH:9][CH:1]=[CH:2][C:3]=2[N:4]=1
Reactant: N#CN
Reactant: [O-][n+]1onc2ccccc21
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1nnc2ccccc2n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 21.9 %

Procedure:
To a suspension of 13.6 g (0.1 mol) of benzofuroxan in a mixture of 40 ml of methanol and 40 ml of water at 20° C. are added in portions 17.2 g (0.2 mol) of disodium cyanamide. In the course of addition, the temperature rises to 50° C.-60° C. and the solution assumes a blue-violet color. It is stirred for a further 40 minutes at about 60° C. and the precipitate which separates out is then removed by filtration from the mother liquor, which is retained and processed further. The precipitate is dissolved in water, the solution is filtered and the filtrate is acidified with acetic acid, whereupon 12.5 g of 3-amino-1,2,4-benzotriazine-1,4,-di-N-oxide (71% of theory) separates out in the form of reddish-golden crystals which melt, with decomposition, at 220° C. On acidifying the mother liquor with acetic acid, a further 3.2 g (18% of theory) of 3-amino-1,2,4-benzotriazine is obtained and after re-crystallization from dimethylformamide, this material melts, with decomposition, at 220° C. Total yield reported is: 89% of theory.
Reaction SMILES: C(O[C:9]([CH2:11][N:12]([C@H](C)[C@@H](C1C=CC(OC2C=CC=CC=2)=CC=1)CCC1C=CC=CC=1)C([C@@H]1[C@@H](C([O-])=O)OC(C(OCC[Si](C)(C)C)=O)(C(OCC[Si](C)(C)C)=O)O1)=O)=O)C1C=CC=CC=1.C([O:69][C:70]([CH2:72][N:73]([C@H:96]([CH3:119])[C@@H:97]([C:106]1[CH:111]=[CH:110][C:109]([O:112][C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)=[CH:108][CH:107]=1)[CH2:98][CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[C:74]([C@@H:76]1[C@@H:80]([C:81]([O:83]C(C)(C)C)=[O:82])[O:79][C@:78]([C:93]([O-])=[O:94])([C:88]([O:90]CC)=[O:89])[O:77]1)=[O:75])=[O:71])(C)(C)C>>[C:70]([CH2:72][N:73]([C@H:96]([CH3:119])[C@@H:97]([C:106]1[CH:111]=[CH:110][C:109]([O:112][C:113]2[CH:114]=[CH:115][CH:116]=[CH:117][CH:118]=2)=[CH:108][CH:107]=1)[CH2:98][CH2:99][C:100]1[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=1)[C:74]([C@@H:76]1[C@@H:80]([C:81]([OH:83])=[O:82])[O:79][C@@:78]([C:93](=[O:94])[NH:12][CH2:11][CH3:9])([C:88]([OH:90])=[O:89])[O:77]1)=[O:75])([OH:69])=[O:71]
Reactant: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)OCc1ccccc1)C(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)[O-]
Reactant: CCOC(=O)[C@@]1(C(=O)[O-])O[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)N(CC(=O)OC(C)(C)C)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1
Product: CCNC(=O)[C@@]1(C(=O)O)O[C@H](C(=O)O)[C@@H](C(=O)N(CC(=O)O)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1

Procedure:
The above identified compound was obtained by carrying out treatment in the same manner as in Example 25(2) except that instead of 2,2-bis{2-(trimethylsilyl)ethyl} (4S,5S)-4-[N-(benzyloxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,2,5-tricarboxylate, 5-tert-butyl 2-ethyl (2R*,4S,5S)-4-[N-(tert-butoxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,2,5-tricarboxylate obtained in Example 20, was used, and carrying out the same reaction as in Example 21.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[CH:18]=[CH:17][C:15]4=3)[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CCOC(C)=O.O>O1CCOCC1>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[NH:19][CH:18]=[CH:17][C:15]4=3)[CH2:10][CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCCN4C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: c1cc2c3c(cnc2[nH]1)CCCN3C1CCCCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of 1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine (0.132 g, 0.323 mmol) in 1,4-dioxane (2.2 mL) was added aqueous NaOH (2 N, 0.32 mL, 0.65 mmol). The reaction was heated at about 80° C. for about 96 h. Aqueous NaOH (5 N, 0.129 mL, 0.646 mmol) was added and the reaction was continued at about 80° C. for about 18 h. Aqueous NaOH (5 N, 0.065 mL, 0.323 mmol) was added and the reaction mixture was heated at about 100° C. for about 4 h. The reaction was cooled to ambient temperature, EtOAc and water were added (5 mL each) and the layers were separated. The aqueous layer was extracted with EtOAc (2×5 mL) and the combined organics were washed with water and brine (5 mL each), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% (95/4.5/0.5) DCM/MeOH/DEA in DCM to give 1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine (0.052 g, 64%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.88 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1cc[n+]([O-])cc1

Procedure:
In a manner analogous to the preparation of the compound of Example 1, from 3,4,5-trimethoxyphenylguanidine nitrate (2.25 g, 7.81 mmol), 3-dimethylamino-1-(1-oxo-pyrid-4-yl)-2-propen-1-one (880 mg, 7.81 mmol) and sodium hydroxide (344 mg, 8.6 mmol) to give the title compound (1.2 g) as a green solid m.p. 220°. MS m/z 355 (M+H). The 3-dimethylamino-1-(1-oxopyrid-4-yl)-2-propen-1-one used as starting material was prepared by heating a solution of 4-acetylpyridine-N-oxide (2.5 g, 18.2 mmol) in dimethylformamide diethylacetal (30 ml) at reflux for 0.5 h. On cooling the resulting solid was collected and washed with diethyl ether to give the desired product (3.18 g) as an orange solid m.p. 181°. The 4-acetylpyridine-N-oxide was prepared by treating a solution of 4-acetylpyridine (3.0 g, 24.8 mmol) in CH2Cl2 with 3-chloro-peroxybenzoic acid [Aldrich 57-86%] (8.4 g) at room temperature for 12 h. The reaction was filtered, the filtrate concentrated under reduced pressure and the resulting residue subjected to column chromatography [silica 10% methanol-ethyl acetate] to give the desired product (3.2 g) as a white solid m.p. 101°.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2)#[N:14]>C(Cl)(Cl)Cl>[Cl:8][C:15]1([C:13]#[N:14])[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2
Reactant: N#CC1CC2C=CC1CC2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1(Cl)CC2C=CC1CC2
Yield: 94.8 %

Procedure:
To a refluxing mixture of pyridine (14.2 g, 0.180 mol), phosphorus pentachloride (28.0 g, 0.135 mol), and chloroform (100 mL) was added drop-wise a solution of 5-cyanobicyclo[2,2,2]oct-2-ene (12 g, 90 mmol) in chloroform (50 mL). The resulting mixture was heated at reflux for 15 h, cooled, and poured onto ice. The organic layer was concentrated, and the residue was purified by chromatography on silica gel, eluting with mixtures of ethyl acetate (0.5% to 1%) in petroleum ether, to give 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (14.3 g, 95% yield) as a white semisolid, 1H NMR (300 MHz, CDCl3) δ 1.3-1.5 (m, 3H), 2.02-2.18 (m, 2H), 2.51 (m, 1H), 2.72 (m, 1H), 3.12 (m, 1H), 6.22 (m, 1H), 6.41 (m, 1H); GCMS (m/z); 167.