Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])[CH3:2].Br.C(N(CC)CC)C.[C:28]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccc(OC(C)=O)cc1
Reaction time: 3 h

Procedure:
17.3 g (0.05 mol) of L-alanyl-L-phenylalanine ethyl ester·HBr was suspended in 250 ml of dichloromethane, and to this susension were added 5.1 g (0.05 mol) of triethylamine and 9 g (0.05 mol) of p-acetoxybenzoic acid, and then 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added in an ice bath. This mixture was stirred for three hours, and then was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution three times and then with distilled water three times, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the dried mixture under reduced pressure to obtain p-acetoxybenzoyl-L-alanyl-L-phenylalanine ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:21][CH2:22][OH:23].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:17][CH2:21][CH2:22][OH:23])([CH3:15])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: CC(C)(N)c1ccc(-c2cncc(Br)c2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(NCCO)c1ccc(-c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(5-bromo-pyridin-3-yl)-phenyl]-1-methyl-ethylamine (Intermediate 229) (1 eq, 1.72 mmol, 500 mg) in DMF (10 ml) is added NaH (1.2 eq, 2.06 mmol, 82 mg) and the resulting mixture is stirred for 30 min at r.t. Then 2-bromoethanol (Sigma-Aldrich, St. Louis, USA) (2 eq, 3.43 mmol, 0.24 ml) is added, and the mixture is heated at 100° C. for 4 h. 2 M aqueous NaOH is added, and the mixture is extracted with DCM.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2O)=[O:10])=[CH:5][CH:6]=1>[Pd]>[C:4]1([CH:7]=[CH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1O
Agent: [Pd]
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
Hydrogenation of 1.06 g (4.38 mmol) of chalcone with catalytic amount of 10% Pd/C gives the dihydrochalcone after purification on silica gel chromatography. 1H NMR (300 MHz, CD3OD): δ 7.91 (d, d, J=1.8, 8.4 Hz, 1H), 7.50 (d, d, d, J=1.8, 7.2, 9.0 Hz, 1H), 6.97-6.92 (m, 2H), 5.83 (s, 1H), 3.34 (t, J=7.8 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.13 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:17]>>[NH2:17][C:7]1[C:6]2([F:16])[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: FC12CCCC1c1cc(Br)ccc1NC2=S
Reactant: N
Product: NC1=Nc2ccc(Br)cc2C2CCCC12F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
75 mg (0.25 mmol) of 8-bromo-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 20 ml of 7 M methanolic ammonia solution. After 1.5 hours of stirring at room temperature, the batch is concentrated by evaporation in a vacuum and the residue is purified by column chromatography on silica gel with ethyl acetate: 60 mg of product, melting point 220° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:15](=[O:17])[C:12]2[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)=[CH:14][CH:13]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: CCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(C(=O)N[C@@H]3CCc4cccc(N5CCN(C)CC5)c4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4'-Ethyl-4-biphenylcarboxylic acid (1.0 g, 4.4 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (130 mg, 0.53 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (99 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 140 mg (53%) of the title compound as white crystals: mp 234-235° C.; [α]21D -73° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (10, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])=O>O=P(Cl)(Cl)Cl>[ClH:18].[F:20][C:19]([F:22])([F:21])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:9]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=1
Reactant: Nc1ccccc1NC(=O)Nc1c(Cl)cccc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: FC(F)(F)c1cccc(Cl)c1Nc1nc2ccccc2[nH]1

Procedure:
0.8 g of 1-(2-aminophenyl)-3-(6-chloro-2-trifluoromethylphenyl)urea was heated under reflux conditions for 5 hours in 10 ml of POCl3, a clear solution resulting. After distilling off the phosphorus oxychloride under reduced pressure, the oily residue was treated with water, slow crystallization taking place. The crystals were filtered off and chromatographed on silica gel using a mixture of 10 parts of dichloromethane and 1 part of methanol. After distilling off the solvent, the residue was dissolved in EA and rendered strongly acidic using a saturated solution of hydrogen chloride gas in diethyl ether. The crystalline precipitate was filtered off. Colorless to slightly yellowish crystals. M.p.: 255-288° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(C=NCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131 %

Procedure:
4-Methoxybenzylamine (40 g, 290 mmol) was cooled to 0° C., and p-anisaldehyde (39.7 g, 292 mmol) was added dropwise. The reaction was stirred at ambient temperature for two hours, concentrated under reduced pressure, and further dried under high vacuum overnight to provide 97 g of N-(4-methoxybenzyl)-N-[(4-methoxyphenyl)methylidene]amine as a white, waxy solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:14][CH2:13]1.N1C=CC=CC=1.Cl.[NH+]1C=CC=CC=1>CCOCC.O>[CH:12]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:9][CH2:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:24])[CH2:13][CH2:14]1
Reactant: O=C(Cl)CCCCCCCCC1CC1
Reactant: Cc1ccc(C=CCO)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(C=CCOC(=O)CCCCCCCCC2CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g. p-methylcinnamyl alcohol in 50 ml. ether at 0° under nitrogen is added 4.9 g. 9-cyclopropylnonanoyl chloride and 3.6 ml. pyridine. The reaction mixture is allowed to warm to room temperature and is then stirred for ten days. Water is then added to dissolve the pyridinium hydrochloride and form a second liquid phase. This mixture is stirred for 4 hours to hydrolyze the excess acid chloride and the mixture is then diluted with a mixture of ether and water. The ether phase is separated and the aqueous phase is extracated once with ether. The combined ether phases are washed with 2N sulfuric acid, 10% potassium carbonate, water, saturated copper sulfate, water, and brine, dried over calcium sulfate and the solvent removed to yield p-methylcinnamyl 9-cyclopropylnonanoate.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=CN(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=[O:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of sodium periodate (1.9 g, 8.7 mmol) in tetrahydrofuran (10 mL) and aqueous pH 7 buffer (15 mL) was added 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (1.0 g, 2.90 mmol) all at once. The reaction was stirred for 1 hour. The precipitate was collected, washed well with water and dried under a nitrogen stream to afford 0.863 g (92%) of 3-(2-chloro-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a yellow solid which was about a 25:1 mixture of hydrate to free aldehyde. The product was characterized as follows: mp 160-164° C.; 1H NMR (DMSOd6) δ (hydrate) 8.51 (dd, J=2, 5 Hz, 1 H), 8.08 (dd, J=2, 8 Hz, 1 H), 7.87-7.78 (m, 3 H), 7.60 (dd, J=5, 8 Hz, 1 H), 6.64 [ABq, Dn1-3=18 Hz, J=7 Hz, 2 H (hydrate OHs], 5.27 [br s, 1 H (hydrate methine CH]. Addition of D2O to the NMR sample caused the multiplet at 6.64 ppm to disappear and sharpened up the singlet at 5.27 ppm. The presence of free aldehyde was demonstrated by a minor singlet at 9.51 ppm.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([Br:17])[CH:15]=[CH2:16]>C(OCC)C>[Br-:17].[CH2:1]([N+:4]1([CH2:16][CH:15]=[CH2:14])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCc2ccccc2C1
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CC[N+]1(CC=C)CCc2ccccc2C1
Product: [Br-]
Temperature: 5 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a 1L 3-necked round-bottomed flask, was added 100.0 g of 1,2,3,4-tetrahydroisoquinoline dissolved in 150 mL diethyl ether. The reaction mixture was cooled to 5° C. with an ice. While stirring, 45.4 g of allyl bromide in 60 mL diethyl ether was added slowly to the amine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with 300 mL diethyl ether, and the white precipitate was removed by filtration. Ether was removed from the filtrate under reduced pressure using a rotary evaporator yielding 64.0 g of N-allyl 1,2,3,4-tetrahydroisoquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 61 g of N-allyl 1,2,3,4-tetrahydroisoquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 42.6 g of allyl bromide in 60 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 55.0 g of N,N-diallyl 1,2,3,4-tetrahydroisoquinolinium bromide as a white solid.
Reaction SMILES: [CH:1]1([C@@H:7]([N:9]2[CH2:14][CH2:13][C@@:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:15][CH2:16][CH2:17][OH:18])[O:11][C:10]2=[O:26])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][CH2:16][CH2:15][C@@:12]1([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:11][C:10](=[O:26])[N:9]([C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:8])[CH2:14][CH2:13]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of (R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-6-(3-hydroxy propyl)-1,3-oxazinan-2-one (200 mg, 0.55 mmol) in CH2Cl2 (10 mL) was added Et3N (290 mg, 2.87 mmol) and MsCl (196 mg, 1.72 mmol) at 0° C. The reaction solution was stirred at rt for 2 h. The reaction was quenched by H2O and extracted with CH2Cl2. The organic phase was concentrated to give the 3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophen-yl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (240 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][C@H:14]([C:19]([NH:21][CH2:22][C:23](O)=O)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].Cl.C1C=CC2N(O)N=[N:33]C=2C=1>CN(C)C=O.C(N(CC)CC)C>[C:23]([CH2:22][NH:21][C:19](=[O:20])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])#[N:33]
Reactant: O=C(O)CNc1ccc(Cl)cc1
Reactant: CC(C)C[C@H](N)C(=O)NCC(=O)O
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)CNc1ccc(Cl)cc1)C(=O)NCC#N
Reaction time: 18 h

Procedure:
(4-Chloro-phenylamino)-acetic acid (0.5 g) and H-Leu-Gly((CN).HCl (0.55 g) are dissolved in dimethylformamide (4 ml). HOBt (0.44 g), WSCD.HCI (0.54 g), triethylamine (0.37 ml) is added and the reaction mixture is stirred for 18 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with 10% citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate and evaporated. The crude product is slurried in diethylether and the solid filtered of and dried (vacuum) yielding a white powder with mp. 131-134° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]1[O:16][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#C)[O:8][CH2:7]1.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([O:19][CH3:20])=[O:18].O>CCOCC>[CH2:7]1[O:8][C:9]([CH3:1])([CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH:25]([C:24]2[CH:27]=[CH:28][C:21]([C:17]([O:19][CH3:20])=[O:18])=[CH:22][CH:23]=2)[OH:26])[O:16][CH2:6]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [Li]CCCC
Reactant: C#CCCCCC1OCCO1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(C(O)C#CCCCC2(C)OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
n-Butyl-lithium (1 equivalent) was added dropwise under nitrogen to a solution of heptan-1-yne-7-one ethylene ketal (5.0 g) in ether at ice salt temperature and gave an intense red colour. The solution was stirred at this temperature for 40 minutes. This solution was added to a solution of 4-carbomethoxybenzaldehyde (5.3 g) at the same temperature and produced a grey precipitate. The mixture was left to warm to room temperature. Water was added, the layers separated and the ether layer dried (MgSO4). Removal of the solvent gave an oil which was chromatographed on silica (300 g). Elution with ether gave 1-(4-carbomethoxyphenyl)-1-hydroxyoctan-2-yne-7-one ethylene ketal as a clear oil (5 g). τ (CDCl3) 8.77 (3H, s), 8.35 (4H, m), 7.75 (2H, t, J=7 Hz), 6.85 (1H, broad), 6.16 (3H, s+4H, s), 4.52 (1H, s), 2.45 (2H, d, J=8 Hz), 2.0 (2H, d, J=8 Hz).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn].O>CO.Cl>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CO
Product: Nc1ccccc1CS(=O)(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A stirred mixture of 2-(phenylsulfonylmethyl)-1-nitrobenzene (5.55 g, 20.0 mmol) and granular tin (10.4 g, 88 mmol) in methanol and concentrated HCl (60 mL) is stirred under nitrogen at 45° C. for 5 h, cooled to ambient temperature over an 18 h period, poured onto NaHCO3 (80 g) with stirring, treated with water and extracted with ethyl acetate. The combined extracts are washed with brine (2×100 mL), dried over MgSO4, and concentrated in vacuo to afford the title product as an off-white solid, 4.41 g (89%) mp 175–176° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:36][OH:37].N1C=CC=CC=1>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][CH2:12][NH:11][C:9]([C:6]3[NH:7][N:8]=[C:4]([C:1](=[N:36][OH:37])[CH3:2])[CH:5]=3)=[O:10])[N:15]=2)=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28])#[N:26]
Reactant: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
5-Acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide (0.17 g, 0.43 mmol) was dissolved in ethanol (15 ml). Sodium acetate (0.071 g, 0.86 mmol) and hydroxylamine hydrochloride (0.060 g, 0.86 mmol) was added and the reaction mixture was stirred at RT for 1.5 h. After addition of pyridine (5 ml) stirring was continued for 65 h. The reaction mixture was evaporated to dryness, co-evaporated two times with toluene and dissolved the residue in ethyl acetate. It was then washed two times with water, dried with Na2SO4 and purified with CombiFlash using DCM and methanol as eluents affording 0.034 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.11-2.15 (m, 3H), 3.68-3.71 (m, 2H), 4.39 (t, 2H), 7.05-7.06 (m, 1H), 7.88 (d, 1H), 8.17-8.20 (m, 1H), 8.32-8-35 (m, 1H), 8.68 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH2:9][CH2:10][CH3:11])=[CH:7][N:8]=1)#[N:2].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22](N)[CH:23]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:22]([NH:2][C:1]2[C:3]3[C:4](=[N:5][C:6]([CH2:9][CH2:10][CH3:11])=[CH:7][N:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=1
Reactant: CCCc1cnc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CC(=O)O
Product: CCCc1cnc2c(Nc3cc(C)ccc3Sc3ccccc3)ncnc2n1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A mixture of the product from Example 243A (38.2 mg, 0.176 mmol) and the product of Example 5I (41.6 mg, 0.193 mmol, 1.1 eq) in acetic acid (1 mL) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The resulting residue was triturated with methanol to provide the title compound (19 mg, 28% yield) as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.97 (t, J=7.35 Hz, 3H), 1.76-1.90 (m, 2H), 2.42 (s, 3H), 2.94-3.05 (m, 2H), 7.08-7.28 (m, 6H), 7.55 (d, J=8.09 Hz, 1H), 8.45 (s, 1H), 8.81 (s, 1H), 8.89 (s, 1H), 10.32 (s, 1H). MS (ESI+) m/z 388.1 (M+H)+ (ESI−) m/z 386.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.CO>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: c1c[nH]cn1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-n2ccnc2)c1

Procedure:
A mixture of 1-(3-bromophenyl)-5-formylbenzimidazol O-methyloxime (29a) from Example 8 (0.7 g, 2.13 mmol), imidazole (0.33 g, 4.85 mmol), potassium carbonate (0.29 g, 2.13 mmol) and a catalytic amount of copper-bronze in 5 ml N-methyl-2-pyrrolidone is heated to 140° C. under a stream of nitrogen for 24 hours. After cooling the mixture is poured into water. A small volume of methanol is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is eluted through silica gel with a mixture of dichloromethane and ethanol (10:1) to yield pure 29b. Yield: 0.23 g (34%) Mp. 197-199° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23]([OH:25])=O)=[CH:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[CH3:26][N:27]([CH3:28])[C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:14][CH:15]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(C(=O)O)c3ccccc32)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 48.4 %

Procedure:
A solution of the above crude carboxylic acid (300 mg, ca. 0.87 mmol), dimethylamine (2.0M in THF, 0.88 ml, 1.76 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 338 mg, 1.76 mmol), hydroxybenzotriazole hydrate (178 mg, 1.31 mmol) in DMF (10 ml) was stirred at room temperature for 24 h, poured into water, extracted with EtOAc (three times). The extracts were dried (Na2SO4), concentrated and purified by flash chromatography (hexane/EtOAc 1:0 to 0:1) to give tert-butyl 4-(dimethylcarbamoyl)-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B2) (156 mg). LC-MS: m/e=371.1 (M+H), 315.0 (M+H−C(CH3)3). Rt=3.16 min. 1H-NMR (500 MHz, CDCl3): 7.32-7.27 (m, 2H), 7.13 (t, 1H), 6.97 (d, 1H), 6.00 (t, 1 H), 3.91 (br. d, 2H), 3.04 (br. s, 3H), 2.97 (t, 2H), 2.85 (br. s, 3H), 2.44 (br. s, 2H), 1.85 (m, 2H), 1.70 (d, 2H), 1.40 (s, 9H).