Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: CC#N
Reactant: COCCCOc1cccc(C=O)c1
Product: COCCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(3-methoxypropoxy)benzaldehyde gave 3-hydroxy-3-(3-(3-methoxypropoxy)phenyl)propanenitrile as a yellow oil. Yield (0.86 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.32 (m, 1H), 6.86-6.97 (m, 3H), 5.02-5.03 (m, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.35 (s, 3H), 2.75 (d, J=6.0 Hz, 2H), 2.03-2.09 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][C:21]1[CH:22]=[C:17]([Cl:16])[N:18]=[CH:19][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cc(Cl)ncn2)c(Br)c1
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a solution of 2-bromo-4-methylphenol (500 mg), in dimethyl sulphoxide (2 ml), was added freshly ground potassium carbonate (407 mg). The mixture was stirred for 20 minutes, and 4,6-dichloropyrimidine (432 mg) was added. The mixture was stirred at ambient temperature for 2 hours, and the reaction mixture preadsorbed onto silica gel (1 g) and purified by column chromatography (eluting with 10% ethyl acetate/dichloromethane) to yield a gum (571 mg, 71%). NMR: 2.35 (3H, s), 7.25 (2H, s), 7.5 (1H, s), 7.55 (1H, s), 8.7 (1H, s); MS; (electrospray) 451 (MH)+.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:24][NH2:25]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][C:2](=[O:3])[NH:24][NH2:25]
Reactant: Nc1nc2ccccc2s1
Reactant: NN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: NNC(=O)Nc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole) in 25 ml of dry chloroform was added dropwise to a to a ice cooled, stirred solution of 2-aminobenzothiazole, 3.75 gm (25 mMole) in 50 ml of dry pyridine. The mixture was stirred at 0° C. for 45 minutes longer. Anhydrous hydrazine, 1.6 ml (250 mMole), was added rapidly to the stirred reaction mixture and the ice bath was removed. Stirring was continued for 3 hours at 22° C. Insolubles were filtered, rinsed with cold methanol and dissolved in dilute aqueous hydrochloric acid. Insolubles were filtered off and the aqueous solution was extracted with ethyl acetate. The aqueous solution was made basic, pH 9.5, by addition of aqueous sodium hydroxide. The insoluble product was filtered, washed with water, dried, and recrystallized from ethanol furnishing 1.35 g of 4-(benzothiazol-2-yl)-semicarbazide melting at 225° C. The product was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:26]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:12])[CH2:15][CH2:16]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)NC1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccccc2c1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a suspension of 1.2 g of 2-methyl-N-(4-piperidyl)indole-3-carboxamide and 1 g of potassium carbonate in 50 ml of toluene and 10 ml of dimethylformamide was added dropwise 0.6 g of benzyl chloride. The mixture was refluxed under heating for 3 hours. After cooling, 50 ml of water was poured into the mixture. The insoluble materials precipitated were filtered by suction and recrystallized from methanol to give N-(1-benzyl-4-piperidyl)-2-methylindole-3-carboxamide, melting at 150°-153° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[C:7]([C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[O:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([N+:25]([O-])=O)=[C:17]([CH3:28])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[O:14][C:15]1[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][C:18]([NH2:25])=[C:17]([CH3:28])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Initially, at room temperature, 37.55 g (166.41 mmol) of tin(II) chloride dihydrate and then, with ice-cooling and slowly, 100 ml of concentrated hydrochloric acid are added to a solution of 19.60 g (55.47 mmol) of 4-(3-tertbutylphenoxy)-5-trifluoromethyl-2-methylnitrobenzene in 100 ml of methanol. The mixture is heated under reflux for 4 h, cooled to room temperature, concentrated, water is added and the residue is filtered off and dried under reduced pressure. The crude product is purified by column chromatography. (13.2 g, purity 86%, yield 63.5%, log P (pH 2.3)=4.67).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2cc(Cl)ccn2)=NO)cc1

Procedure:
2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone in methanol (200 mL) was treated with hydroxylamine hydrochloride (27.2 g, 392 mmol) and a sodium hydroxide solution (15.7 g, 392 mmol in 50 mL of water) as described in Example 12 to give 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g) as a white solid. 1H NMR (CDCl3): δ 8.47 (d, 1H), 7.72 (d, 2H), 7.36 (d, 1H), 7.19 (dd, 1H), 6.91 (d, 2H), 4.43 (s, 2H), 3.84 (s, 3H); MS m/z 277 (M+1).
Reaction SMILES: CN(C)C=O.[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:16]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1nn(CCCN2CCCCC2)c2ccccc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN2CCCCC2)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 8.4 g of the 1-(3-piperidinopropyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.22 g of 1-(3-piperidinopropyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 53%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Br:25][C:26]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH:30]=O>C(Cl)Cl.[Zn]>[Br:25][C:26]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH:30]=[C:20]([Br:24])[Br:21]
Reactant: O=CCOc1ccc(Oc2cccc(Cl)c2)cc1Br
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(Oc2ccc(OCC=C(Br)Br)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
First, 0.38 g of zinc dust, 1.54 g of triphenylphosphine, 1.94 g of carbon tetrabromide and 20 ml of methylene chloride were charged into a reaction vessel, and stirred at room temperature. After 24 hours, a solution prepared by dissolving 1.0 g of (2-bromo-4-(3-chlorophenoxy) phenoxy)acetaldehyde in 5 ml of methylene chloride was added dropwise to the solution with stirring. After stirring at room temperature for 6 hours, the reaction solution was concentrated to give a residue. This residue was subjected to silica gel column chromatography to give 0.48 g of 2-bromo-4-(3-chlorophenoxy)-1-(3,3-dibromo-2-propenyloxy)benzene, yield 33%; nD24.0 1.6282.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])#[N:2].[OH-:21].[Na+].OO>C(O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:2][C:1](=[O:21])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a mechanically stirred suspension of N-(2-cyano-5-methylphenyl)-2-methoxybenzamide (180 g, 0.67 mol) in 1.8 L ethanol under an N2 atmosphere was added 6 N sodium hydroxide solution (310 g in 1.25 L water). To the above mixture, 30% hydrogen peroxide (350 mL, 3.64 mol) was slowly added. The solution was then slowly heated to 80° C. and maintained at this temperature for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol, giving a suspension which was quenched with ice cold water (1.8 L) and acidified with acetic acid to pH 5-6 to give a solid residue. The solid was filtered and washed with water, then dissolved in 5.5 L CH2Cl2 and washed with water (2×18 L). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a light yellow solid (100 g, 54%). mp165-170° C. 1H NMR (CDCl3) δ 2.429 (s, 3H), 4.2 (s, 3), 6.8-7.2 (m, 3H), 7.4-7.6 (m, 2H), 8.2-8.4 (d, 1H), 8.6 (s, 1H), 10.8 (bs, 1H) ppm; 13C NMR (CDCl3) δ 21.68, 55.6, 111.3, 118.2, 119.6, 121.1, 125.7, 127.14, 127.64, 130.96, 132.56, 144.9, 149.06, 150.42, 157.25, 161.52. M/z (obs., [m+H]+)=268.
Reaction SMILES: O[C:2]1[CH:11]=[C:10](C(OC)=O)[C:9](O)=[CH:8][C:3]=1[C:4](OC)=O.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:30](=[O:33])([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:33][CH2:30][CH2:11][CH2:2][CH2:3][CH2:4][CH2:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:3][CH3:4])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C(=O)OC)cc1O
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOCCCCCCCCCCCC
Yield: 280.6 %

Procedure:
Dimethyl 2,5-dihydroxyterephthalate (5.00 g), bromododecane (11.6 g) and anhydrous potassium carbonate (7.63 g) were reacted in N,N′-dimethylformamide at 120° C. under nitrogen for six hours. The solution was cooled and poured into water. After filtration and washing, 11.0 g of the di-dodecyl ether was obtained. This was hydrolyzed with sodium hydroxide to the diacid salt, acidified and the diacid chloride formed by reaction of 6.6 g of the diacid with a 100% molar excess of thionyl chloride. The acid chloride was added over 30 minutes to a solution of glycidol (2.0 g) and triethylamine (2.56 g) in dry toluene maintained at −10° C. Reaction was continued for 5 hours at 20° C. after which the reaction mixture was extracted with dichloromethane and water and the dichloromethane layer dried over sodium sulfate, filtered and the solvent removed under vacuum. The resulting solid was recrystallized from ethyl acetate to give 2.4 g of a pale yellow solid melting at 66-68° C., the diglycidyl ester of 2,5-didodecyloxyterephthalic acid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:30])[C:15]([C:28]#[N:29])=[CH:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][C:11]=2[N+:31]([O-])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C1COCC1.C(O)C.[Pd]>[NH2:31][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:16]=[C:15]([C:28]#[N:29])[C:14]2=[O:30]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc(N)c(NCCN3CCOCC3)cc21
Yield: 110.3 %

Procedure:
A suspension of 916.4 mg (1.93 mmol) of 7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-([2-(trimethylsilyl)ethoxy]methyl)-1,4-dihydro-3-quinolinecarbonitrile in 52 mL of THF and 19 mL of ethanol is hydrogenated in a Parr apparatus at 40 psi for 6 hours in the presence of 183.3 mg of 10% palladium-on-carbon. The catalyst is removed by filtration and the solvent is evaporated in vacuo to give 944.0 mg of 6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile as a deep yellow solid which is used directly in the next step.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[OH-].[K+]>C(O)C.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(I)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
134 g (0.478 mol) of ethyl 3-iodo-1-methyl-1H-pyrazole-4-carboxylate were initially charged in 850 ml of ethanol, and a solution of 29.5 g (0.526 mol) of KOH in 340 ml of water was added dropwise. After 2 days of stirring at room temperature, the mixture was concentrated, the residue was taken up in water and extracted with ethyl acetate and, after separation, the aqueous phase was adjusted to pH 1 using hydrochloric acid, resulting in the precipitation of a solid. Filtration with suction and 3 hours of drying under reduced pressure at 40° C. gave 88 g (70% of theory) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid [log P (pH 2.3)=0.57]. The aqueous phase was extracted with ethyl acetate and the organic phase was concentrated, which gave another 5.1 g (2.1% of theory) of product.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([OH:27])C.OO.[OH-].[Na+]>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:27])[C:9]3=[C:8]([CH2:23][CH3:24])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccccc2)c1C#N
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole (2.4 g, 7.4 mmol), ethanol (100 ml), 30% H2O2 (4.5 ml, 40 mmol), NaOH (0.3 g, 7.5 mmol) and water (10 ml) was stirred at room temperature for 1 hour, then at reflux for 1 hour. Additional 30% H2O2 (2.5 ml) was added and the mixture was refluxed for another 1 hour. The solvent was concentrated in vacuo, the residue was treated with water (25 ml) and acetic acid (3 ml) and the yellow precipitate which formed was collected by filtration, washed with water and recrystallized from isopropanol to afford 0.79 g of 1-cyclopentyl-3-ethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimdin-4-one, as orange needles, m.p. 175°-176° C.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[N:27]=[N:28][N:29]([CH3:31])[N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[N:27]=[N:28][N:29]([CH3:31])[N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 158.2 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.09 mmol, 50.6 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.27 mmol, 0.020 mL) and 1 drop of acetic acid. Sodium triacetoxyborohydride (0.36 mmol, 80.3 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1.5 h and partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19 to 1:14, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The light yellow solid was dried overnight under high vacuum to provide the title compound (41.2 mg). LCMS: m/z 508 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.00 and 8.03 (1H, d), 7.77-7.86 (1H, m), 7.63-7.69 (1H, m), 7.39-7.43 (1H, m), 5.38-5.56 (1H, m), 4.65-4.68 (1H, m), 4.44 and 4.44 (3H, s), 3.13-3.69 (6H, m), 2.94 (3H, s), 1.29-2.58 (18H, m), 0.82 (3H, t).
Reaction SMILES: C1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.N1C=CN=C1.N[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.N[C:32]1[CH:37]=[CH:36]C=C[C:33]=1[C:38]1[NH:42][N:41]=[N:40][N:39]=1>O1CCCC1>[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:24][CH:19]=[CH:20][C:21]=1[C:37]1[CH:36]=[CH:10][C:9]([NH:8][C:6]([NH2:3])=[O:7])=[C:33]([C:38]2[NH:42][N:41]=[N:40][N:39]=2)[CH:32]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1-c1nnn[nH]1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc(-c2ccccc2-c2ccccc2)cc1-c1nnn[nH]1
Reaction time: 4 h

Procedure:
To a solution of N,N-carbonyidiimidazole (0.96 g, 5.0 mmol) and imidazole (0.68 g, 10 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 4-aminobiphenyl (1.0 g, 5.9 mmol) in tetrahydrofuran (10 mL). After stirring at 0 C for 10 min 5-(2-aminophenyl)tetrazole (1.14 g, 7.1 mmol) was added. The reaction was stirred for another 4 hours and filtered. The filtrate was evaporated to dryness and the crude product purified by column chromatography. A yield of 0.28 g was obtained. M.p. 224-226° C.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1.N>>[O:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([NH2:3])[CH2:5][CH2:6]1
Reactant: CON=C1CCOc2ccccc21
Agent: CON=C1CCOc2ccc(C)cc21
Agent: N
Product: NC1CCOc2ccccc21

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 16A for the product of Example 7A. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (dd, J 1.0 and 7.5 Hz, 1H), 7.05 (m, 1H), 6.81 (m, 1H), 6.70 (dd, J 1.0 and 7.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.83 (t, J 6.0 Hz, 1H), 2.03-1.66 (m, 4H). MS (DCI/NH3) m/e 150 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].Cl.O>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of 1-(4-methyl-3-nitrophenyl)ethan-1-one (2.00 g) in ethanol/tetrahydrofuran (15 mL/7.5 mL) was added sodium borohydride (211 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added 0.5 mol/L hydrochloric acid and water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (1.96 g). 1H-NMR (CDCl3) δ ppm: 1.52 (3H, d, J=6.5 Hz), 1.84-1.95 (1H, m), 2.59 (3H, s), 4.91-5.02 (1H, m), 7.32 (1H, d, J=7.9 Hz), 7.52 (1H, dd, J=1.8, 7.9 Hz), 7.99 (1H, d, J=1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Cl)cc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of methyl 4-chloro-2-iodobenzoate (5.93 g, 20 mmol), 4-bromo-2-nitroaniline (4.34 g, 20 mmol), copper (1.26 g, 20 mmol), and K2CO3 (2.76 g, 20 mmol) in chlorobenzene (300 mL) was heated to reflux for 2 days, cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite®). The solution was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 6.86 g (89%) of the desired product. MS (DCI) m/e 386 (M+H)+, 403 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.82 (dd, J=9.1, 2.4 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2 Hz, 1H), 3.87 (s, 3H).