Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(OCC)C>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
The product from step (i) above (2.00 g) in acetonitrile (10 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.04 g) and triethylamine (0.89 ml) in acetonitrile (15 ml) and the mixture stirred overnight. The precipitated solid was removed by filtration and the filtrate evaporated. Purification of the residue by flash chromatography on silica, eluting with 0 to 5% v/v methanol/dichloromethane, gave a yellow gum. Trituration of this gum with diethyl ether gave methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]phenoxy]isobutyrate, 170 mg, as a white solid: m.p. 88°-90° C.; NMR (d6DMSO) δ 8.15 (2H, d), 7.96 (2H, d), 6.82 (4H, m), 3.92 (2H, s), 3.70 (3H, s), 3.33 (4H, t), 2.63 (4H, t), 1.60 (6H, s); m/e 398 (M+H)+ ; calculated for C22H27N3O4.0.25H2O: C, 65.8; H, 6.8; N, 10.5. found: C, 65.8; H, 7.1; N, 10.4%.
Reaction SMILES: C[C:2]([CH3:9])([C:6]([O-:8])=[O:7])[C:3]([O-:5])=[O:4].O[C:11]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:16]=[CH:15][C:12]=1C=O.N1CCCC[CH2:29]1.C(O)(=O)C>CO>[CH2:20]([O:19][C:17]1[CH:16]=[C:15]2[C:12]([CH:9]=[C:2]([C:3]([O:5][CH3:29])=[O:4])[C:6](=[O:7])[O:8]2)=[CH:11][CH:18]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOc1ccc(C=O)c(O)c1
Reactant: C1CCNCC1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc2cc(C(=O)OC)c(=O)oc2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a mixture of dimethylmalonate (4ml), 2-hydroxy-4-octyloxybenzaldehyde (2.50 g) and piperidine (0.1 ml) in methanol (10 ml) was added acetic acid (0.01 ml), and the mixture was stirred for 3 hours at 70° C. The solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 0.5N hydrochloric acid, water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure, and the precipitate was collected by filtration, and washed with n-hexane, and dried to give Methyl 7-octyloxycoumarin-3-carboxylate (0.94 g).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:22][CH2:21]4)=[CH:16][C:15]=3[O:32][CH3:33])[N:11]=[CH:12][C:7]=2[C:6](=[O:34])[C:5]([C:35]([NH2:37])=[O:36])=[C:4]1[NH:38][CH3:39])[CH3:2].CC[Cl:42].CCOCC>ClCCl.CO>[ClH:42].[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25]4)=[CH:16][C:15]=3[O:32][CH3:33])[N:11]=[CH:12][C:7]=2[C:6](=[O:34])[C:5]([C:35]([NH2:37])=[O:36])=[C:4]1[NH:38][CH3:39])[CH3:2]
Reactant: CCCl
Agent: CCn1c(NC)c(C(N)=O)c(=O)c2cnc(Nc3ccc(C4CCN(CCC(F)(F)F)CC4)cc3OC)nc21
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.08 g (0.15 mmol) of the product prepared in step 16.5 in 6 mL of a dichloromethane/methanol mixture (v/v=1/1) is added 0.44 mL (0.44 mmol) of a 1M solution of hydrochloric ether. The mixture is stirred for 1 hour at room temperature, and ether is then added. The solid is drained by suction, rinsed with pentane and dried in an oven under vacuum. 0.09 g of the expected product is finally obtained in the form of a yellow solid. Yield (dihydrochloride)=99%. M+H+=548.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2cccs2)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
2-Thiophenylacetyl chloride (12.38 g, 77.1 mmol) in CH2Cl2 (40 ml) was added to a solution of anisole (8.33 g, 77.1 mmol) and AlCl3 (10.3 g, 77.1 mmol) in CH2Cl2 (200 ml) at room temperature. The reaction was completed after 2 hours, and the mixture was poured over a 10% HCl/ice slurry. The organic layer was washed with H2O and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was chromatographed on SiO2 (1 kg) eluting with CH2Cl2 /Hexane, 3/1, to afford 23 (9.37 g, 52.4%), m.p. 44.0°-45.5° C. and the ortho isomer (2.14 g, 12%)
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[F:27][C:28]1[C:33]([CH2:34]O)=[C:32]([F:36])[C:31]([F:37])=[C:30]([F:38])[C:29]=1[F:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH2:34][C:33]1[C:32]([F:36])=[C:31]([F:37])[C:30]([F:38])=[C:29]([F:39])[C:28]=1[F:27])=[O:24]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(F)c(F)c2F)C1(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 4.12 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride was added at 0° C. to a mixture of 3 g of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid, 30 ml of methylene chloride, 3.96 g of pentafluorobenzyl alcohol and 100 mg of 4-dimethylaminopyridine and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 hexane-ethyl acetate mixture yielded 4.78 g of pentafluorobenzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-23° (c=0.5% in chloroform).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]3[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=P(Cl)(Cl)[Cl:22]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]3[N:17]=[C:16]([Cl:22])[CH:15]=[C:14]([CH3:19])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(O)nc(/C=C/c2ccc3c(c2)OCO3)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2ccc3c(c2)OCO3)n1
Yield: 89.6 %

Procedure:
In analogy to example 12c), by heating (E)-2-(2-benzo[1,3]dioxol-5-yl-vinyl)-6-methyl-pyrimidin-4-ol (0.5 g, 1.95 mmol) in POCl3 (3.5 ml, 39 mmol) at 130° C. for 4.5 h there was obtained (E)-2-(2-benzo [1,3]dioxol-5-yl-vinyl)-4-chloro-6-methyl-pyrimidine (0.48 g, 90%) as a yellow solid. ISP mass spectrum, m/e: 275.2 (M+1 calculated for C14H11Cl2N2: 275).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[O:38])=[CH:35][CH:34]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a solution of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.55 g) and triethylamine (0.7 ml) in chloroform (15 ml) was dropwise added p-methoxybenzoyl chloride (0.85 g) at ambient temperature with stirring, which was continued for 20 minutes. The reaction mixture was washed successively with aqueous sodium bicarbonate and water. The organic layer was separated, dried and evaporated in vacuo. The resultant oily product was subjected to column chromatography on silica gel eluting with ethyl acetate. The fractions containing the desired compound were combined and evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and hexane to give 1-[3-(4-methoxybenzoylamino)propyl]-4-benzhydrylpiperazine (1.1 g) as white crystals. mp: 126°-128° C.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:14])=[N:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ncn(-c2ccccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ncn(-c3ccccn3)n2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-(3-Bromo-1H-1,2,4-triazol-1-yl)pyridine (0.25 g, 1.12 mmol) and 3-cyanophenylboronic acid (0.33 g, 2.23 mmol) were dissolved in toluene (20 mL) and methanol (2 mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium (129 mg, 0.11 mmol) were then added to the stirred solution. The reaction flask was fitted with a reflux condenser and the mixture stirred at 90° C. for 16 h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (100 mL). The EtOAc solution was washed with H2O (2×100 mL), then brine (100 mL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (40:60)to afford 3-(1-pyridin-2-yl-1H-1,2,4-triazol-3-yl)benzonitrile as a white solid which was then dissolved in dichloromethane (10 mL) and precipitated as the hydrochloride salt (M.p.=185–188° C.) upon treatment with 1M HCl in diethyl ether (1 mL).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH:26]([CH3:29])[CH:27]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH:26]([CH3:29])[CH3:27])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CC(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-methyl-propionaldehyde (0.20 g, 2.77 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with a mixture of 25% ethyl acetate in hexanes and filtered to give the title compound as a solid (0.073 g, 65%). MS (APCI+) m/z 417 (M+H)+.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: OC1CCCCCC1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC1CCCCCC1

Procedure:
Prepared as in Example 22b from cycloheptanol and 2-amino-6-fluorobenzonitrile as yellow oil (11%). 1H NMR (400 MHz, DMSO-d6) δ 1.42-1.71 (m, 10H), 1.88-1.93 (m, 2H), 4.56 (m, 1H), 5.95 (s, 2H), 6.20 (d, J=8.0 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:13])(P(O)(O)=O)[C:6]([OH:8])=[O:7].[C-]#N.[K+].[C:17](O)(=O)[CH3:18]>C(O)C.O>[C:2]([CH2:3][CH2:4][C:5](=[O:13])[C:6]([O:8][CH2:17][CH3:18])=[O:7])#[N:1]
Reactant: CC(=O)O
Reactant: NCCCC(O)(C(=O)O)P(=O)(O)O
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CCC#N
Temperature: 25 °C

Procedure:
To a solution of 12.8 g (0.10 mole) of ethyl 2-oxo-3-butenoic acid (prepared as in Example 1) in 100 ml of ethanol and 50 ml of water is added 6.5 g (0.10 mole) of potassium cyanide. The mixture is stirred at 30°-50° for about one hour, during which time a solution of 6.0 g (0.10 mole) of acetic acid in 20 ml of ethanol is slowly dripped in. After addition is complete, the mixture is cooled to room temperature and the solvent is removed under vacuum. The residue is partitioned between water and CH2Cl2, the layers separated, and the water extracted further with CH2Cl2. The combined organic layers are dried (Na2SO4) and the solvent is removed to give the crude product. This is purified by flash chromatography on silica gel to give ethyl 4-cyano-2-oxo-butanoate as an oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.C(OO)(=[O:17])C>C(Cl)Cl>[O:17]1[CH:10]2[CH:11]1[CH:12]1[CH2:13][CH:14]2[C:3]([F:7])([C:2]([F:9])([F:8])[F:1])[C:4]1([F:6])[F:5]
Reactant: C1=CCC=C1
Reactant: CC(=O)OO
Reactant: FC(F)=C(F)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1(F)C2CC(C3OC32)C1(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
8.6 g (40 mmol) of the Diels-Alder reaction product of hexafluoropropene and cyclopentadiene are mixed in 20 ml of dry methylene chloride with 97 ml (80 mmol) of a 0.83 molar solution of peroxyacetic acid in methylene chloride, and the mixture is stirred for 96 hours at room temperature. Thelow-boiling components are then distilled off under reduced pressure. The residue is washed with two 20 ml portions of water, and the organic phase is dried with magnesium sulfate. The product distils at a pressure of 100 mbar and a boiling point of 60° to 65° C. In order to increase product purity, the distillation is repeated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:34][CH2:35][N:31]([CH3:30])[C:32]5=[O:36])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: CN1CCNC1=O
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C#N)c2)C1=O
Yield: 80.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (377 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[O:13]1CCC[CH2:14]1.CCCCCC.C([Li])(CC)C>C(O)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[CH:14]=[O:13]
Reactant: COc1cccc(OC)c1OC
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(OC)c1OC
Reaction time: 0.75 h
Yield: 24 %

Procedure:
A mixed solution of 20 g of 1,2,3-trimethoxybenzene and 100 ml of tetrahydrofuran (THF) was cooled to -78° C., and 140 ml of a hexane solution containing 1M sec-butyl lithium (sec-BuLi) was added dropwise thereto. After stirring the mixture at the same temperature for 45 minutes, 11 ml of dimethylformamide (DMF) was added to the reaction mixture. The mixture was stirred at -50° C. or lower for 45 minutes. Then, a 10% acetic acid aqueous solution was added to the mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 5.7 g of 2,3,4-trimethoxybenzaldehyde (yield: 24%, oily product).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[CH:24]=[N:25][N:26]([CH3:27])[C:22]=1[OH:21])=[O:5]
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)C1
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C)c3O)c2Cl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
At 0–5° C., a solution of 6.7 g (20 mmol) of 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 80 ml of dimethoxyethane was added dropwise to a solution of 2.0 g (20 mmol) of 5-hydroxy-1-methylpyrazole and 3.3 g (24 mmol) of potassium carbonate in 30 ml of anhydrous dimethoxyethane. After 12 hours of stirring at room temperature, a further 8.2 g (60 mmol) of potassium carbonate were added, and the batch was refluxed for six hours. After cooling, the reaction mixture was stirred into 1 l of water and extracted with methylene chloride. The aqueous phase was then adjusted to pH 4 using 10% strength hydrochloric acid and extracted repeatedly with methylene chloride, with readjustment of the pH. The organic phase was dried and the solvent removed, giving 5.3 g (13 mmol, 67%) of the desired compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH3:2].[C:18]1([CH2:24][C:25]#[N:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.[OH-].[Na+]>O>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]#[N:26])=[CH:8][CH:7]=1)[CH3:2]
Reactant: N#CCc1ccccc1
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(CC)COc1ccc(C=C(C#N)c2ccccc2)cc1

Procedure:
70.2 Grams of 4-[(2-ethylhexyl)oxy]benzaldehyde (prepared as described in the preceding paragraph) and 38.6 g of phenylacetonitrile were added to 800 ml of methanol and stirred cold (10°-15° C.). To this was added (dropwise) 125 ml of aqueous sodium hydroxide (50 percent) with continued stirring at 10°-15° C. for an additional two hours. The mixture was then stirred overnight at room temperature and then poured into cold water and extracted with ethyl acetate. The extract was dried and evaporated to yield α-[[4-(2-ethylhexyloxy)phenyl]methylene]benzeneacetonitrile which was catalytically reduced as follows.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([Cl:37])[CH:36]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([NH2:21])=[N:13]3)[CH:7]=2)[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Solvent: CC(=O)O
Product: COc1ccc(C2(c3cccc(-c4cc(Cl)cc(Cl)c4)c3)N=C(N)c3ccccc32)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-(4-methoxyphenyl)-1H-isoindole-3-amine acetate (Example 87) and (3,5-dichlorophenyl)boronic acid in 28% yield: 1H NMR (DMSO-d6) δ 7.78-7.74 (m, 2 H), 7.59-7.52 (m, 5 H), 7.47-7.41 (m, 2 H), 7.41-7.34 (m, 2 H), 7.23-7.18 (m, 2 H), 6.82-6.77 (m, 2 H), 3.69 (s, 3 H), 1.88 (s, 3 H); MS (ES) m/z 459, 461, 463 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12](O)=[O:13]>>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: O=NO
Reactant: Oc1cccc2cccnc12
Product: O=Nc1ccc(O)c2ncccc12

Procedure:
The 8-hydroxyquinoline is reacted with nitrous acid to form 5-nitroso-8-hydroxyquinoline. The nitrous acid is generated in situ by the action of mineral acid, such as hydrochloric, sulfuric, and the like, on sodium nitrite usually under cold temperature conditions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[CH:12][CH:11]=[N:10]1.[N:17](OCCC(C)C)=[O:18]>CCOC(C)=O.CCO.Cl.CC(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([N:17]=[O:18])[CH:11]=[N:10]1
Reactant: CCNc1ccnn1-c1ccc(F)cc1F
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNc1c(N=O)cnn1-c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 1-(2,4-difluorophenyl)-N-ethyl-1H-pyrazol-5-amine (1.15 g, 5.16 mmol) in 4.0 mL of EtOAc, 2.0 mL of EtOH and 4.0 mL of 5-6 N HCl in 2-propanol was cooled in an ice/brine bath and treated with isoamyl nitrite (0.70 mL, 5.28 mmol) drop wise. After stirring at this temperature for 15 min, the reaction was quenched by the addition of 28-30% NH4OH solution and EtOAc, forming a deep blue solution. The EtOAc layer was separated, washed with brine, dried and concentrated to afford the title compound as a brown crystalline solid. MS (ES+): 253.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:21]2[N:26]=[C:25](Cl)[N:24]=[C:23]([Cl:28])[C:22]=2[CH:29]=[O:30])[CH2:19][CH3:20])=[CH:16][CH:15]=1>O1CCCC1>[Cl:28][C:23]1[C:22]([CH:29]=[O:30])=[C:21]([N:18]([CH2:19][CH3:20])[C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:26]=[C:25]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:24]=1
Reactant: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1nc(Cl)c(C=O)c(N(CC)c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
Over five hours, at a temperature of -30° C., a solution of 9.28 g (0.127 mole) of diethylamine and 12.84 g (0.127 mole) of triethylamine in 80 ml of tetrahydrofuran was added dropwise to a solution of 40.0 g (0.121 mole) of 6-(4-chloro-N-ethylanilino)-2,4-dichloro-pyrimidine-5-carbaldehyde in 400 ml of tetrahydrofuran. The solution was then stirred for four hours at -30° C. and for two hours at 20° C., the triethylammoniumchloride was filtered off, and the filtrate evaporated in vacuo. After the filtrate was mixed by stirring with 120 ml of diethylether, 27.3 g of colorless crystals were obtained.