Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:32]3[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[NH:35][CH2:34][CH2:33]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: OCC1CCNCCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC(CO)CC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and the product of step i).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Br:15].[C:17](Cl)(=[O:19])[CH3:18]>>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Br:15])[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1Br
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared from 4-[N-(2-dimethylamino-ethyl)-amino]-3-bromo-nitrobenzene and acetyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[C@@H:6]([OH:22])[CH2:5]2.O1CCC[CH2:24]1.CI.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[C@@H:6]([O:22][CH3:24])[CH2:5]2
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccc(Cl)cc2C[C@@H]1O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a solution of 2-[(1R,2S)-5-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (25.8 g, 0.0822 mol) in tetrahydrofuran (186 mL, 2.29 mol) was added methyl iodide (20.5 mL, 0.329 mol) and the solution was stirred at 0° C. To this solution was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (90.4 mL, 0.0904 mol) dropwise via an addition funnel over 1 hour. The reaction was quenched via addition of 0.1 N HCl (250 mL) and transferred to a separatory funnel containing EtOAc (600 mL). The layers were separated, and the organic layer was washed with 1N NaOH (2×100 mL each) and with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (25.8 g, 96%) which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)[OH:6].[H][H]>[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[OH:6]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1O
Temperature: 80 °C

Procedure:
One-tenth mol of methyl-m-nitrosalicylate is dissolved in 250 ml. of ethyl acetate and 10 gms. of Raney nickel added. The mixture is placed in a suitable container to permit pressure hydrogenation and hydrogen gas is passed into the solution. When the gas pressure reaches 10 pounds psi. at 80° C., the mixture is agitated and when the absorption of hydrogen has reached equilibrium, it is shaken for four hours and cooled. The mixture is filtered and the formed methyl-m-aminosalicylat is isolated by distillation and is obtained as an oily compound which distills at 126° C. at 2 mm. Hg. pressure.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: C1COCCN1
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(N6CCOCC6)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4 S,4 aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and morpholine.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].Br[CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11](=[O:12])[CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:5][CH2:6][N:7]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: O=C(O)CCCBr
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(CCCC(=O)O)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-bromo-butyric acid in the presence of a hindered tertiary amine base such as Hunig's base in a solvent such as methylene chloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:10][CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:14][CH:13]=1
Reactant: CSc1nccc(CO)n1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nccc(COc2ccc(Cl)cc2)n1
Yield: 93.6 %

Procedure:
To a solution of (2-(methylthio)pyrimidin-4-yl)methanol (US 2005/0148610) (0.515 g, 3.30 mmol), 4-chlorophenol (0.466 g, 3.63 mmol), and triphenylphosphine (1.297 g, 4.95 mmol) in THF (10 mL) was added a solution of 1,1′-(azodicarbonyl)dipiperidine (1.248 g, 4.95 mmol) in THF (10 mL) dropwise. After stirring the reaction at RT overnight, the solids were filtered. The filtrate was diluted with EtOAc (30 mL), washed with water (20 mL) and by brine. The organic phase was dried (Na2SO4) and concentrated to afford the crude product. The crude product was purified using flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the desired product 4-((4-chlorophenoxy)methyl)-2-(methylthio)pyrimidine 6A (0.825 g, 3.09 mmol, 94% yield) as a light yellow solid. 1H NMR (400 MHz, Chloroform-D) δ 8.45 (1H, d, J=5.02 Hz), 7.18 (2H, d, J=8.78 Hz), 7.07-7.13 (1H, m), 6.80 (2H, d, J=8.78 Hz), 4.99 (2H, s), 2.51 (3H, s).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[CH:20]=[O:21]>O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH:20]=[O:21]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 2-(hydroxymethyl)-pyridine (3.00 g, 27.5 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 3,4-Difluorobenzaldehyde (4.69 g, 33.0 mmol) was then added at 0° C., and stirred for 20 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (2.90 g, 45.6%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.[OH-].[K+].CC([OH:35])(C)C>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]([NH2:25])=[O:35])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1
Reactant: CC(C)(C)O
Reactant: N#Cc1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Yield: 99 %

Procedure:
A mixture of 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile (0.072 g, 0.198 mmol), potassium hydroxide (0.111 g, 1.981 mmol, v/w) and t-BuOH (2 mL, Acros) was heated at 80° C. overnight. LCMS showed the product. The mixture was diluted with water and extracted with a mixture of CHCl3:i-PrOH (3:1) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (75 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C3C=CC=CC=3)[C@@H:13]([CH2:27][O:28]C(=O)C3C=CC=CC=3)[CH2:12]2)=[C:4]([O:37]CCOC)[N:3]=1.C[O-].[Na+].Cl>CO>[OH:28][CH2:27][C@@H:13]1[C@@H:14]([CH2:17][OH:18])[CH2:15][CH2:16][C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:4](=[O:37])[NH:3][C:2]([NH2:1])=[N:10][C:9]2=3)[CH2:12]1
Reactant: COCCOc1nc(N)nc2c1ncn2[C@H]1CC[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(ncn2[C@H]2CC[C@H](CO)[C@@H](CO)C2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
Anhydrous methanol (1 ml) was added to 2-amino-9-[(1S,3S,4S)-3,4-bis(benzoyloxymethyl)-cyclohexyl]-6-(2-methoxyethoxy)-purine (17.4 mg, 0.03 mmole). While cooling the mixture with ice, sodium methoxide (1.62 mg, 0.03 mmole) was added thereto, and the whole mixture was stirred at room temperature overnight. The reaction mixture was neutralized with dilute hydrochloric acid, and the solvent was distilled off under reduced pressure. Then, ethyl ether and water were added to the mixture, an ethyl ether layer was removed, and water was distilled off. The residue was heated at 100° C. for one hour together with 2N aqueous hydrochloric acid (1 ml). After neutralizing the reaction mixture with 1N solution of sodium hydroxide, the reaction mixture was subjected to Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1S,3S,4S)-3,4-bis(hydroxymethyl)cyclohexyl]-guanine (5.7 mg, 31.3%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:46][CH2:47][C:48]([CH2:50][F:51])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:48]([CH2:50][F:51])[CH2:47][F:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added 1,3-difluoroacetone (139 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:34]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg (0.112 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in 0.5 mL of THF was added 60% sodium hydride (8.96 mg, 0.244 mmol) at 0° C. After being stirred at 0° C. for 30 min, iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowed to warm to 25° C., and stirred for an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:25].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:6]2[CH:21]=[CH:22][C:3]([C:1]([NH2:2])=[O:25])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCO)cc1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42–7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])=[CH2:3]>C1(C)C=CC=CC=1.C1(O)C=CC=CC=1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)([CH2:4][C:2]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)([CH3:4])[CH3:3])[CH3:3])=[CH:6][CH:7]=1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(CC(C)(c1ccc(O)cc1)c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Hydrogen chloride is introduced for 6 hours at 0° C into a solution of 78.6 g (0.2 mol) of the bischlorocarbonic acid ester of dimeric p-isopropenylphenol prepared according to (a) in 180 ml of toluene and 150 g of phenol. The solvent and excess phenol are removed at reduced pressure and the reaction product is dissolved in 400 ml of methanol, and 200 ml of concentrated sodium hydroxide solution are added dropwise. The reaction mixture is then diluted with an equal quantity of water and heated to reflux. The methanol is distilled off, 400 ml of toluene are added and the tris-phenol is precipitated with dilute hydrochloric acid. The solvent phase is washed with water, dehydrated over sodium sulphate and concentrated by evaporation. After removal of the excess phenol by distillation, a small amount of bisphenol A distils over, which is followed by the tris-phenol fraction which distils over at 270°-280° C/0.05 Torr. Melting point 150°-151° C (from methylene chloride). Yield: 48 g = 66% of theoretical.
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.[Br:6][C:7]1[CH:12]=[CH:11]C(Br)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[Br:6][C:7]1[N:8]=[CH:9][C:5]([CH:4]=[O:3])=[CH:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 66 %

Procedure:
To a diethyl ether (60 mL) solution of 2,5-dibromopyridine (3.00 g, 12.7 mmol) was added n-butyl lithium (7.99 mL, 1.6 M hexane solution, 12.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 50 minutes at −78° C. Then, N,N-dimethylformamide (1.18 mL, 15.2 mmol) was added to the mixture, which was stirred for 35 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (1.56 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[CH:21][CH:22]=1.Cl>COCCO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[CH:21][C:22]=23)=[CH:4][CH:3]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: COCCO
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 47.2 %

Procedure:
In a volumetric flask, 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (23.56 g, 109.4 mmol, obtained in reference example 1) and 2-methoxyethanol (150 mL) were introduced. A solution of 3-amino-2H-pyrazole (10.00 g, 120.3 mmol) in 2-methoxyethanol (170 mL) and 37% HCl (3.23 g, 32.8 mmol) were added under argon atmosphere. This was heated to reflux for 3 days. It was allowed to cool and concentrated. The solid obtained was dissolved in CHCl3 (400 mL) and MeOH (50 mL) and washed with 0.1 N HCl (300 mL) and 1 N NaOH (300 mL). The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 9.93 g of the desired product in solid cream form (yield: 47%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH2:13][Cl:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:13][Cl:14]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: COCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1ccc(Br)c(CCl)c1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
Under an argon atmosphere, 12.5 g (64 mmol) of 1-bromo-4-isopropylbenzene was placed in a 300 mL Schlenk flask, and 40 mL of carbon tetrachloride and 28.9 mL (384 mmol) of chloromethyl methyl ether were added. The mixture was cooled to −30° C., and after adding 17.1 g (128 mmol) of aluminum chloride, heated to 0° C., then stirred for 20 minutes, and thereafter heated to room temperature and then stirred for 5 minutes. The reaction solution was poured into ice water, and 100 mL of 2M hydrochloric acid and 100 mL of dichloromethane were added while stirring well. After separating the organic layer, the aqueous layer was extracted two times with 50 mL of dichloromethane, and then the organic layers were combined. The organic layer was then dried on anhydrous sodium sulfate and then filtered, and by then distilling off the dichloromethane, 15.6 g of 1-bromo-2-chloromethyl-4-isopropylbenzene was obtained as a transparent, pale-yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.[N+](C)([O-])=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccccc1C(=O)NC1CCc2cccc(Cl)c2C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CCCc1ccccc1C(=O)NC1CCc2c([N+](=O)[O-])ccc(Cl)c2C1

Procedure:
Fuming nitric acid (100 ml), 33% in concentrated sulphuric acid was added dropwise to a solution of 72g (0.22 mol) 8-chloro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene in 300 ml nitromethane at 0° C. The mixture was allowed to reach ambient temperature and was stirred over night. After pouring on ice water/diethyl ether the mixture was basified (sodium carbonate solution) and the phases separated. The organic phase was dried (magnesium sulphate), filtered and evaporated to a residue of 65.5 g of an isomeric mixture. Elution of the mixture on a silica column (isooctane/diethyl ether, 1:1) gave 19 g of 8-chloro-5-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene and 12 g of the desired isomer; 8-chloro-7-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene. MS m/e 372 (M+, 3), 374 (M++2, isotope, 1), 105 (100), 164 (72), 77 (35), 134 (16), 165 (9).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C(OCC)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH2:17]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(Br)cc2)CC1

Procedure:
A solution of 8.5 g of p-dibromobenzene in 35 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-bromophenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.