Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH:7]([CH3:10])[C:8]#[CH:9].C(=O)([O-])[OH:13].[Na+]>CC(C)=O.O>[OH:1][CH:5]1[CH:4]=[CH:3][C:2](=[O:13])[CH:6]1[CH:7]([CH3:10])[C:8]#[CH:9]
Reactant: C#CC(C)C(O)c1ccco1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C#CC(C)C1C(=O)C=CC1O
Reaction time: 48 h
Yield: 52 %

Procedure:
1-(2-Furyl)-2-methyl-3-butyn-1-ol (15 g, 0.1 mole) was dissolved in a 2:1 mixture (150 ml) of acetone and water in a reactor, and p-toluenesulfonic acid (3 g) was dried. Thereafter, reaction was carried out at 50° to 60° C. for about 48 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (30 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extrect was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 7.8 g (yield, 52%) of pure (±)-3-hydroxy-2-(1-methyl-2-propynyl)-4-cyclopenten-1-one having a boiling point of 110°-115° C./3 mmHg.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl.[O:19]([NH2:21])[CH3:20]>O>[CH3:20][O:19][N:21]=[CH:10][C:5]1[C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To an amount of 1H-Indole-4-carbaldehyde (50 mg, 0.34 mmol) is added pyridine (10 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (31.6 mg, 0.38 mmol). The mixture is stirred at ambient temperature for 24 h, and 2 mL of water is added. After the solvents were evaporated, the residue is dissolved 2 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a white solid (35 mg). MS (ESI) m/z 175.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:31]=[C:32]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[CH:33]=[CH:34][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
The title compound was prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from Example 118A (114 mg, 0.42 mmol) using Example 115C. The final product was purified by silica gel column chromatography (25-100% EtOAc/hexanes) to give 1-(3-tert-butylphenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (74 mg, 0.14 mmol, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 7.61-7.58 (m, 2H), 7.49-7.36 (m, 3H), 7.27-7.16 (m, 3H), 7.03 (d, 1H), 6.92 (d, 1H), 4.38-4.32 (m, 2H), 4.00 (s, 3H), 3.81-3.73 (m, 2H), 3.33 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 517 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1Br
Temperature: 62.5 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
Combine 2-bromophenylacetic acid (500.0 g, 2.33 mol) with methanol (5.0 L) under a nitrogen atmosphere. Add concentrated sulfuric acid (185.8 mL) drop-wise at 20-35° C., and then warm to 60-65° C. with stirring for 3-4 hours. Cool the reaction mixture to 45° C. and concentrate under reduced pressure below 45° C. to a volume of approximately 750 mL. Cool the reaction mixture to 10-30° C. and add dichloromethane (2.5 L). Adjust the pH to 7-8 with sodium hydroxide (7%, 380.0 mL) and separate the layers. Concentrate the organic phase to dryness under reduced pressure below 45° C. to obtain the title compound (516.5 g, 97.0%) as a yellow oil.
Reaction SMILES: CN1CCN(C)[C:3]1=[O:8].Cl[C:10]1[CH:11]=[C:12](C(C)(C)CCl)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18]>>[O:16]([C:15]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:3][OH:8])[C:17]1[CH:18]=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: CN1CCN(C)C1=O
Reactant: CCOc1ccc(C(C)(C)CCl)cc1Cl
Product: OCc1cccc(Oc2ccccc2)c1
Yield: 500 %

Procedure:
3 l (3,156 g) of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI), 618.0 g (2.50 mol) of purified 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl chloride obtained in the same manner as in Example 1, 1,251.0 g (6.25 mol) of m-phenoxybenzyl alcohol (a product of Ethyl Corp.) and 280.0 g (5.00 mol) of potassium hydroxide in the form of flakes were charged in a 5 l four-neck flask and stirred at 120° C. under nitrogen stream for 15 h to complete the reaction.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=C(F)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCC3(CC3N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A 346 mg (1.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-b) was dissolved in 30 ml of ethanol, and the solution was mixed with 350 mg of 10% palladium-carbon and subjected to 4 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 10 ml of acetonitrile, and the suspension was mixed with 210 mg (0.67 mmol) of 5-amino-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.93 ml (6.67 mmol) of triethylamine, and heated under reflux for 18 hours. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 30 minutes, adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was recrystallized from ethanol-ether to yield 198 mg (78%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid (0.2 g, reference Example 69) in dry dimethylformamide (5 mL), under nitrogen, was treated with 1,1′-carbonyldiimidazole (0.2 g). After stirring at room temperature for 1 hour the resulting tan coloured solution was treated with tert-butanol (260 μL) and DBU (203 μL). This mixture was stirred at 40° C. overnight then evaporated. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueous layer was then extracted twice with ethyl acetate (10 mL). The combined organics were washed twice with brine (10 mL), then dried over sodium sulfate and then evaporated to give the title compound (0.21 g) as a yellow solid.
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>CCO.O>[N:18]1[C:19]2[CH2:20][CH2:21][CH2:22][C:13](=[O:25])[NH:12][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ncccc32)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2ncccc2N1
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 95 and 2.3 eq of potassium acetate in 70 mL of EtOH and 140 mL of H2O was refluxed for 17 hrs. After cooling to rt and rotary evaporation of the EtOH, the solution was made alkaline with 10 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to yield 96.
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)[C:3]1[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.[F:34][C:35]([F:45])([F:44])[O:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:17]3[CH2:18][CH2:19][C:14](=[C:2]([C:3]4[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=4)[O:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][C:35]([F:34])([F:44])[F:45])=[CH:38][CH:39]=4)[CH2:15][CH2:16]3)=[CH:22][CH:23]=2)=[N:31]1)[CH3:33]
Reactant: CCn1nnc(-c2ccc(CN3CCC(C(Cl)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nnc(-c2ccc(CN3CCC(=C(Oc4ccc(OC(F)(F)F)cc4)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1

Procedure:
A solution of {4-[chloro(1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))methyl]phenoxy}trifluoromethane, 4-(trifluoromethoxy)phenol and potassium carbonate in DMF is stirred at ambient temperature for about two hours. After this time the reaction mixture is poured into water and the mixture is extracted with ethyl acetate. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding compound 137.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[N:9][CH:8]=1
Reactant: ClCCCI
Reactant: CC(C)Oc1cncc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-isopropoxypyridin-3-ol (1.04 g, 6.80 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.25 g of an 80% dispersion in mineral oil, 8.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (1.67 g, 8.16 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.92 g, 59.0%).
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CN(C=O)C.S(Cl)([Cl:22])(=O)=O>C(Cl)(Cl)Cl>[Cl:22][C:8]1[O:7][C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:11]([F:12])[F:13])=[N:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)=C(F)CCSc1ncco1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(F)=C(F)CCSc1ncc(Cl)o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
4.0 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole was added to 40 ml of DMF (dehydrated) to which a mixture of 10 ml of chloroform and 2.6 g of sulfuryl chloride was added dropwise at 50 in 1 hour. After the reaction mixture was stirred at 50° C. for 3 hours, a mixture of 5 ml of chloroform and 0.8 g of sulfuryl chloride was further added dropwise in 15 minutes. After stirring at 50° C. for 15 hours, the reaction mixture was cooled to room temperature, poured into 200 ml of ice water and extracted with 100 ml of hexane. The aqueous layer was neutralized with 1N aqueous solution of sodium hydroxide and further extracted with 100 ml of hexane. The extracted hexane layers were put together, washed with 200 ml of saturated common salt water and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: hexane:dichloromethane=1:1) to obtain 2.4 g of 5-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 51.5%, n20D=1.4830).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([Br:18])[C:15](Br)=[O:16]>CC(C)=O>[CH3:1][S:2][C:3](=[NH:4])[NH:5][C:15](=[O:16])[CH:14]([C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6])[Br:18]
Reactant: O=C(Br)C(Br)c1c(Cl)cccc1Cl
Reactant: CSC(=N)N
Solvent: CC(C)=O
Product: CSC(=N)NC(=O)C(Br)c1c(Cl)cccc1Cl
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To 7 g S-methylisothiourea in 50 ml of acetone at 10 degrees C., there are added in drops 12 g of 2-(2,6-dichlorophenyl)-2-bromo-acetyl bromide in 30 ml acetone. The mixture is stirred for 30 minutes at 10 degrees C., and the precipitate is suction-filtered. After concentration of the mother liquor, a second fraction of S-methyl-N-[2-(2,6-dichlorophenyl)-2-bromo acetyl] isothiourea is obtained. The decomposition point is 177 degrees.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[OH:38]/[N:37]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-tert-butyl 3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=486.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Temperature: 60 °C
Yield: 94.1 %

Procedure:
To a solution of methyl [2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.244 g; 0.57 mmol) in methanol (5.7 mL) was added a solution of sodium hydroxide 5 N (1.14 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.222 g (94%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1.[K+].[Br-]>C(OCC)(=O)C>[CH3:53][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][C:21]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[O:22])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)S(=O)(=O)c1ccc(C)cc1
Reaction time: 72 h

Procedure:
To a mixture of 0.50 g of the product of Example 7, excess triethylamine, and ethyl acetate at room temperature was added 0.25 g p-toluene sulfonyl chloride and this was allowed to sit 3 days at room temperature. The reaction mixture was then washed with H3PO4, NaHCO3, and NaCl solutions, dried over MgSO4, filtered, and stripped to an oil. This oil was purified by chromatography on silica gel (70-230 mesh) using 1/1 hexane/EtoAc as eluant. The product was obtained as a viscous oil. 0.28 g (42%). NMR (CDCl3) δ 0.88 (3H, z), δ 1.26 (24H, m), δ 1.66 (2H, m), δ 2.01 (4H, m), δ 2.44 (3H, s), δ 3.21 (2H, m), δ 3.79-3.88 (9H, m), δ 5.34 (2H, m), δ 6.15 (2H, s), δ 7.26-7.75 (5H, m). IR (KBr) 3019, 2925, 1599, 1466, 1206 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2[N:17]=[C:18]([CH3:22])[N:19]=[C:20](Cl)[C:15]=2[C:14]([CH3:23])=[C:13]1[CH3:24].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]#[N:32])[CH2:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2[N:17]=[C:18]([CH3:22])[N:19]=[C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]#[N:32])[CH2:26]3)[C:15]=2[C:14]([CH3:23])=[C:13]1[CH3:24]
Reactant: N#CC1CCCNC1
Reactant: Cc1nc(Cl)c2c(C)c(C)n(-c3ccc(C(F)(F)F)cc3Br)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(N2CCCC(C#N)C2)c2c(C)c(C)n(-c3ccc(C(F)(F)F)cc3Br)c2n1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 7-(2-bromo-4-trifluoromethylphenyl)-4-chloro-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg), piperidine-3-carbonitrile (290 mg), N,N-diisopropylethylamine (309 mg) in ethanol (2 mL) was heated at reflux for 6 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to obtain two diastereoisomers (low polar diastereoisomer: 62 mg and high polar diastereoisomer: 36 mg) of 1-[7-(2-bromo-4-trifluoromethylphenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]piperidine-3-carbonitrile.
Reaction SMILES: C=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=O)[CH2:8]3)[CH2:5][CH2:4]1.[CH3:24]OC(OC)(C)C.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:22][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][CH2:4][C:3]2=[CH2:2])[CH:11]=1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: C=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Refer to FIG. 190. To 17-methylenandrost-4-en-3-one (9, 2.0000 g, 7.0314 mmol) in 2,2-dimethoxypropane (9.4 ml, 76 mmol) and DMF (9.4 ml) were added 0.37 ml of anh. methanol and 47.0 mg of p-toluenesulfonic acid. After refluxing 4 h the reaction mixture was allowed to cool and then partitioned between 140 ml of hexanes and 90 ml of water. The organic phase was washed with two 90 ml portions of water+90 ml of brine, dried over magnesium sulfate, and flash filtered through a 30 mm dia.×37 mm high column of silica gel (200-400 mesh). Product continued eluting with 200 ml of hexanes. Concentration of the combined filtrates under reduced pressure and recrystallization of the residue from acetone/methanol gave very slightly yellow platelets (1.5291 g, 5.1231 mmol, 73%), m.p. 97-99° C., homogeneous to TLC (25% ethyl acetate/hexanes on silica gel, Rf 0.72).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([OH:42])([CH3:41])[CH2:39]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][C:38]([OH:42])([CH3:41])[CH3:39])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CC(C)(O)CO
Product: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, substituting 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-methyl-1,2-propanediol in place of 2-ethyl-1-hexanol (yield: 55 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (s, 6H), 3.30 (s, 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.98 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 451 (M+H)+; (APCI−) m/z 485 (M+Cl)−; Anal. calc. for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C, 56.00; H, 4.48; N, 5.87.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 4-methoxy-3-benzyloxybenzaldehyde 1.79 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.69 g.