Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8][CH:9]1[CH:11]([C:12]([OH:14])=[O:13])[C:10]1([CH3:16])[CH3:15])#[N:6].[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)=[CH:26][CH:25]=1.C1OCCOCCOCCOCCOCCOC1.[C-:57]#[N:58].[K+]>C1(C)C=CC=CC=1.O>[C:5]([C:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:8][C@H:9]1[C@H:11]([C:12]([O:14][CH:32]([C:57]#[N:58])[C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:28][C:27]3[CH:37]=[CH:38][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:30]=2)=[O:13])[C:10]1([CH3:16])[CH3:15])#[N:6]
Reactant: CC1(C)C(C=C(C#N)c2ccccc2)C1C(=O)O
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(C#N)c2ccccc2)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (1.61 ml, 2.6 g; 0.022 mole), 3-(β-cyanostyryl)-2,2-dimethyl-cyclopropanecarboxylic acid (4.82 g; 0.02 mole) and toluene are mixed and heated at 100° C. for 1 hour. The reaction mixture is cooled to 25° C. and a solution of m-(p-chlorophenoxy)benzaldehyde (4.65 g; 0.02 mole) and 18-crown-6 (0.49 g; 0.002 mole) in toluene (10 ml) is added. To this reaction mixture a solution of potassium cyanide (2.6 g; 0.04 mole) in water (6 ml) is added slowly while maintaining the temperature between 20°-25° C. The reaction mixture is then stirred for 18 hours at room temperature. The resultant black reaction mixture is poured in water and extracted with ether (3×). The combined ether extracts are washed with water, 10% hydrochloric acid, 10% sodium bicarbonate, water and saturated sodium chloride solution. The ether layer is dried over sodium sulfate and evaporated in vacuo to leave a brown gum. This gum is purified by dry column chromatography (silica gel; eluent: 1:1 methylene chloride:hexane) to afford the title product, a yellow glass (1.0 g, 8.6%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.[OH-].[Na+].Cl>CS(C)=O.C(OCC)(=O)C.O>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: OC1CNC1
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 64.2 %

Procedure:
In 30 mL of dimethyl sulfoxide was dissolved 6.50 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and to the solution were added 5.60 g of 3-azetidinol hydrochloride and 15.3 mL of a 5 mol/L aqueous sodium hydroxide solution, after which the resulting mixture was stirred at 65° C. for 3.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 5 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 10:1) to obtain 4.77 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][Cl:39]>C(#N)C>[Cl-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][CH2:41][CH3:42])=[O:43])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)OCCl
Solvent: CC#N
Product: CCOC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 22 h
Yield: 21.7 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone(0.50 g) and chloromethyl ethyl carbonate (2.9 g) was added acetonitrile (0.5 ml), and the mixture was stirred for 22 hours at 100° C. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate/acetone=1/1→acetone→acetone/ethanol=9/1→4/1), and the fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo, and the residue was dissolved in water(15 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-ethoxycarbonyloxymethyl-1H-1,2,4-triazolium chloride (Compound 15, 0.14 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[Br:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C(#N)C.C1COCC1>[BrH:7].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:6]2[CH:5]=[CH:4][O:3][C:2]2=[NH:1])=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncco1
Solvent: C1CCOC1
Solvent: CC#N
Product: Br
Product: N=c1occn1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A solution of 2-amino-oxazole (14.9 g, 0.179 mol) in acetonitrile (100 ml) was slowly added over a period of 20 minutes to a solution of 2-bromo-1-(4-fluorophenyl)ethanone (57.6 g, 0.36 mol) in THF (150 ml). The reaction mixture was stirred at room temperature for 24 hrs then cooled to 0° C. A precipitate formed and was filtered off. The solid was washed with three portions of 30 ml of cold acetonitrile and dried at 50° C. under vacuum, yielding 38.75 g (72%) of an off-white solid. M.p.=218-221° C.; 300 MHz 1H NMR (DMSO-d6) δ: 9.80 (br. s, 1H), 8.16-8.11 (m, 2H), 8.00 (s, 1H), 7.62 (s, 1H), 7.52-7.46 (m, 2H), 5.80 (s, 2H); LCMS: 221 [M+H]. Calc. for C11H9N2O2F.1.05HBr.0.14ACN: C, 43.58; H, 3.39; N, 9.64. Found C, 43.63; H, 3.38; N, 9.65.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=[C:14]2[C:34]2[CH:35]=[N:36][C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][C:39]=2[O:40][CH2:41][CH3:42])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>O.O1CCCC1>[C:43]([C:37]1[N:36]=[CH:35][C:34]([C:14]2[N:13]([C:11]([N:8]3[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[O:12])[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=2)=[C:39]([O:40][CH2:41][CH3:42])[CH:38]=1)([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
A mixture of 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid methyl ester (575 mg, 0.864 mmole, example 210) and lithium hydroxide hydrate (217 mg, 5.179 mmole) in water (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 4 h before neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with brine and dried over sodium sulfate and concentrated to give the title compound (552.5 mg, 98%). HR-MS (ES, m/z) calculated for C35H41Cl2N4O4 [(M+H)+] 651.2500, observed 651.2498.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH:16]=[O:17].FC(F)(F)S(O)(=O)=O.[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1.[OH-].[Na+]>O>[NH4+:10].[OH-:17].[Cl:1][C:2]1[C:3]2[CH2:8][CH2:9][N:10]3[C:11](=[N:12][C:13]([I:15])=[CH:14]3)[CH:16]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1Cl
Reactant: CN1CCC(O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC2c3cccc(Cl)c3CCn3cc(I)nc32)CC1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-[2-(2-chlorophenyl)ethyl]-4-iodoimidazole-2-carbaldehyde (example 78B) (200 mg, 0.55 mmole) is added trifluoromethanesulfonic acid (2 mL). The purple solution is stirred at room temperature overnight, 4-hydroxy-N-methylpiperidine (190 mg, 1.65 mmole) is added and solution is stirred at room temperature for 2 hours. Water is added and the solution is made alkaline by adding 5N NaOH to pH 10. The aqueous phase is extracted with AcOEt. The organic phase is washed with water, brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (90:10) then (CH2Cl2:MeOH:NH4OH) (9:1:0.1) to give 8-chloro-2-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([C:22](OC)=[O:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10].O>O1CCCC1>[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([CH2:22][OH:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(=O)c2cc(C(=O)OC)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
To a suspension of 0.013 g of lithium aluminum hydride in 5.0 ml of tetrahydrofuran is added 0.100 g of methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate followed by stirring at room temperature for 5 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for 18 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for an additional 8 hours. The reaction mixture is poured into 75 ml of water and extracted with ethyl acetate. The extract is evaporated in vacuo to a residue which is stirred with acetone and filtered to give 0.040 g of the desired product as a white solid.
Reaction SMILES: [Mg].Cl[C:3]1[CH:11]=[CH:10][C:6]([C:7]([CH3:9])=[CH2:8])=[CH:5][CH:4]=1.CI.[C:14]([O:18]OC(=O)C1C=CC=CC=1)([CH3:17])([CH3:16])[CH3:15].C(C1C=CC(C2C=CC(C(C)=C)=CC=2)=CC=1)(C)=C>C(OCC)C.O1CCCC1>[C:14]([O:18][C:3]1[CH:11]=[CH:10][C:6]([C:7]([CH3:9])=[CH2:8])=[CH:5][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: C=C(C)c1ccc(-c2ccc(C(=C)C)cc2)cc1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)c1ccc(OC(C)(C)C)cc1
Yield: 69.3 %

Procedure:
The procedure of Example 1 was repeated, except that there was utilized 16.9 grams (0.70 mole) of magnesium metal and 100 grams (0.66 mole) of 4-chloro-α-methylstyrene dissolved in 200 ml. of tetrahydrofuran. The Grignard reaction was started by the addition of a small amount of methyl iodide. After the reaction mixture had been refluxed for 12 hours, there was added at 0° C. in a dropwise manner a solution of 85 grams of t-butylperbenzoate in 300 ml. of ethylether. A crystalline product identified as 4,4'-diisopropenylbiphenyl was isolated from the oil which was recovered by filtering the mixture and washing with methanol. After stripping the methanol, a 69.3% yield of 4-t-butoxy-α-methylstyrene was isolated by fractional distillation as a colorless liquid having a boiling point of 65°-68° C. at 0.03 millimeters.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:24][CH:23]=2)[C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([S:12][CH2:13][CH2:14][F:15])[N:11]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:26][CH:27]=2)[C:9]([C:16]([OH:18])=[O:17])=[C:10]([S:12][CH2:13][CH2:14][F:15])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(SCCF)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(SCCF)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 72 h

Procedure:
2.25 cm3 of a 2N solution of sodium hydroxide is added at ambient temperature to 450 mg of the product obtained in Example 43 dissolved in 10 cm3 of ethanol, then the mixture is left for 3 days. The solvents are evaporated under reduced pressure, the residue is taken up in water, 2.25 cm3 of hydrochloric acid 2M/1 is added. The precipitate formed is filtered, washed with water, dried under reduced pressure and 380 mg of expected product is obtained which is recrystallized from isopropanol. M.p.=185°-186° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]3[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=3[CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]5[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=5[CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2cc3c(s2)CCCC3)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1cn(CCCc2ccc(OCc3coc(-c4cc5c(s4)CCCC5)n3)cc2)cn1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 83-84° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
Anisole (0.1 mole, 10.8 grams) and benzoyl chloride (0.1 mole, 14 grams) were dissolved in 200 milliliters of hexane and stirred at room temperature while 15 grams of anhydrous aluminum chloride were added slowly over a period of 15 minutes. The reaction mixture was stirred an additional 15 minutes and then the hexane decanted. The resulting viscous residue in the reaction flask was carefully hydrolyzed with 200 milliliters of a mixture of ice and dilute hydrochloric acid. The resulting organic fraction was taken up in dichloromethane and the resulting solution washed with water. Dichloromethane solvent was removed on a rotary evaporator leaving an oil product that solidified on standing. The solidified product was broken-up, washed with two 50 milliliters portions of pentane, and suction dried yielding 4-methoxybenzophenone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][N:13]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCCOc1ccccc1
Reactant: Clc1ncnc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCOc1ccccc1)c1ncnc2ccccc12
Reaction time: 7 h
Yield: 88.3 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in benzene were added 2.3 g (0.015 mole) of N-methyl-N-phenoxyethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 7 hours. After completion of the reaction, the benzene was removed by evaporation. Water was added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the resulting oil was purified by column chromatography through silica gel (eluted with a 1:1 by volume mixture of benzene and ethyl acetate) to give 3.7 g (88%) of the desired Compound No. 4 in the form of a pale yellow liquid having a refractive index nD27 1.6329.
Reaction SMILES: [C:1]1([CH2:7][OH:8])([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:9]1(O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:29]#[C:30][CH3:31])[CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=1>>[O:6]([CH2:5][C:1]1([CH2:7][O:8][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:29]#[C:30][CH3:31])[CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: OCC1(CO)CCC1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccccc3)CCC2)cc1

Procedure:
Analogously to example 1, cyclobutane-1,1-diyldimethanol, phenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-[4-(1-phenoxymethylcyclobutylmethoxy)phenyl]hex-4-ynoic acid.
Reaction SMILES: O=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC=CC=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].O=P(Cl)(Cl)Cl>O>[O:21]=[C:17]1[CH2:18][CH2:19][CH2:20][N:16]1/[C:2](=[CH:7]\[CH3:8])/[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C1CCCN1
Reactant: CCC(=O)C(=O)OC
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C/C=C(/C(=O)OC)N1CCCC1=O
Yield: 35.1 %

Procedure:
A 100 ml flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with methyl 2-oxobutanoate (7.5 g, 73 mmol), toluene (50 ml, 7 vol) and 2-pyrrolidinone (8.4 ml, 111 mmol, 1.5 equiv) followed by dropwise addition of POCl3 (1.6 ml, 20 mmol. 0.27 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Stark trap for 8 hours. After cooling down the solution was washed with 10% aq KHSO4 (2×3 vol). The aqueous phase was saturated with NaCl and back extracted with toluene (1×6 vol). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford crude material (7.5 g) as an orange mobile oil. The crude oil was distilled (92-94° C., 0. 1 mm Hg) and gave pure product (4.7 g, 60%) as a colourless oil.
Reaction SMILES: [OH-].[K+].C([O:6][C@@H:7]1[C@@:26]2([CH3:27])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[C@H:18]2[C@@H:9]([C@:10]3([CH3:29])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:28])[CH:12]=[CH:11]3)[CH2:8]1)(=O)C.C1C=CC=CC=1>CO>[OH:6][C@@H:7]1[C@@:26]2([CH3:27])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[C@H:18]2[C@@H:9]([C@:10]3([CH3:29])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:28])[CH:12]=[CH:11]3)[CH2:8]1
Reactant: CC(=O)O[C@H]1C[C@H]2[C@@H](CCC3=CC(=O)C=C[C@@]32C)[C@@H]2CC[C@H](C(C)=O)[C@@]12C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 10 h
Yield: 82.3 %

Procedure:
To a solution of 2.2 g of potassium hydroxide in 80 ml of methanol was added 7.4 g of 12α-acetoxypregna-1,4-diene-3,20-dione, and the mixture was stirred at room temperaature for 10 hours. The reaction mixture was concentrated to about one tenth the original volume by distilling off the methanol under reduced pressure. To the concentrated reaction mixture was added 150 ml of benzene, and the solution was washed in sequence with water, diluted hydrochloric acid and water and then driedover anhydrous magnesium sulfate. Low-boiling fractions were distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to give 5.4 g of 12α-hydroxypregna-1,4-diene-3,20-dione (Gaschromatographic analysis revealed that purity thereof was 90%). It has the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24]([C:26]3[S:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)=[O:25])[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@H:15]([NH:23][C:24]([C:26]3[S:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)=[O:25])[C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a stirring solution of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate INT-17 (15.7 g, 28.8 mmol) in DCM (30 mL) was treated with TFA (30.0 g, 263.1 mmol). The reaction mixture was stirred at room temperature for 18 hours to complete. The solvent was evaporated and then co-evaporated with toluene (3×20 mL) to remove trace TFA. The compound was dried under vacuum overnight to afford 13.7 g (97%) of (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid as powder. LCMS-ESI (m/z) calculated for C22H22BrN3O3S: 487.1. found 488.1 [M+H]+, tR=2.55 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.05 (d, J=5.0 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.1 Hz, 2H), 7.62 (d, J=3.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.92 (d, J=3.8 Hz, 2H), 4.64 (td, J=10.5, 4.5 Hz, 1H), 3.26 (dd, J=13.8, 4.4 Hz, 1H), 3.11 (dd, J=13.7, 10.7 Hz, 1H), 1.32 (s, 9H).
Reaction SMILES: [CH:1]([N:4]([CH2:20][CH2:21][CH:22]=O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=1[O:18][CH3:19])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1>C(O)C.O=[Pt]=O>[CH3:32][O:31][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][N:25]([CH3:24])[CH2:22][CH2:21][CH2:20][N:4]([CH:1]([CH3:2])[CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=2[O:18][CH3:19])(=[O:6])=[O:7])[CH:37]=[CH:36][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(S(=O)(=O)N(CCC=O)C(C)C)c(OC)c1OC
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2ccc(OC)c(OC)c2OC)cc1OC

Procedure:
N-isopropyl-N-(3-oxopropyl)-2,3,4-trimethoxybenzenesulfonamide prepared in the previous paragraph (7.50 g, 0.0384 m), N-methyl-homoveratrylamine (6.83 g, 0.350 m) in absolute ethanol (100 ml) containing PtO2 (0.5 g) was shaken under hydrogen all day. The crude product (8.01 g) obtained from this procedure after chromatography gave the pure title compound, a white gum (5.71 g).