Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:11]=[CH:12][CH:13]=1.CN(C)[CH:23]=[O:24]>>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]([N:14]2[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cccc(-n2cccn2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn(-c2cccc(C(F)(F)F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Into a 500 ml., 2-neck flask, fitted with a condenser and a magnetic stirrer, containing 60.5 ml. (0.78 M.) of absolute dimethylformamide (dried over 3A sieves) is slowly added, while the temperature is maintained at less than 10° C., 36.9 ml. (0.39 M.) of phosphorus oxychloride, after which time the reaction mixture is allowed to stand at room temperature until a bright red color develops (typically, between 30 and 60 minutes). To the resultant reaction mixture is then added 23.2 g. (0.109 M.) of 1-(m-trifluoromethylphenyl)-pyrazole, while the temperature is maintained at between 50° and 70° C. The reaction mixture is then slowly heated to 100° C. and allowed to stand overnight, while the temperature is maintained at 100° C. The reaction mixture is then cooled, quenched in ice water and allowed to stand overnight at room temperature. The resultant precipitated solids are then filtered and washed successively with water and petroleum ether. The solvent is then removed under vacuum to yield 1-(m-trifluoromethylphenyl)pyrazole-4-carboxaldehyde (Yield: 57%). A second crop was also obtained, m.p. 80°-82° C. (Yield: 63%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH2:14][N:41]1[CH2:42][CH2:43][CH:38]([C:36]([C:28]2[S:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])[CH2:39][CH2:40]1)[C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3s2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 2.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)benzamide and 4-(benzthiazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccnc2cc(O)ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 7-hydroxy-4-methylquinoline (80 mg, 0.5 mol), (Chem. Berich. 1967, 100, 2077), to give 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (155 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[O:13]COC.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[OH:13]
Reactant: COCOc1c(Br)cccc1/C=C/[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])/C=C/c1cccc(Br)c1O
Reaction time: 4 h

Procedure:
To a suspension of Example 383B in methanol (15 mL) was added 4 N HCl in dioxane (1 mL). The mixture was stirred for 4 hours, concentrated, and diluted with water. The precipitates were collected to afford the titled compound.
Reaction SMILES: CN(C)C=O.O[CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(-c2ccccc2)c(CCO)o1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(CCCl)o1

Procedure:
N,N-Dimethylformamide (4.0 ml) was added to a solution of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole (10.5 g) in chloroform (100 ml) and, under ice-cooling and stirring, thionyl chloride (11.4 ml) was added dropwise. The mixture was refluxed for 30 minutes and the solvent was distilled off. Then, ice water was added and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-chloroethyl)-2-methyl-4-phenyloxazole, yield 11.0 g (96.5%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]2[NH:16][C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:21])[NH:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])[CH3:2].[OH-].[Na+:23]>CO>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]2[NH:16][C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:21])[NH:13]2)=[C:7]([CH:11]=1)[C:8]([O-:10])=[O:9])[CH3:2].[Na+:23]
Reactant: CCc1cnc(C2NC(=O)C(C)(C(C)C)N2)c(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cnc(C2NC(=O)C(C)(C(C)C)N2)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.0 g 5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl)nicotinic acid is added a solution of 0.1498 g sodium hydroxide in 20 mL absolute methanol. The mixture is stirred under nitrogen at room temperature overnight. The solvent is removed to give a solid which is dried in a vacuum oven at 60° C. for two days. The thus-formed sodium 5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl)nicotinate darkens at 230° C. and decomposes at 247°-250° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].[OH-].[NH4+]>C(O)(C)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ncnc2ccc(-n3ccnc3)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncnc3ccc(-n4ccnc4)cc23)cc1Cl
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
A mixture of 4-chloro-6-(1-imidazolyl)quinazoline (3.8 g) and 3-chloro-4-fluoroaniline (2.64 g) in isopropanol (50 ml) was heated to reflux for 3 hours. The solid product so obtained was filtered off, washed with isopropanol and with diethyl ether and dried. The solid so obtained was suspended in water (40 ml) and an aqueous ammonium hydroxide solution (15 ml) was added. The mixture was stirred for 10 minutes. the solid was filtered off, washed with 20% aqueous ammonium hydroxide solution, with water, with acetone and with diethyl ether and dried to give 4-(3-chloro-4-fluoroanilino)-6-(1-imidazolyl)quinazoline (1.10 g); NMR Spectrum: (CD3SOCD3) 7.22 (s, 1H), 7.49 (t, 1H), 7.84 (m, 1H), 7.88 (s, 1H), 7.96 (d, 1H), 8.19 (t, 1H), 8.24 (m, 1H), 8.40 (s, 1H), 8.68 (s, 1H), 8.74 (d, 1H), 9.90 (s, 1H);
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:31]N>C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[CH2:13][CH2:12][C:11]2[C:10](=[CH:15][NH:16][N:31]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=C1CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To crude [1-(3-tert-Butyl-phenyl)-3-dimethylaminomethylene-4-oxo-cyclohexyl]-carbamic acid tert-butyl ester (91 mg, 0.227 mmol) was added ethanol (6 mL) and hydrazine hydrate (0.010 mL, 0.32 mmol). The reaction mixture was stirred at room temperature for 12 h then placed in a freezer overnight. The reaction mixture was concentrated under reduced pressure yielding the title compound: Rf=0.35 in 5% MeOH/CH2Cl2; retention time=1.92 min, method [7]; mass spec (ESI) 392 (25), 370 (2), 315 (24), 314 (100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[N:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
After a mixture of ethyl 3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propionate (800 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propionic acid (740 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 120–121° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([C:20]2[N:25]3[N:26]=[CH:27][N:28]=[C:24]3[N:23]=[C:22]([CH2:29][CH3:30])[CH:21]=2)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][CH:29]([C:22]1[CH:21]=[C:20]([C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:13][N:12]=2)[N:25]2[N:26]=[CH:27][N:28]=[C:24]2[N:23]=1)[CH3:30]
Reactant: CCc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Br)c1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
4.47 g of N-bromosuccinimide and 50 mg of azobisisobutylonitrile (AIBN) were added to a solution having 5.76 g of 7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidine dissolved in 30 mL of chloroform, followed by stirring overnight under reflux with heating. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/2) to obtain 4.47 g of the desired product as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 84.5 %

Procedure:
A solution of Example 34B (0.053 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 84%). 1HNMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.74 (m, 7 H) 1.34 (m, 1 H) 1.57 (m, 3 H) 2.15 (m, 2 H) 3.08 (m, 3 H) 7.56 (m, 3 H) 7.75 (m, 3 H) 8.16 (m, 1 H) 10.26 (m, 1 H) 13.76 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:7]=1Br.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][NH2:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>O.O1CCOCC1>[Br:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:7]=1[NH:34][CH2:33][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: O=c1[nH]nc(OCCSc2ccc([N+](=O)[O-])cc2)c(Br)c1Br
Reactant: COc1ccc(CN)cc1OC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2c(OCCSc3ccc([N+](=O)[O-])cc3)n[nH]c(=O)c2Br)cc1OC
Temperature: 25 °C
Yield: 61.6 %

Procedure:
1.5 g of 4,5-dibromo-6-[2-(4-nitrophenylthio)ethyloxy]-3(2H)-pyridazinone and 1.32 g of 3,4-dimethoxyphenylmethyl amine were disolved in water-dioxane (1:1) and refluxed for 7 hr. The reaction mixture was cooled to room temperature. The resulting crystals was collected by filtration and recrystallized from dioxane to give 1.1 g of the objective compound. Yield, 60%, Melting point, 170°-171° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]=[C:15](Cl)[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][C:15](=[NH:1])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(Cl)c(N=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Reactant: N
Solvent: CCO
Product: N=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 40 ml of ethanol and 10 ml of 28% aqueous ammonia was added 3.9 g (10.0 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionimidoyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and water was poured into the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 3.70 g of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamidine (hereinafter referred to as present compound 4).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8]/[CH:9]=[C:10](/[CH:12]=[CH:13]/[CH:14]=[C:15]([CH3:17])[CH3:16])\[CH3:11]>>[CH3:11][C:10]1[CH2:12][CH:13]([CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3]2[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]2[C:9]=1[CH3:8]
Reactant: C/C=C(C)/C=C/C=C(C)C
Reactant: O=C1C=CC(=O)O1
Product: CC(C)=CC1CC(C)=C(C)C2C(=O)OC(=O)C12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Maleic anhydride (39.88 g), 0.407 mol) and allo-ocimene (55.34 g, 0.407 mol) were charged in a 250 ml three necked round-bottom flask, connected with a reflux condenser. Immediately after addition of the maleic anhydride to the allo-ocimene, the mixture turned intense orange/yellow. The mixture was warmed carefully to 50° C. Then, as the maleic anhydride started to melt, a violent and exothermic Diels-Alder reaction took place. The temperature rose rapidly to 170-190° C. while the color of the mixture became less intense. After about 10 minutes the temperature started to drop. The mixture was kept at 100° C. for one hour. 93.71 g (0.401 mol=98.4%) of a yellow product was obtained that solidified on standing (melting point 78-82° C.). The product was washed with pentane in order to remove the yellow color to a great extent. The yield dropped during washing to about 65%. The anhydride was recrystallized from heptane to yield a white solid (melting point 83.5° C.-84° C.). Yield after recrystallization was 60%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25]Br)[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:32])(=[S:31])[CH3:30]>C(#N)C>[CH:3]1[C:4]2[CH:12]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH:18]3[CH2:19][CH2:20][CH:21]([C:24]4[N:32]=[C:29]([CH3:30])[S:31][CH:25]=4)[CH2:22][CH2:23]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:13]=[CH:1][CH:2]=1
Reactant: CC(N)=S
Reactant: O=C(NC1CCC(C(=O)CBr)CC1)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Product: Cc1nc(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cs1

Procedure:
4.00 g (7 mmol) of 9H-fluoren-9-ylmethyl[4-(2-bromoacetyl)cyclohexyl]carbamate (cis compound) and 0.700 g (9 mmol) of thioacetamide are refluxed in 50 mL of acetonitrile for 72 hours with stirring. Then the reaction mixture is concentrated by evaporation, the residue is purified by chromatography. Corresponding fractions are combined and evaporated to dryness. The crystalline residue is extracted with diisopropyl ether and suction filtered. Yield: 1.10 g (39%) of cis compound; NMR: LH201648; m.p.: 140° C.-141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13]C2CCC(C)CC2)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26]>>[CH:3]1([CH2:8][CH2:13][N:12]2[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: CC1CCC(Cn2c(-c3ccccc3Br)nc3ccccc32)CC1
Reactant: C#Cc1ccc(C#N)cc1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CCC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-(4-methyl-cyclohexylmethyl)-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). White solid (43%). MS (Turbo Spray): m/z=430.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[OH:37])[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(O)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 71.5 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(4-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (2 g; 4.07 mmol), 4-(3-chloropropyl)morpholine (1.66 g; 2.5 equiv.) and caesium carbonate (8.3 g; 6.25 equiv) in DMF was heated at 90° C. overnight then evaporated. The residue was dissolved in EtOAc, washed with brine, dried (MgSO4) and evaporated. Purification of the crude material using a Biotage SP4 (40S, 40 mL/min), using gradient elution form 0% to 10% MeOH/EtOAc gave 1.8 g of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone as a pale yellow gum. MS: [M+H]+ 619.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:26][CH2:27][C@@H:28]1[CH2:32][C@@H:31]([OH:33])[CH2:30][N:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(OCC)(=O)C>CN(C)C(=O)C>[CH2:37]([O:36][C:34]([N:29]1[CH2:30][C@H:31]([OH:33])[CH2:32][C@H:28]1[CH2:27][CH2:26][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:35])[CH3:38]
Reactant: COc1cccc(CCc2cc(F)ccc2O)c1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1cccc(OC)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 76.5 %

Procedure:
399 mg of 4-fluoro-2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 4) were dissolved in 8 ml of N,N-dimethylacetamide, and then 363 mg of potassium t-butoxide and 718 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine were added, whilst ice-cooling, to the resulting solution. The resulting mixture was then stirred at 40° C. for 5 hours. At the end of this time, 50 ml of ethyl acetate were added, and the reaction mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 3:7 by volume mixture of hexane and ethyl acetate as the eluent, to give 535 mg (yield 76%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][CH:9]([CH3:28])[C:10]([O:12][CH:13]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[CH:14]([CH3:16])[CH3:15])=[O:11]>>[C:10]([O:12][CH:13]([O:17][C:18]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:19])[CH:14]([CH3:15])[CH3:16])(=[O:11])[CH:9]([CH3:28])[CH3:8]
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC1(C(=O)O)CC1
Product: CC(C)C(=O)OC(OC(=O)NC1(C(=O)O)CC1)C(C)C
Yield: 51.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.2 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate (301 mg, 1.0 mmol) were reacted to provide 148 mg (51% yield) of the title compound (2) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 127.4-129.0° C. 1H NMR (CDCl3, 400 MHz): δ=6.59 (d, 1H), 5.68 (br s, 0.3H), 5.39 (s, 0.7H), 2.58 (m, 1H), 2.01 (m, 1H), 1.61 (m, 2H), 1.30 (m, 2H), 1.19 (d, 3H), 1.18 (d, 3H), 0.99 (d, 6H). MS (ESI) m/z 305.20 (M+NH4)+; 310.15 (M+Na)+; 286.21 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[C:16](=[CH:9]/[C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)/[C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])s2)cc1OC
Yield: 8.5 %

Procedure:
5-Nitrothiophene-2-carboxaldehyde (3.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 540 mg, 8.5%).