Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])=[O:25])=[CH:33][CH:34]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-(methylsulfonyl)ethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=530.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=O)[CH2:3]1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:4]1[CH2:3][C:2]([CH3:1])([CH3:10])[CH2:9][C:7](=[O:8])[CH:6]=1
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Product: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with ispropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152°C. Elementary analysis: C14H16NOCL Calcd. C, 67.32; H, 6.45; N, 5.60 Found C, 67.13; H, 6.31; N, 5.82 (b) A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175°C for 45 minutes followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152°C. By procedures similar to those described in Example 1-(a) and (b), the following compounds are produced.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH2:18]>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:18]=[C:14]2[N:15]([CH:2]=1)[CH:16]=[CH:17][S:13]2
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: Nc1nccs1
Solvent: CCO
Product: Fc1ccc(-c2cn3ccsc3n2)c(F)c1
Temperature: 85 °C
Yield: 77.5 %

Procedure:
2-Bromo-2′,4′-difluoroacetophenone (7.50 g, 31.9 mmol) and thiazol-2-amine (3.20 g, 31.9 mmol) were added to EtOH (85 mL) and then heated to about 85° C. in an oil bath for about 16 h. The mixture was cooled in ice water, filtered, and washed with EtOH. Drying under vacuum at about 60° C. provided the title compound (5.84 g, 77%): LC/MS (Table 1, Method a) Rt, =2.68 min; MS m/z: 237.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: BrCCCBr
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr

Procedure:
A mixture of 7.6 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 25 ml 1,3-dibromopropane and 2.0 g of anhydrous potassium carbonate in 200 ml of anhydrous acetone was stirred at reflux. Additional 2.0 g portions of potassium carbonate were added at 3, 7, 21, 47 and 55 hours. After a total reflux time of 78 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester as a slightly impure oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.P(=O)(O)(O)O.[CH:15](=O)[CH:16]([CH3:18])[CH3:17]>>[CH:15]([NH:1][C:2]([NH2:4])=[O:3])([NH:1][C:2]([NH2:4])=[O:3])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C=O
Reactant: NC(N)=O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(C)C(NC(N)=O)NC(N)=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The urea solution was added to the reactor followed by requisite amount of sulfuric acid and phosphoric acid. The mixture was then stirred and heated up to 40° C. The liquid isobutyraldehyde was then added slowly through the dropping funnel and no exotherm was observed and reaction was not initiated. The reaction was run at the same temperature for 30 minutes, but the white solid isobutylidene diurea product was not formed. The GC analysis did not show any significant conversion of isobutyraldehyde. Consequently, the unreacted isobutyraldehyde was ˜100%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 1.4 g (2.4 mMol) of tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 15 ml of trifluoroacetic acid in 30 ml of methylene chloride is stirred for 14 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with about 30 ml of water and made alkaline with 2N sodium hydroxide solution. After extracting twice with 30 ml of diethyl ether, the aqueous phase is acidified with 20% citric acid. The crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant:methylene chloride/ethanol=96:4).
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[N:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[N:10]1[CH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>C(Cl)Cl>[O:8]=[C:9]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[N:10]1[CH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step C (169 mg, 0.485 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=293 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([N:9]2C(=O)C3=CC=CC=C3C2=O)[C:5](=[O:20])[N:4]2[C@H:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][N:3]12.O.NN>C(O)C>[NH2:9][C@@H:6]1[C:5](=[O:20])[N:4]2[C@H:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23][N:3]2[C:2](=[O:1])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2.48 g of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate [prepared as described in Example 3(D)] were stirred at room temperature for 0.5 hour in 80 ml of ethanol with 0.3 g of hydrazine hydrate and the mixture was then evaporated. 90 ml of 2N acetic acid were added, the mixture was stirred at room temperature for 1 hour and was then filtered. The filtrate was made basic with solid sodium carbonate and then extracted twice with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated to give 1.58 g (93%) of tert.butyl 8(S)-amino-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a gum.
Reaction SMILES: C(OC([N:8]([CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]([B:36]2[O:44]C3C(C)(C4CC(C3)C4(C)C)O2)[CH2:20][C:21]2[C:22]([O:34]C)=[C:23]([CH:31]=[CH:32][CH:33]=2)[C:24]([O:26]C(C)(C)C)=[O:25])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>>[CH3:52][N:51]([CH3:53])[CH2:50][CH2:49][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([NH:18][C@H:19]2[CH2:20][C:21]3[CH:33]=[CH:32][CH:31]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=3[O:34][B:36]2[OH:44])=[O:17])[CH2:11][CH2:10]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N(CCN(C)C)C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Product: CN(C)CCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
To the compound from step 2 (40 mg) was added 3N HCl (2 ml) and the resultant reaction mixture was heated at reflux for 1 hr. The solvents were then removed in vacuo and the residue purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 418 (MH)+.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.[BH4-].[Na+]>O.C(O)(=O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (2.21 g) and dimethylamine hydrochloride (20 g) in water (5 ml) was added 2 N hydrochloric acid (5 ml). After 10 min, dimethylamine (33% in ethanol) (2 ml) was added, the solution cooled to 18° and sodium borohydride (1 g) added portionwise. The suspension was acidified with acetic acid (2.5 ml) and after 15 mins was heated at 60° for 15 mins. The suspension was evaporated to low bulk and an excess of anhydrous sodium carbonate and tetrahydrofuran (100 ml) added. The suspension was refluxed for 2 hours and after 2 hours at room temperature was filtered and the filtrate evaporated in vacuo. The oily residue was chromatographed (silica/methanol) and the appropriate eluate evaporated in vacuo to give the title compound (0.45 g) which was crystallised from methyl isobutyl ketone, m.p. 64°-67° .
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>CCOC(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a Kontes glass tube was added 2-fluoro-nitrobenzene (3.34 g, 23.7 mmol), 1-methyl-piperazine (3.90 mL, 35.6 mmol), and anhydrous THF (10 mL). The tube was sealed and the reaction mixture was allowed to stir at 60° C. for 1 day. The reaction solution was diluted with EtOAc (150 mL), washed with aq NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5.07 g (97% yield) of the title product. MS (ES) 222.3 [M+H]+.
Reaction SMILES: C[C:2](C)([C:6]([O-:8])=O)[C:3]([O-])=[O:4].Cl.[CH:11]1([C:14]([NH2:16])=[NH:15])[CH2:13][CH2:12]1.C[O-].[Na+]>>[CH:11]1([C:14]2[N:16]=[C:6]([OH:8])[CH:2]=[C:3]([OH:4])[N:15]=2)[CH2:13][CH2:12]1
Reactant: N=C(N)C1CC1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1cc(O)nc(C2CC2)n1

Procedure:
Under a nitrogen atmosphere 1.50 mL (13.06 mmol) dimethylmalonat, 1.60 g (13.27 mmol) cyclopropanecarboxamidine hydrochloride and 15.0 mL (80.80 mmol) sodium methoxide solution (30%) were refluxed for 1.25 h with stirring. The reaction mixture was slightly acidified and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.O.N1C(=O)[C:24](=O)[C:22](=[O:23])NC1=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]=[CH:24][C:22]2=[O:23])=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ccccc2N)cc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2c(=O)cnc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-methoxyphenyl)benzene-1,2-diamine (9.0 g) in ethanol (150 ml) was added a solution of alloxan monohydrate (6.7 g) in water (150 ml) and the mixture was stirred for 30 minutes. The precipitate was filtered off and recrystallised from glacial acetic acid giving the title compound mp 236°-238° C.
Reaction SMILES: [C:1]([C:4]1[S:5]C(Cl)=C[CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: N#CCC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: CCC(C)=O
Product: Cc1sc(N)c(C(=O)c2ccc(Cl)s2)c1C
Yield: 46 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 46%; IR (KBr) cm−1: 3377, 3259, 2918, 1551, 1424, 1326, 1266, 1003, 764; 1H NMR (CDCl3):δ 1.90 (s, 3H), 2.17 (s, 3H), 5.77 (bs, 2H), 6.89 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); red solid, mp: 125–127° C. (petroleum ether).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.N1([C:30]([O:32][CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[O:31])C=CN=C1.C(N(CC)CC)C>C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(OCC1CCCCO1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC4CCCCO4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (100 mg, 0.31 mmol) and (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (98 mg, 0.47 mmol) was added 1.04 mL CH2Cl2 and triethylamine (65 μL, 47 mg, 0.46 mmol). The mixture was stirred at room temperature overnight. An additional equivalent of (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (100 mg, 0.47 mmol) was added to the mixture, and the reaction was heated at 45° C. for 4 hours. Purification via silica gel chromatography using 10-100% ethyl acetate/hexanes gave (tetrahydro-2H-pyran-2-yl)methyl (R)-1-(2(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 463.4 (M+H)+ at 2.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>>[C:24]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: COC1=CCCCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CCOC2=CCCCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 89.7 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclodecene (841 mg, 5 mmol) in the same manner as the example 41 to give the compound 48 (432 mg, 89%). Mp 94-96° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 6.6 Hz, (CH3)2C), 3.13 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, m, (CH3)2CH), 3.52 (3 H, s, NCH3), 4.01 (2 H, t, J 6.2 Hz, OCH2), 4.38(1 H, t, J 8.4 Hz, =CH), 6.80 (2 H, d, J 1.6 Hz, arom-H), 7.10 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3436, 3035, 1660, 1567, 1558, 1471, 1408, 1376, 1237, 1104. Elementary analysis (for C25H34N2Ocl2S) Calcd. : C, 62.36% H, 7.12% N, 5.82% S, 6.66% Cl, 14.73% Found: C, 62.54% H, 7.18% N, 5.69% S, 6.60% Cl, 14.52%
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].NN>C(O)C>[C:1]1([S:7]([NH:10][N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(C=NNS(=O)(=O)c2ccccc2)cc1

Procedure:
Benzenesulfonyl hydrazine (20.5 g, 0.12 mole) was dissolved by warming in 110 ml absolute ethanol. p-Cyanobenzaldehyde (15.6 g, 0.12 mole) was separately dissolved in 50 ml of hot ethanol and added to the hydrazine solution The resulting slurry was refluxed 0.5 hour, cooled and filtered to yield 28.1 g; m.p. 209°-213°. Recrystallization from CH3CN gave purified title product: 23.7 g; m.p. 210°-213°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Morpholine (0.235 mL, 2.7 mmol) was added to a solution of Example 133 (0.6 g, 1.3 mmol) in DMF (8 mL). The reaction mixture was stirred at 120° C. for 4 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.57 g, (85%); 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3), 3.2 (s, 2H, CH2), 3.7 (t, 4H, 2CH2), 3.9 (s, 2H, CH2), 4.28 (s, 2H, CH2), 5.35 (s, 2H, CH2), 7.82 (d, 1H, Ar), 8.0 (s, 1H, Ar), 8.12 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (CI+) 495 (M+1).
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:27]1[CH2:31][CH2:30][C:29]([C:32](O)=[O:33])=[CH:28]1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:27]1[CH2:31][CH2:30][C:29]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])=[CH:28]1)[CH3:26]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC1C=C(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3=CC(CC)CC3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.5 g of 3-ethyl-1-cyclopentene-1-carboxylic acid and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
Methyl 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.99 g) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL). 1M Aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at 50° C. for 45 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual amorphous solid was solidified with diethyl ether to give the title compound (0.9 g, 95%) as a pale yellow solid. MS 363 (MH+).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([C:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:20]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)/C=C/I
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 14.92 g. (0.0588 mole) of 1-iodo-trans-1-octen-3-ol (Example 74) and 18.2 g. (0.0588 mole) of p-anisyldiphenylmethyl chloride in 165 ml. of dry pyridine is heated at 60° C. for 18 hours under an inert atmosphere. The mixture is cooled and the solvent is evaporated in vacuo. The residue is partitioned between ether and water, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated. The residue is chromatographed upon 300 g. of Florisil® packed in hexane and the product is eluted with hexane and 4:1 hexane-benzene the yield a colorless oil.