Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of 3-nitropyrrole (500 mg, 4.46 mmol), cesium carbonate (3.63 g, 11.2 mmol, 2.5 equiv), 1-chloro-2-dimethylaminoethane (835 mg, 5.8 mmol, 1.3 equiv) and DMF (5 mL) was stirred for 16 h at rt. The reaction mixture was quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM DCM/MeOH, 97:3) to afford 656 mg of the title compound as a yellow oil. Title compound: ESI-MS: 184.1 [M+H]+; TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (200.0 mg, 0.96 mmol) and Et3N (195.5 mg, 1.93 mmol) in DMF (2.0 mL) at 0° C. was added (S)-3-methylmorpholine (97.7 mg) dropwise. The mixture was stirred overnight at rt then was partitioned between H2O and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, evaporated and then the crude product which was purified by column chromatography on silica gel (eluent: PE/EA=20:1-2/1) to provide (S)-2-chloro-4-(3-methylmorpholino)-6,7-dihydrothieno[3,2-d]pyrimidine as a light yellow solid (120 mg, 46%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F-:22].[K+].C(#N)C.O>C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([F:22])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: [F-]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2CC1)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(N1CCc2ccc(S(=O)(=O)F)cc2CC1)C(F)(F)F
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A mixture of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (23 g, 67 mmol), potassium fluoride (12 g, 200 mmol), 18-crown-6 (0.1 g), and acetonitrile (100 mL) was stirred overnight. Water (200 mL) and ethyl acetate (200 mL) were added and the organic layer was washed with brine (100 mL), dried (MgSO4), and evaporated to give the title compound D1 as a white solid (21 g). 1H NMR 3 (d6-DMSO) 3.2 (4H, m), 3.7 (4H, m), 7.6 (1H, m), and 8.0 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[NH2:13][C:12]1[C:14]([CH3:27])=[CH:15][C:16]([C:2]2[CH:3]=[N:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:17][C:11]=1[CH3:10]
Reactant: Cn1cc(Br)cnc1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Product: Cc1cc(-c2cnc(=O)n(C)c2)cc(C)c1N
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 5-bromo-1-methylpyrimidin-2(1H)-one and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 70° C. LC (method 9): tR=0.63 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]([C:11]([O:18][CH3:19])=[O:17])[C:13]([O:15][CH3:16])=[O:14])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-nitropyridine (25.0 g, 158 mmol) and dimethyl malonate (21.9 g, 166 mmol) in DMF (150 mL) was cooled to 0° C., and sodium hydride (6.50 g of a 60% dispersion in mineral oil, 162 mmol) was added in small portions. The mixture was stirred at 0° C. for 1 hour following completion of the addition. Then, another equivalent of sodium hydride (6.5 g of a 60% dispersion in mineral oil, 162 mmol) was added in small portions. The reaction was quenched by the addition of acetic acid (10 mL), and the mixture was evaporated to dryness. The residue was triturated with diethyl ether (150 mL) overnight and filtered, providing crude dimethyl 2-(5-nitropyridin-2-yl)malonate as an orange solid.
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([C:10]3=[O:17])[CH2:8]1)[CH2:14]2.[CH3:18]O.[CH:20]([OH:22])=[O:21]>>[CH3:18][O:21][C:20]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([C:10]3=[O:17])[CH2:8]1)[CH2:14]2)=[O:22]
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: CO
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
38 mL of fuming sulfuric acid were placed in a two necked flask and warmed to 60° C. 1.5 g of 5-hydroxy-2-adamantanone, dissolved in formic acid (8.5 ml) were added dropwise over the course of 2 h. Another 9 mL of formic acid were added over a period of 2 h and stirring was continued at 60° C. for 1 h and at room temperature overnight. Under ice cooling, the reaction mixture was poured on 100 mL of dry methanol, stirred at room temperature for 2 h and subsequently poured onto 400 mL of ice. The aqueous layer was extracted with dichloromethane three times, the combined organic layer was dried over sodium sulphate and evaporated to dryness to give 1.64 g of the desired product. Rt=1.75 min (5). Detected mass: 209.2 (M+H+).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]1([NH:20][C@@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C:39]([O:41][CH3:42])=[O:40])[C@H:31]3[C@H:22]2[C@:23]2([CH3:44])[C@@H:28]([CH2:29][CH2:30]3)[CH2:27][C@@H:26]([OH:43])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O.N>CC(C)=O.CCOCC>[CH:14]1([NH:20][C@@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C:39]([O:41][CH3:42])=[O:40])[C@H:31]3[C@H:22]2[C@:23]2([CH3:44])[C@@H:28]([CH2:29][CH2:30]3)[CH2:27][C:26](=[O:43])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Agent: O=[Cr](=O)=O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Yield: 96.8 %

Procedure:
Jones reagent was added dropwise to a stirred solution of methyl 11α-cyclohexylamino-3β-hydroxy-5α-androstane-17β-carboxylate (300 mg) in acetone (40 ml) until the reagent colour was not discharged. Water (200 ml) was added and the mixture was brought to pH 10 with 0.88 NH3 solution. Ether (50 ml) was added and the mixture was filtered. The aqueous phase was separated, extracted with ether (50 ml) and the organic phase was washed with water, dried and evaporated to leave an oil (289 mg) which crystallised from petrol to give the title compound m.p. 93°-94° C., [α]D -12°.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[N+:34]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].CO>CN1CCCC1=O.[C].[Pd]>[NH2:34][C:20]1[C:21]2[S:25][C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[N:23][C:22]=2[CH:32]=[CH:33][C:19]=1[O:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:37]=[CH:38][CH:39]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3[N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3N)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]-7-nitro-1,3-benzothiazol-6-yl}oxy)phenyl]benzamide (2.5 g, 4.62 mmol) produced in Example 37(iii) in 1-methylpyrrolidin-2-one (20 ml)/methanol (50 mL) was added 10% palladium-carbon (250 mg), and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere (3 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with water (200 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (870 mg, 37%) as a pale-yellow powder.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5][C:6](=[NH:8])[NH2:7])[CH3:4].C([O:11][CH:12]=[C:13]([C:19]#[N:20])[C:14](OCC)=O)C>CO>[CH2:3]([S:5][C:6]1[N:7]=[C:12]([OH:11])[C:13]([C:19]#[N:20])=[CH:14][N:8]=1)[CH3:4]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCSC(=N)N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ncc(C#N)c(O)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
To a solution of potassium hydroxide (640 mg, 10 mmol) in methanol (6 mL) at 0° C. was added 2-ethyl-2-thiopseudourea (1.85 g, 10 mmol). The mixture was warmed to room temperature, stirred for 5 min, then filtered off potassium bromide under N2. The filtrate was cooled down to 0° C. then ethyl (ethoxymethylene)cyanoacetate (420 mg, 2.5 mmol) was added. The mixture was gradually warmed to room temperature and stirred for 20 h. The solvent was removed under reduced pressure, and the crude material was purified by flash chromatography using 4% 2M NH3 in MeOH/CH2Cl2 system to obtain 288 mg of the title compound. Mass spectrum 181 (EI, M+).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:29](I)[CH3:30]>O1CCOCC1.CN(C)C=O>[C:23]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][N:15]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:29][CH3:30])[CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(CNC(=O)C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCN(CC1(C)CN(C(c2ccccc2)c2ccccc2)C1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
0.16 g (3.6 mmol) of 55% strength sodium hydride is added to a solution of 1.3 g (3.6 mmol) of 1-diphenylmethyl-3-methyl-3-trifluoroacetylaminomethylazetidine in 40 ml of dioxane and 10 ml of dimethylformamide, and the mixture is stirred for two hours at 60°-70° C. The solution is cooled to room temperature, 0.73 g (4.6 mmol) of ethyl iodide is added, the mixture is stirred for 4 hours at 70° C. and evaporated to dryness, the residue is dissolved with chloroform, the organic phase is washed with water, dried with anhydrous sodium sulphate and evaporated and 1.1 g (79%) of 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine are obtained. This compound is dissolved in ethanol, and ethyl ether saturated with hydrochloric acid is added. The product is allowed to crystallize and is filtered off, and 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine hydrochloride, melting point 191°-4° C., is obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:23][C:24]1([CH3:30])[NH:28][C:27](=O)[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCCl>[ClH:3].[CH3:23][C:24]1([CH3:30])[N:28]=[C:27]([N:6]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:25]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCC(=O)N1
Reactant: c1ccc(NCc2c[nH]c3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1(C)CCC(N(Cc2c[nH]c3ccccc23)c2ccccc2)=N1
Product: Cl
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (7.67 g., 0.05 mole) in 20 ml. of 1,2-dichloroethane is added rapidly to 3-(anilinomethyl)indole (11.1 g., 0.05 mole), 5,5-dimethyl-2-pyrrolidinone (5.66 g., 0.05 mole) and triethylamine (5.06 g., 0.05 mole) in 80 ml. of 1,2-dichloroethane at ice bath temperature. After stirring the mixture for about 15 min., the ice bath is removed and stirring continued at room temperature for 16 hr. Workup of the reaction mixture is as follows. The mixture is quenched in 100 ml. of 10% sodium hydroxide and crushed ice and the organic layer separated. The organic layer is extracted with 100 ml. of 1.5 N hydrochloric acid and then with 100 ml. of water. After washing the combined extracts with ether and making basic with 10% sodium hydroxide, a solid precipitates which is collected and crystallized from ethyl acetate, yield 3.2 g., m.p. 124°-126° C. of free base product. The dichloroethane fraction is dried over magnesium sulfate and concentrated in vacuum and the residue (10.4 g.) triturated with water and filtered. The aqueous filtrate is made basic with sodium hydroxide providing a second free base fraction, yield 3.1 g., m.p. 125°-127° C. The two free base fractions are combined, dissolved in ethanol and treated with ethanolic hydrogen chloride affording 3.7 g., m.p. 185°-185.5° C. (dec.) (corr.) of analytically pure 3-[(N-(5,5-dimethyl-1-pyrrolin-2-yl)anilino]methyl]indole hydrochloride.
Reaction SMILES: CI.[CH3:3][N:4]([CH3:35])[C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=2)[CH:16]=1)=[O:9].[C:36](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH3:35][N:4]([CH3:3])[C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:36])[CH:20]=2)[CH:16]=1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Yield: 74.4 %

Procedure:
Methyl iodide (0.1 g) was added to a mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-methanesulphonylaminobenzamide (0.3 g), caesium carbonate (0.23 g) and DMF (20 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The reaction mixture was poured into water (250 ml). The precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.23 g); m.p. 168-169° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.95 (s, 6H), 3.0 (s, 3H), 6.9 (d, 1H), 7.21 (m, 3H), 7.29 (t, 1H), 7.58 (m, 3H), 7.81 (d, 1H), 7.9 (d, 1H), 7.98 (d, 1H) 9.97 (br s, 1H), 10.09 (br s, 1 H); Mass Spectrum: M+H+ 481.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]([F:28])([F:27])[F:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c(c1)CCNC2C(F)(F)F
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(F)ccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1CNCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4-difluoro nitrobenzene (12.2 ml, 110.5 mmol) and diisopropyl ethylamine (28.6 ml, 165 mmol) in dry DMF (80 ml) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was dried under air to yield the nitro compound (19.5 g, 78.5%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1.S(=O)(=O)(O)[OH:26].N>>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21
Reactant: O=S(=O)(O)O
Agent: N
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C(N)=O)cc4)[nH]c3cc21

Procedure:
3.6 g. of the compound obtained in Example 26 were introduced into 70 ml. concentrated sulphuric acid and stirred for 24 hours at 25° C. Subsequently, the reaction mixture was poured on to ice, neutralised with a concentrated aqueous solution of ammonia, filtered off with suction and well washed with water to give 1.8 g. of the title compound which, after crystallisation from ethanol/water, had a melting point of 317-319° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH2:2].[OH2:27].C[N+]1([O-])CC[O:32]CC1.[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O.C(OCC)(=O)C>[OH:27][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:2][OH:32]
Reactant: O
Reactant: C=Cc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OC(C)(C)C)CC3
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(C(O)CO)cc13
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of 3-vinyl-N-(tert-butyloxycarbonyl)morphinan 44 (10.5 mg, 0.03 mmol) in acetone:water=2:1 solution (0.3 mL) were added N-methylmorpholine-N-oxide (10 μL, 50 wt. % in water), and osmium tetroxide (one drop) sequentially and the mixture was stirred for 2 h at rt. After starting material disappeared on TLC, ethyl acetate (2 mL) and aqueous Na2SO3 solution (2 mL) were poured into the mixture, and the organic layer was separated, dried over MgSO4, and concentrated. Column chromatography gave 10 mg (87%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.29˜7.36 (1H, m); 7.17˜7.10 (2H, m); 4.79 (1H, d); 4.37 (0.55H, br); 4.19 (0.45H, br); 3.77˜3.66 (3H, m); 3.11 (1H, m); 2.72˜2.41 (4H, m); 2.03 (1H, m); 1.71˜1.04 (19H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:12][C:13]([C:15]1[N:16]=[C:17]([CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[CH:20][CH:19]=2)=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH2:43]([Sn](CCCC)(CCCC)C(C)=C)[CH2:44][CH2:45]C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:12][C:13]([C:15]1[N:16]=[C:17]([CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[CH:20][CH:19]=2)=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:44]([CH3:45])=[CH2:43])=[CH:9][CH:10]=1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2c(CC2CCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)c1ccc(C[C@H](NC(=O)c2cc3cc(Oc4ccc(C(C)(C)C)cc4)ccc3c(CC3CCCC3)n2)C(=O)OC)s1

Procedure:
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester (prepared in Example 38) was treated with tributyl-isopropenyl-stannane and Pd(PPh3)4 as described in the general procedure M to afford 2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl ester. This was treated with Pd/C and H2 (1 atm) by the general procedure N to afford 2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cccc(NN)c1Cl
Product: CCOC(=O)C(C)=NNc1cccc(C)c1Cl

Procedure:
The title compound was prepared in accordance with the general method of example 25b) from (2-Chloro-3-methyl-phenyl)-hydrazine and ethyl pyruvate.