Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([CH:8]1[CH2:10][NH:9]1)#[N:7].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(OCC)C.C(N(CC)CC)C>[C:1]([N:9]1[CH2:10][CH:8]1[C:6]#[N:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: N#CC1CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(=O)N1CC1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.92 g. propionyl chloride in 40 ml. anhydrous diethyl ether is added dropwise at 0° to 5° C., in the course of about 15 minutes, to a solution of 0.68 g. 2-cyanoaziridine and 1.2 g. triethylamine in 40 ml. anhydrous diethyl ether. The reaction mixture is stirred for 1 hour at 0° C. and then for 2 hours at ambient temperature. The precipitated salt is filtered off with suction and washed with diethyl ether into the filtrate and the filtrate is evaporated in a vacuum to give 1.44 g. of an oil. This is dissolved in ethyl acetate, shaken with a saturated aqueous solution of sodium bicarbonate, dried and then evaporated in a vacuum. There is thus obtained 1.14 g. 1-propionyl-2-cyanoaziridine in the form of a pale oil, the analytical data (elementary analysis, NMR and mass spectra) of which confirm the structure. The product is slightly contaminated with water.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C([BH3-])#N.[Na+]>CO>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH2:12][N:24]3[CH2:25][CH2:26][CH:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccn(-c2ccccc2)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CC2CCN(Cc3ccn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL of methanol was added 525 mg of 4-benzylpiperidine, 175 mg of 4-benzylpiperidine.HCl and 63 mg of sodium cyanoborohydride. The reaction mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 50 mL of ethyl acetate, then washed successively with 50 mL aliquots of 10% sodium hydroxide and water. The ethyl acetate extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 1-phenyl-3[(4-benzylpiperidin-1-yl)methyl]pyrrole, which was purified by chromatography on silica gel using 5% methanol in dichloromethane as elvent. On evaporation of the solvent, the free base was dissolved in ethanol and treated with 1 equivalent of maleic acid. The 1-phenyl-3[(4-benzyl-piperidin-1-yl)methyl]pyrrole maleate salt (compound 7) had a melting point of 159°-161° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][OH:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]=[O:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of [2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]methanol (0.49 g), Dess-Martin reagent (0.50 g) and acetonitrile (10 mL) was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.46 g, yield 98%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). melting point 175-176° C. MS: 471 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([N:15]4[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[N:16]4)[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([N:15]4[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[N:16]4)[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1
Reactant: O=c1cccnn1-c1ccc2nc(C3CC(O)C3)sc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C1CC(c2nc3ccc(-n4ncccc4=O)cc3s2)C1
Reaction time: 3 h

Procedure:
The product of Example 48C (1.63 g, 5.45 mmole) was dissolved in 50 ml anhydrous dichloromethane. Dess-Martin periodinane (3.0 g, 7.07 mmole, [87413-09-0]) was added. After 3 hours at room temperature, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product which was purified by column chromatography (0.25% ammonium hydroxide and 2.5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.20 (d, J=2.03 Hz, 1H) 8.07 (d, J=8.82 Hz, 1H) 7.94 (dd, J=3.73, 1.70 Hz, 1H) 7.75 (dd, J=8.82, 2.37 Hz, 1H) 7.26-7.31 (m, 1H) 7.09 (dd, J=9.49, 1.70 Hz, 1H) 4.01-4.15 (m, 1H) 3.54-3.79 (m, 5H). MS: (M+H)+=298.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[CH2:6]([OH:9])[CH:7]=[CH2:8]>O>[CH3:1][C:2]([O:9][CH2:6][CH:7]=[CH2:8])([CH2:4][CH3:5])[CH3:3]
Reactant: C=CCO
Reactant: CC=C(C)C
Solvent: O
Product: C=CCOC(C)(C)CC

Procedure:
100 gms 2-methylbut-2-ene, 300 gms allyl alcohol and 10 gms Amberlyst 15 resin were charged to a 1-liter flat-bottomed flask containing a magnetic follower and fitted with a stopper incorporating a gas inlet tube dipping below the surface of the liquid in the flask and with an exit tube leading from the gas space to a Drechsel bottle filled with water. The flask was purged with nitrogen and then placed in a water bath at 30° C. on a magnetic stirrer. The contents of the flask were maintained at this temperature for 16 hours and then filtered. After washing 5 times with deionised water, each time at an approximately 1:1 ratio by volume, in order to remove the bulk of the unreacted allyl alcohol, the resulting organic layer was dried over anhydrous sodium carbonate and the ether was purified by distillation. The yield was 137 gms (74.9% based on the olefin), b.p. 125°-127° C. at 770 mm Hg.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH3:25])[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:14]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][C:15]3[CH:14]=[C:13]([CH3:25])[CH:18]=[CH:17][CH:16]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1cccc(OC2CCNC2)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C)c2)C1
Yield: 49.3 %

Procedure:
The title compound (D96) (200 mg) was prepared according to the experimental procedure described in Description 62 starting from methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and 3-(m-tolyloxy)pyrrolidine (D61) (247.7 mg, 1.39 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]1([CH2:26][O:27][C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:26][CH:23]4[CH2:24][CH2:25]4)[CH:29]=3)[CH2:39][CH2:38]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: c1cc(OCC2CC2)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(OCC3CC3)c2)CC1
Yield: 90 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-cyclopropylmethoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:11]1([N:16]2[CH2:17][CH2:18][N:19]([C:2]3[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:21]2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=[N+]([O-])c1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 95 °C
Yield: 29.5 %

Procedure:
A mixture of 5.6 g (35 mmol) 2-chloro-4-nitropyridine, 5.75 g (37 mmol) 1-cyclo-pentyl piperazine and 4.59 g (35 mmol) N,N-diisopropylethylamine in 35 ml DMF and 12 ml water was heated to 95° C. for 3 h. After evaporation to dryness the residue was taken up in 150 ml NaHCO3 aq. and 150 ml ethyl acetate. The aqueous phase was extracted two times with 150 ml ethyl acetate each and the combined organic phases were washed twice with 100 ml NaHCO3 aq each and 100 ml NaCl aq. sat. and dried with MgSO4 and evaporated to dryness. The residue was purified with column chromatography to yield 2.85 g (29%) 1-cyclopentyl-4-(4-nitro-pyridin-2-yl)-piperazine (m/e): 277.3 (MH+; 100%) and 4.47 g (47%) 1-(2-chloro-pyridin-4-yl)-4-cyclopentyl-piperazine (m/e): 266.3 (MH+; 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:32][NH:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([N:33]([CH3:32])[N:34]([CH3:35])[C:17](=[O:19])[CH2:16]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Reactant: CNNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N(C)N2C
Temperature: 22 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
A mixture of intermediate 3, ethyl 5-benzyloxy-1-(methoxycarbonylmethyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.487 g, 1.15 mmol) in N,N-dimethylformamide (25 ml) was treated with 1,2-dimethylhydrazine dihydrochloride (1.56 g, 11.7 mmol) followed by N,N-diisopropylethylamine (4.1 ml, 11.7 mmol) and the resulting mixture stirred at 22° C. for 4 h. The solvent was then removed in vacuo and the residue diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution with a gradient of ethyl acetate 0–50% in toluene) gave 0.294 g (69% yield) of the title ester as a clear syrup.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH2:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(F)c(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCc1cc(F)c(F)cc1C(=O)OC
Temperature: 90 °C
Yield: 78.1 %

Procedure:
A mixture of methyl 2-bromo-4,5-difluorobenzoate (0.5 g, 1.992 mmol), allyltributylstannane (0.679 mL, 2.191 mmol), lithium chloride (0.169 g, 3.98 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.070 g, 0.100 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution for 5 times, then dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4,5-difluorobenzoate (330 mg, 1.555 mmol, 78% yield) as an oil. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J=11.1, 8.2 Hz, 1H), 7.11 (dd, J=11.1, 7.7 Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.16-5.02 (m, 2H), 3.91 (s, 3H), 3.76 (d, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC(OC)=O.C(N(CC)CC)C.[CH:26]([C:29]([CH3:38])([N:33]1CC=CC1)[C:30]([NH2:32])=[O:31])([CH3:28])[CH3:27]>O1CCCC1.O>[C:30]([C:29]([NH:33][C:1](=[O:13])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:38])[CH:26]([CH3:28])[CH3:27])(=[O:31])[NH2:32]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)C(C)(C(N)=O)N1CC=CC1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of quinaldic acid (20 g, 0.116 mol) in tetrahydrofuran (500 ml) cooled to -9° C. is added methyl chloroformate (8.92 ml, 0.116 mol) followed by triethylamine (18.4 ml, 0.139 mol). After 20 minutes α-isopropyl-α-methyl-3-pyrroline-1-acetamide (15.1 g, 0.116 mol) is added and the mixture stirred overnight at room temperature. Water is added and the solution is reduced to 200 ml on a rotorvap. A white solid separates and is filtered off, water washed and dried. Recrystallization from absolute ethanol gives the product mp 179°-180° C., 26.86 g (87%). Anal. calcd. for C16H19N3O2 : C, 67.34; H, 6.73; N, 14.72. Found: C, 67.14; H, 6.17; N, 14.72.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[Li+].[OH-].O1CCOC[CH2:14]1.O>>[CH3:14][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1cc(I)ccn1
Reactant: C1COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(I)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ester 11a′ (Z=ethyl, n=1; 25 mg, 0.07 mmol) in dioxane/water (3:1, 3 mL), LiOH (15.0 mg, 0.35 mmol) solid was added. The resulting mixture was stirred vigorously at rt for 3 h. The organic solvent was removed under reduced pressure, and the residue was dissolved in H2O (10 mL), acidified with aq. HCl (1.0 M) to pH value 3-4, and then extracted with DCM (3×15 mL). The combined organic layers were dried over MgSO4, the solvent was removed, and the residue was dried in high vacuum to afford the desired acid 11b′ (R=OEt, n=1; 22 mg, 95%) as colorless oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:46]=[CH:45][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20]C(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:47])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:48](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>>[Si:48]([O:17][C@@H:16]1[C@@H:18]([CH2:19][OH:20])[O:44][C@@H:14]([N:13]2[CH:45]=[CH:46][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:47])[CH2:15]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO

Procedure:
This compound was prepared from N4 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:14]([C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][CH:18]=1)=[C:15]=[O:16]>CN(C)C1C=CN=CC=1.O1CCCC1.C(N(CC)CC)C.CO>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:4]=1[NH:5][C:15]([NH:14][C:17]1[CH:18]=[CH:19][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: COc1cc(C(F)(F)F)ccc1N
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 4 h
Yield: 20.6 %

Procedure:
To a solution of 1 g of 2-methoxy-4-(trifluoromethyl)aniline and 128 mg of 4-dimethylaminopyridine in 150 mL of tetrahydrofuran and 1.5 mL of triethylamine are added, at 20° C., 1.28 g of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. After 4 hours, the reaction is evaporated to dryness under reduced pressure. The residue is taken up in a mixture of ethyl acetate and water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The residual yellow oil is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (eluent: 8/2 cyclohexane/ethyl acetate). A pale yellow powder is obtained, which is taken up in methanol. An insoluble white material is formed, which is separated out by filtration, and the filtrate is then evaporated to dryness under reduced pressure to give 0.47 g of a pale yellow powder of 1-(2-methoxy-4-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH3:20])=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][N:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:45])[NH2:28])=[CH:25][CH:26]=4)[CH3:20])=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 73% of theory, C28H29N5O3S (515.64) Rf value:0.29 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =516
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[C:18]([F:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])[CH3:5].C1COCC1.[OH-].[Na+].Cl>O.C(OCC)(=O)C.CO>[F:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:33])=[O:2])=[O:9])[CH:19]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To 0.198 g of 2-{[4-fluoro-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester was added 15 ml of THF and 5 ml of methanol followed by 5 ml of 1 M NaOH. The solution was stirred at ambient temperature for 12 h. The reaction mixture was poured into water/ethyl acetate, acidified to pH 1-2 with 1M HCl, extracted with ethyl acetate, washed with water, dried (sodium sulphate), filtered and concentrated to a colorless oil which crystallized on standing. The material was triturated with ether, filtered and dried at 50° C. for 1.5 h to provide 45 mg of 2-{[4-fluoro-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:14][CH2:13][CH2:12][O:11]2.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:3]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(c1)CC1(C2)OCCO1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CC1(C2)OCCO1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-ylamine (1.0 g, 5.23 mmol) in CH2Cl2 (15 mL) was added phenyl chloroformate (0.66 mL, 5.23 mmol) drop wise at room temperature followed by triethylamine (1.15 mL, 8.3 mmol). The reaction mixture was stirred at r.t for 30 min and then solvent was removed under vacuum. Water was added to the resulting crude product and the precipitate was filtered and dried to give the crude (1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-carbamic acid phenyl ester as a pale yellow solid (1.62 g, quantitative).
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][C:18]1[N:19]=[C:20]([NH:23][CH2:24][CH2:25][NH2:26])[S:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:9][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:20]1[S:21][CH:22]=[C:18]([CH3:17])[N:19]=1)=[O:7]
Reactant: Cc1csc(NCCN)n1
Reactant: CC(F)(F)/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(NCCNC(=O)/C=C/C(C)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in DCM (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N′-(4-methylthiazol-2-yl)ethane-1,2-diamine hydrochloride (24 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 11 mg of a solid (0.04 mmol, 27%).