Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:3].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:61]>C1COCC1>[ClH:61].[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:15][C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1CNc2cc(O)ccc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg), and triphenylphosphine (525 mg) in THF (20 ml) was added diethyl azodicarboxylate (348 mg). After stirring at room temperature for one hr, the reaction mixture was poured into 1 N aqueous hydrochloric acid and washed with ethyl acetate. The water layer was neutralized by 1 N aqueous sodium hydroxide, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and converted into its hydrochloride, which was further recrystallized from ethanol-diisopropyl ether to obtain the titled compound (214 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:23]([NH2:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40]([NH:32][C:23]([CH3:25])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:41]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C
Yield: 79.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-methoxymethoxy-4-methylbenzoic acid (2.69 g) was dissolved in DMF (53 mL), and the solution was treated with EDCI (5.04 g, 26.3 mmol), HOBT monohydrate (2.01 g, 13.1 mmol) and cumylamine (3.80 mL, 26.4 mmol), followed by purification by slurry using hexane to obtain 3-methoxymethoxy-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (3.42 g, yield 83%, 2 steps).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1cccc2c1SCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCOc1cccc2c1SCCC2
Reaction time: 2 h

Procedure:
Under argon and with stirring, 2.25 g (8.02 mmol) of the compound obtained in Step A are dissolved in 30 cm3 of methanol. 4.5 cm3 of a 10% potassium hydroxide solution are added dropwise. After 2 hours at room temperature, the methanol is evaporated off. The residue is acidified very slowly with a 2N hydrochloric acid solution. The resulting precipitate is extracted with CH2Cl2 and dried over MgSO4. 1.94 g of a white solid are recovered.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]3=[CH2:22].[OH-:24].[Na+]>CO>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]3[O:24][C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]4=[CH2:22]
Reactant: [OH-]
Reactant: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)[C@H]1CC12
Agent: [Na+]
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C3C[C@@H]3C(=O)C3OC132
Temperature: 0 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
1,2β-methylen-6-methylenandrost-4-ene-3,17-dione (3.104 g, 10 mmol) is dissolved in 120 ml of methanol and cooled to 0° C. Thereupon ice cold 36% H2O2 (10 ml) and 2% NaOH (5 ml) is added gradually, the reaction mixture kept for about 20 hours at 5° C. and then poured into 900 ml of ice water. The raw product is filtered off, washed with water, dried and then chromatographed on silica gel using CHCl3 as eluant. Thus pure title compound is obtained in 60% yield (1.959 g).
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:20]([O:19][C:17]([C:14]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:16][N:11]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:12][C:13]1=[O:22])=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a suspension of 30.9 g NaH (55%, 772 mmol) in 1000 ml DMF was added under argon atmosphere portionwise 115 g ethyl (SR)-N-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride (386 mmol, commercially available) at 0-5° C. The reaction mixture was stirred for 1 h at r.t. and a solution of 45.9 ml benzylbromide (66.0 g, 386 mmol) in 200 ml DMF was added at 0° C. The reaction mixture was stirred for 1.5 h at r. t. and 200 ml sat. NaHCO3 solution were added at 0-10° C. The reaction mixture was reduced to 500 ml and 1000 ml water were added. The aqueous phase was extracted three times with 1000 ml ethyl acetate and the combined organic phases were washed with water (3×200 ml) and brine (3×200 ml). The organic phase was dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The crude product was purified by chromatography over silica gel (ethyl acetate/hexane 1/8, then 1/4) to give 101 g of the product (290 mmol, 75%) as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:40][O:41][CH2:42][C:43]([O:45]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:44])[C:15]([NH:17][CH:18]2[C:38](=[O:39])[N:20]3[C:21]([C:27]([O:29][CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:40][O:41][CH2:42][C:43]([OH:45])=[O:44])[C:15]([NH:17][CH:18]2[C:38](=[O:39])[N:20]3[C:21]([C:27]([O:29][CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
Trifluoroacetic acid (5.75 g) was added to a solution of pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.7 g) in methylene chloride (14.8 ml) and anisole (1.09 g) under ice-cooling, and the mixture was stirred for an hour at ambient temperature. Then the reaction mixture was added dropwise to diisopropyl ether (160 ml). The precipitates were collected by filtration and washed with diisopropyl ether, followed by adding them to a mixture of water (60 ml) and ethyl acetate (60 ml). The resultant mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate. The separated aqueous solution was further adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and then dried over phosphorus pentoxide in vacuo to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.13 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43](O)[CH3:44])=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:43]([CH3:44])[CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)Cc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OC(C)Cc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.09 g, 0.192 mmol), 1-(4-fluorophenyl)propan-2-ol (0.08 g, 0.519 mmol) and Ph3P (0.151 g, 0.576 mmol) in THF (5 mL) was added DEAD (0.091 ml, 0.576 mmol) at 0° C. After 2 h, cold bath was removed and stirred for 15 h at rt. Then, purified by prep-HPLC to afford (2S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((1-(4-fluorophenyl)propan-2-yl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0778 g, 0.129 mmol, 67.0% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.21 (m, 2H), 7.15 (dd, J=8.6, 2.3 Hz, 1H), 7.07 (dt, J=8.2, 2.1 Hz, 1H), 7.03-6.93 (m, 4H), 6.08 (s, 1H), 4.63 (qd, J=6.1, 3.8 Hz, 1H), 4.26 (dq, J=10.8, 7.1 Hz, 1H), 4.17 (dq, J=10.9, 7.1 Hz, 1H), 3.18 (d, J=11.0 Hz, 1H), 3.08 (dd, J=13.9, 6.0 Hz, 1H), 2.93-2.83 (m, 2H), 2.61 (s, 3H), 2.27 (d, J=8.8 Hz, 1H), 2.22 (s, 3H), 2.04 (t, J=11.7 Hz, 1H), 1.67-1.60 (m, 1H), 1.59-1.51 (m, 1H), 1.36 (d, J=6.1 Hz, 3H), 1.34 (d, J=6.1 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.21 (s, 9H), 1.19-1.15 (m, 1H), 1.09-1.03 (m, 1H), 0.90 (br. s., 3H), 0.62 (br. s., 3H). LCMS (M+H)=605.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:33](=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CCc1ccccc1
Yield: 66.4 %

Procedure:
In a manner analogous to that described in Example 21, from 249 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 94 mg of hydrocinnamoyl chloride and 72 mg of diisopropylethylamine there were obtained 214 mg of N-[3(S)-[(N-hydrocinnamoyl-L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white solid (from ethyl acetate/n-hexane); MS: m/e 581 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])(C)(C)C>Cl.CC(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
Dissolve [2-(2-chloro-benzoyl)-phenyl]-carbamic acid tert-butyl ester (850 mg, 2.6 mmol) in a saturated HCl in AcOH solution (10 mL, ˜3N in HCl), stir at room temperature for 3 hours. Concentrate, add CHCl3 and concentrate (3×) to remove remaining AcOH. Dissolve the residue in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (2×) and brine. Dry the combined organic layers over MgSO4 and concentrate to afford the title compound (495 mg, 83%): MS(IS) 232 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:22])[CH2:8][CH2:7]1)=O)C.C(O)C.[BrH:26]>>[BrH:26].[CH3:21][C:17]1[C:16]2[N:12]([CH:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[C:13](=[O:22])[NH:14][C:15]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cccc(C)c32)CC1
Agent: Br
Solvent: CCO
Product: Cc1cccc2[nH]c(=O)n(C3CCNCC3)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine (59 mg) was dissolved in 48% hydrobromic acid (0.3 ml) and stirred at 100° C. for 1 hour. The reaction mixture was added with ethanol, and the produced crystals were collected by filtration to obtain 26.8 mg of the title compound. Yield: 44%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH2:12])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][OH:14])=[CH2:12])=[CH:22][CH:23]=1
Reactant: C=C(CCOCc1ccc(OC)cc1)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(CO)CCOCc1ccc(OC)cc1

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-(t-butyldimethylsilyloxymethyl)but-1-ene (1.5 g, 4.75 mmol) and a solution of tetrabutylammonium fluoride (4.75 mL, 1M, 4.75 mmol). After 2.5 hours chromatograph on silica gel eluting with 1/2 ethyl acetate/hexane to give the title compound; Rf =0.24, silica gel, 1/2 ethyl acetate/hexane.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:10]#[N:11])=[C:5](SC)[S:6][CH3:7].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>C(O)C>[OH:2][C:3]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:5]([S:6][CH3:7])[C:4]=1[C:10]#[N:11]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CSc1nc2ccnn2c(O)c1C#N
Temperature: 25 °C
Yield: 55.5 %

Procedure:
3.0 g of 2-cyano-3,3-bismethylthio-2-propenoic acid methyl ester, 1.3 g of 3-aminopyrazole and 20 ml of ethanol were stirred under reflux with heating for about 2.5 hours and then cooled to room temperature, and the precipitated crystals were collected by filtration. The collected crystals were washed with ethanol and then dried to obtain 1.69 g of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 49) having a melting point of over 250° C.
Reaction SMILES: C[Si](C)(C)[Cl:3].[CH3:6][N:7]([CH3:37])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:13][CH2:12][C:11](=[CH:14][C:15]([NH:17][CH:18]([CH3:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:3].[CH3:37][N:7]([CH3:6])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:13][CH2:12][C:11](=[CH:14][C:15]([NH:17][CH:18]([CH3:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2cccc(F)c2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trimethylchlorosilane (0.109 ml, 0.86 mmol) was added to a solution of the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexylidene]-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide (249 mg, 0.57 mmol) in ethyl methyl ketone (10 ml) and the mixture was stirred at RT for 1.5 h. The hydrochloride which had precipitated out was filtered off with suction and isolated as a colourless solid with an m.p. of 171-174° C. in a yield of 81% (218 mg) (Example 27).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>C(Cl)(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCn3ccnc3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+) and [α]D20=−68.5° (c=0.3050 in chloroform), was prepared in accordance with the general method of example 82b from (2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][C:68]([CH3:72])([CH3:71])[CH2:69][CH3:70])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][C:68]([CH3:72])([CH3:71])[CH2:69][CH3:70])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(1,1-dimethyl-propylamino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=563, obsd.=563).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CCOCC>[CH2:27]([O:26][C:24]([C:21]1([C:29](=[O:30])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)CC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
A solution of n-butyllithium (2.5M in hexane, 40 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (10.1 g) in anhydrous ether (100 ml) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 5 hour and a solution of t-butyl acetate (11.6 g) in anhydrous ether (20 ml) was added dropwise, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and a solution of diethyl cyclopropane-1,1-dicarboxylate (18.6 g) in anhydrous ether (20 ml) was added dropwise whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and the temperature was allowed to rise to room temperature. A saturated solution of ammonium chloride (150 ml) was added cautiously and the layers were separated. The organic extract was washed with water (2×50 ml) hydrochloric acid (2M, 2×50 ml) and water (2×50 ml). The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-(1-ethoxycarbonylcyclopropyl)-3-oxopropionate (11.66 g) as a clear oil bp 89°-90° C./0.5 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].[CH2:15]=O>C(O)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: C=O
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: O=CO
Product: CN1CCN(c2ccccc2C#N)CC1

Procedure:
7.48 g of 1-(2-cyanophenyl)-piperazine are refluxed for one hour with 30 ml of formaldehyde and 30 ml of formic acid. The solvents are evaporated in vacuo and the residue is taken up in ether and mixed with water. The mixture is made alkaline with 20% sodium hydroxide solution, saturated with potassium carbonate and extracted with ether. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. To purify the residue it is chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 1% of a 25% ammonia solution). Yield: 6.7 g (83% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=[O:36])O1>>[CH:35]([C:34]1[C:37]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:38]([C:2]2[C:16]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:39]=[CH:32][CH:33]=1)=[O:36]
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Reactant: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1Br
Product: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting methyl-3-formyl-4-hydroxy-5-bromophenylacetate (2.47 g, 9.0 mmol) and 2-methoxymethoxy-5-fluorophenylboronic acid (2.0 g, 10.0 mmol), gave methyl 5′-fluoro-5-formyl-6-hydroxy-2′-methoxymethoxy-biphenyl-3-yl)-acetate (2.2 g, 70%) as a yellow oil which crystallized overnight Proceeding as in Reference 19, but substituting tert-butyl [3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol) and 2-2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (60 mL, 0.1 M in toluene), gave tert-butyl [3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (2.96 g).