Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[O:20]1[CH2:25][CH2:24][CH2:23]OS1(=O)=O>C1COCC1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:23][CH2:24][CH2:25][OH:20])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=S1(=O)OCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCOc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and potassium tert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was stirred at room temperature for 30 minutes. The solution was cooled at 0° C. and [1,3,2]dioxathiane 2,2-dioxide (Example 291, Step 5) (3.6 g, 26.34 mmol) in THF (25 mL) was added. The mixture was stirred at room temperature for 5 hours, and the solvent was removed under vacuum. The residue was dissolved in 6N HCl (15 mL) and heated at 100° C. for 16 hours. The mixture was cooled to room temperature, and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with H2O (3×25 mL) and brine (25 mL), dried (MgSO4), filtered, and concentrated to produce a white solid. 1H-NMR (200.15 MHz, CDCl3): d 7.57–7.49 (m, 4H), 7.45–7.37 (m, 3H), 6.98 (dd, 2H, J=6.72, 2.14), 4.17 (t, 2H, J=5.9), 3.88 (q, 2H, J=5.9), 2.07 (qn, 2H, J=5.9).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:42])([F:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:41])[F:42])=[CH:40][CH:39]=3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 4-trifluoromethylbenzyl bromide (478 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (176 mg, 37.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.13 (br. s., 1 H), 7.69 (d, J=8.08 Hz, 2 H), 7.51 (d, J=8.08 Hz, 2 H), 5.07 (s, 2 H), 4.64 (t, J=12.13 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.13-2.32 (m, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.50-1.72 (m, 3 H), 1.28 (q, 2 H), 1.11 (q, J=13.22 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][CH:15]([C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:15]1[CH2:24][NH:25][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14]1
Reactant: COC(=O)C(CC(C#N)c1cccc(F)c1F)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-4-cyano-4-(2,3-difluorophenyl)butanoate (11.0 g, 31.0 mmol) in methanol (621 mL) was added palladium hydroxide on carbon powder (20% palladium, with moisture ca 60%) (5.45 g, 3.10 mmol). The mixture was pressurized to 50 psi under an atmosphere of hydrogen. After 90 min, the mixture was filtered and concentrated. Purification by chromatography (Chiral Pak® AD® column, 60% ethanol/hexanes with 0.1% diethylamine) gave the title compound (2.0 g). MS 349.3 (M+Na). 1H NMR (500 MHz, CDCl3): δ 7.11-6.96 (m, 3H); 5.87 (s, 1H); 5.47 (s, 1H); 4.22-4.16 (m, 1H); 3.63-3.52 (m, 2H); 3.38 (t, J=11.2 Hz, 1H); 2.70 (s, 1H); 2.09 (q, J=12.3 Hz, 1H); 1.45 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: BrCc1cccc(Br)c1
Product: N#Cc1ccc(N(Cc2cccc(Br)c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 3-bromobenzyl bromide
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[I-].CS[C:16]1[S:17][CH2:18][C@H:19]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]=12>>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:16]1[N:20]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@@H:19]3[CH2:18][S:17]1)[CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2c3ccccc3C[C@@H]2CS1
Agent: [I-]
Product: Cc1cc2c(N=C3SC[C@H]4Cc5ccccc5N34)cccc2cn1
Yield: 67.5 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-methylisoquinoline (5.7 g) and (R)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (11.4 g), (R)-3-[(3-methylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (7.3 g) is obtained, after recrystallisation from ethanol, in the form of white crystals melting at 181° C. [α]D20 =+92.0±1.5° (c=1, chloroform)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1(C)C=CC=CC=1.CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCC

Procedure:
The results of the flux and retention tests of 1.0%, by weight, solutions of n-docosane in n-hexane and in toluene and of a 1.0%, by weight, solution of PEG 300 in methanol, evaluated at room temperature and a pressure of 40 bars, are mentioned in Table C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 80 °C

Procedure:
657 gm (3.66 mol) of hippuric acid and 2,618 gm of acetic anhydride were charged into a 5 1 glass reaction vessel, and heated at 80° C. for 15 minutes. When the reaction liquid became transparent, the reaction vessel was placed into a water bath to lower the internal temperature to 30° C., followed by cooling to 0° C. on a dry ice-methanol bath.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Br[CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:18][CH2:17][CH2:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (2.03 g, 60% in oil) was added portionwise to a ice-cooled solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (8 g) in DMF (20 ml). The mixture was stirred at 0° C. for 20 minutes and benzyl 2-bromoethyl ether (8.03 ml) was added. The mixture was heated at 80° C. for 18 hours. After cooling, the mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent and chromatography on silica gel (eluting with 20% to 50% ethyl acetate in petroleum ether gave tert-butyl 3-(2-benzyloxyethoxy)azetidine-1-carboxylate (9.15 g).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([OH:3])=[O:2].S(=O)(=O)(O)O.C(N(CC)CC)C.[CH2:42](O)[CH:43]=[CH2:44]>C(OCC)(=O)C>[CH2:44]([O:2][C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18])=[O:3])[CH:43]=[CH2:42]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.20 g) in allyl alcohol (52 ml) was refluxed in the presence of sulfuric acid (0.5 ml) for 5 hours. After cooling, triethylamine (3.14 ml) was added to the mixture. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (100 ml), washed in turn with water (100 ml) and brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(allyloxycarbonylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (6.05 g).
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].C([O:18][C:19](=O)[CH:20]([CH3:22])[OH:21])C>P([O-])([O-])([O-])=O>[C:19]([O:11][CH2:10][C@H:8]1[O:9][CH:2]([OH:1])[C@@H:3]([NH:12][C:13](=[O:14])[CH3:15])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:18])[CH:20]([CH3:22])[OH:21]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCOC(=O)C(C)O
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)N[C@@H]1C(O)O[C@H](COC(=O)C(C)O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
ManNAc (200 mg) and 50 mg of subtilisin mutant 8399 were added to a mixture of lactic acid ethyl ester 10 (4 mL) and 400 mL of 0.5 N phosphate buffer (pH 7.5). The reaction mixture was shaken under 50° C. for three days. The solvent was then evaporated and methanol was added to the residue. After the insoluble materials were filtered off, the filtrate was concentrated. The residue was chromatographed on silica gel with ethyl acetate/methanol (5/1) to give 6-O-Lactyl N-acetylmannosamine in 50 percent yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:30]([O:37][C:38]([CH2:40][C:41]1([OH:47])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][C:23]([C:26]([N:44]3[CH2:45][CH2:46][C:41]([CH2:40][C:38]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])([OH:47])[CH2:42][CH2:43]3)=[O:27])=[CH:24][N:25]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1(O)CCNCC1)OCc1ccccc1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2ncc(C(=O)O)cn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2ncc(C(=O)N3CCC(O)(CC(=O)OCc4ccccc4)CC3)cn2)cc1

Procedure:
Prepared by reacting 2-[4-[N-(benzyloxycarbonyl)-amidino]-phenyl]-5-carboxy-pyrimidine with 1.2 equivalents of N,N-carbonyl-diimidazole in dimethylformamide at 5° C. followed by the addition of 1.2 equivalents of 4-[(benzyloxycarbonyl)-methyl]-4-hydroxy-piperidine-hydrochloride and 1.2 equivalents of N-methylmorpholine at ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH2:38]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH:38][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
23.3 of t-butoxycarbonylisoleucine is dissolved in 200 ml of methylene chloride. 33.3 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 13.1 ml of isobutylchloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 26.0 g of histidine methyl ester dihydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylisoleucylhistidine methyl ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: Cc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: Cc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[Na].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: CC(C)O
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Agent: [Na]
Product: CC(C)Oc1cc(CCl)nc(C(C)C)n1

Procedure:
6-Chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61) is reacted with isopropanol and sodium analogously to the process described in Example 62 in order to produce 4-chloromethyl-2-isopropyl-6-isopropoxy-pyrimidine which is required as the starting material in Example 22. This product is obtained in the form of an oil, 1H-NMR (CDCl3): 1.30 (d, 2×CH3), 1.37 (d, 2×CH3), 3.10 (m, CH), 4.50 (s, CH), 5.40 (m, CH), 6.65 (s, CH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1>[C].[Pd].CO>[F:1][C:2]1[CH:14]=[C:13]([CH:12]=[C:4]([O:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1)[NH2:15]
Reactant: O=[N+]([O-])c1cc(F)cc(Oc2cccnc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A palladium-carbon catalyst was added to a solution of 3-(3-fluoro-5-nitrophenoxy)pyridine (8.0 g) in methanol (70 ml), and the reaction solution was stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through Celite, and the filtrate was distilled off under reduced pressure to obtain a crude product as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.17 mmol), 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (49 mg, 0.25 mmol) and camphorsulformic acid (4 mg, 0.02 mmol) in IPA (5 mL) was microwave-heated at 120° C. for 3.5 h. The mixture was concentrated and chromatographed with preparative TLC (methylene chloride and ethyl acetate (4:1)) to give 54 mg of 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (71%): 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 7.95 (s, 1H), 7.56 (d, 1H), 7.43 (dd, 1H), 7.34 (d, 1H), 7.26 (m, 1H), 7.1 (t, 1H), 7.05 (d, 1H). 4.35 (t, 2H), 3.3 (s, 3H), 2.9 (s, 3H), 2.85 (t, 2H); MS (m/e): 453.3 (M+1).
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>[Rh]>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [Rh]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 5% Rhodium on carbon (10 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: C([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[CH:13]([CH2:19][NH:20]C(OC(C)(C)C)=O)[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([CH2:19][NH2:20])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:29])=[O:5])=[O:28])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(CN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[3-(acetylthio)-2-tert-butyloxycarbonylaminomethylpropanoyl]-L-proline tert-butyl ester (1.5 g) is dissolved in a mixture of anisole (6 ml) and trifluoroacetic acid (12 ml) and the solution is stored at room temperature for one hour. The solvent is removed in vacuo, the residue is distributed between water and ether. The aqueous phase is washed twice with ether and freeze-dried to yield 1-(3-acetylthio-2-aminomethylpropanoyl)-L-proline.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:18](OC)=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][OH:19])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c2ccc(O)cc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(-c2ccccc2)c2ccc(O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 1-phenyl-3-carbomethoxy-6-naphthol (Naphthol 11) (2.5 g, 9 mmoL) in dry THF (50 mL) at 0° C. was added (4.8 mL, 2.7 mmoL, 3 eq.) of DIBAL-H. The resulting solution was stirred for 2 hr. Then methanol (excess) was added and the solvent evaporated. The mixture was diluted with EtOAc, washed successively with HCl, 1N, H2O, brine, to give the title compound.
Reaction SMILES: B.[Na].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:31]=[CH:30][C:19]4[O:20][CH2:21][C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[C:24](=[O:25])[C:18]=4[CH:17]=3)=[N:11]2)=[CH:6][C:5]=1[F:32]>CO>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:31]=[CH:30][C:19]4[O:20][CH2:21][C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[CH:24]([OH:25])[C:18]=4[CH:17]=3)=[N:11]2)=[CH:6][C:5]=1[F:32]
Reactant: O=C1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Agent: B
Agent: [Na]
Solvent: CO
Product: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 72.1 %

Procedure:
0.5 g of sodium boron hydride was added to 2.58 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 34 suspended in 70 ml of methanol and the mixture was stirred at room temperature for 11 hours. During stirring, 0.35 g of sodium boron hydride was added to the mixture twice. After completion of the reaction, the solvent was removed under reduced pressure, ice water was added to the residue and the mixture was extracted with methylene chloride. Then, the organic layer was washed with water and then dried over anhydrous sodium sulfate and the solvent was removed. The resulting solid was washed with a methylene chloride-hexane mixed solution to obtain 1.87 g of the title compound. Mass (CI); m/z=422 (M+ +1)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12]>O1CCCC1.O>[C:4]([C:5]([CH2:12][C:11]#[N:13])=[O:6])([CH3:10])([CH3:9])[CH3:3]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of 9.6 g of sodium hydride in 300 ml of tetrahydrofuran was stirred at 60° while a mixture of 23.2 g of methyl trimethylacetate and 8.2 g of acetonitrile was added in one portion. The reaction mixture was heated at reflux for five hours, and then cooled to room temperature and concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in water and washed with dichloromethane. The aqueous layer was made acidic with 1N hydrochloric acid, and the acidic solution was extracted with fresh dichloromethane. The organic extracts were combined, washed with water, dried, and the solvent was removed by evaporation to give 14.0 g of cyanomethyl tert.-butyl ketone.