Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C(C1C=CC(S(C)(=O)=O)=C(Cl)C=1)CC1CCCC1)C.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (prepared in Example 27, 937 mg) in ethanol (30 mL) at 25° C. was treated with a solution of potassium hydroxide (733 mg, 13.1 mmol) in water (7 mL). This solution was stirred at 25° C. for 3 h. At this time, the reaction mixture was concentrated in vacuo. The residue was acidified to pH=2 by treatment with a 1N aqueous hydrochloric acid solution. This solution was then extracted with methylene chloride (3×15 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (787 mg, 82% over two steps) as a white solid: mp 123.9-126.2° C.; FAB-HRMS m/e calcd for C15H19ClO4S (M+H)+331.0771, found 331.0776.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CCOCC>[Br:9][C:10]1[N:11]=[C:12]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:13]=[CH:14][CH:15]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)CCOc1cccc(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2-dimethylaminoethanol (2 mL, 20 mmol) was added at rt to a suspension of NaH (oil was not removed) in dry DMF (3 mL). The mixture was stirred at rt for 2 hours and 1 h at 60° C. Then commercial 2,6-dibromopyridine (6.16 g, 26 mmol, 1.3 eq) was added at rt and the whole was stirred at rt overnight. The crude mixture was dissolved in some Et2O and was extracted with 2 portions of citric acid 30%. Combined aqueous phases were washed with 2 portions of Et2O. The aqueous phase was basified with NaOH 5N at 0° C. and was extracted with 3 portions of Et2O. Combined organic phases was dried over MgSO4, filtrated and evaporated. As some DMF remained, HCl in Et2O was added. The solvents were evaporated and the resulting solid was put at the pump for 4 hours. It was dissolved in H2O and basified with NaOH 5 M. The desired product (the base) was extracted with 3 portions of Et2O. Combined organic layers were dried over MgSO4, filtrated and evaporated to give the desired product (XXIII), N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (4.4309 g, 18.076 mmol, 90.4%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].Cl.Cl.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[OH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][NH:20][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH2:24][CH2:25]1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCN1CCC(O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (1.5 g, 5.4 mmol) in tetrahydrofuran (100 ml) was added over 1 hour to a stirred mixture of 1-(2-aminoethyl)-4-hydroxypiperidine dihydrochloride (1.2 g, 5.4 mmol) and triethylamine (2.3 ml, 16.5 mmol) in tetrahydrofuran (75 ml) cooled in an ice bath. After stirring at room temperature for 6 hours, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate extract was dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed on silica gel and eluted with 5% methanol-95% chloroform to give pure product, 1.0 g, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH:34]([N:37]([CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:39][CH2:38][N:37]([CH:41]([CH3:43])[CH3:42])[CH:34]([CH3:36])[CH3:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21)C(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]34[CH2:30][CH:31]5[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]5)[CH2:36]3)[CH2:38]4)=[O:28])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: O=C(OCCCBr)C12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
To a stirred solution of 3-bromopropanol (5.5 g, 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g, 0.02 mol) and triethylamine (4 g, 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight, the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g of the intermediate adamantane-1-carboxylic acid bromopropyl ester. The title compound was prepared by stirring 4-[bis(4-fluorophenyl)-methylene]piperidine (2 g, 0.07 mol), adamantane-1-carboxylic acid bromo-propyl ester (2.1 g, 0.007 mol) and triethylamine (1 g, 0.01 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.7 in 30% ethanol/ethylacetate system) was separated and converted to the hydrochloride salt (0.6 g, 16% yield), mp. 267°-269° C.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:22]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[Na+]>CN(C=O)C>[CH2:22]([O:29][C:30]([NH:31][CH2:32][CH2:33][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]1[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:4])=[O:21])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: COC(=O)c1cccc(F)c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCNC(=O)OCc1ccccc1)c1c(F)cccc1C(=O)O
Temperature: 25 °C

Procedure:
Sodium hydride (60%, 120 mg, 3.0 mmol) was added to a solution of 2-tert-butoxycarbonylamino-3-fluorobenzoic acid methyl ester from Example 20A (750 mg, 2.8 mmol) in DMF (8.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 30 min. (2-bromoethyl)carbamic acid benzyl ester (360 mg, 2.8 mmol) and sodium iodide (420 mg, 2.8 mmol) were added and the mixture was heated at 65° C. for 18 h. The mixture was cooled and evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (EtOAc:pet. ether 30:70) to give a colourless gum; yield 340 mg, 27%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([N:20]2[CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: C1CNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N2CCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S,2R,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (340 mg, 1.20 mmol) and azetidine (98%, Aldrich, 1.0 mL) and methanol (6 mL) were maintained at 60° C. in a sealed tube for 18 hours. To the cooled solution was added 1N sodium hydroxide (1.2 mL). Volatiles were evaporated and the residue chromatographed on silica gel. Title compound was eluted with methanol:ethyl acetate/15:85 as a white foam which solidified to white powder from methanol-acetonitrile (333 mg, 91%), mp 194-195°; mass spectrum (Cl, CH4) 305 (M+1); 1H-NMR (DMSO-d6)δ: 7.81 (s, 1, H8), 5.88 (br s, 2, NH2), 495-4.80 (m, 1, CH--N), 4.76 (d, J=3.9 Hz, 1, OH), 4.66 (t, J=5.0 Hz, 1, CH2 --OH), 4.4-4.15(br m, 4, 2CH2N), 4.10-4.0 (m, 1, CHO), 3.6-3.4 (m, 2, CH2O), 2.5-1.9 (m, 6, methylene), 1.75-1.5((m, 1, 1/2CH2); [α]20589 +10.1°, [α]20578 +10.7°, [α]20540 +11.9°, [α]20436 +18.3°, [α]20365 +25.2° (c=0.812, methanol).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1.C([N:22](CC)C(C)C)(C)C>C(O)(C)C>[Cl:8][C:9]1[NH:10][C:11]([NH2:22])=[C:12]2[C:16]([N:17]=1)=[N:15][CH:14]=[N:13]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1[nH]c(Cl)nc2ncnc1-2
Temperature: 100 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
A glass tube was charged with the above amount of TFA salt 13, commercially available 2,6-dichloropurine (1.02 g, 5.43 mmol), N,N-diisopropylethylamine (DIPEA, 3.14 mL, 4.96 mmol) and isopropyl alcohol (IPA, 6 mL). The glass tube was sealed and then shaken at 100° C. for 17 hours. The volatiles were evaporated and the resulting residue was purified by flash chromatography eluting with ethyl acetate-methanol (100:5, including 1% triethylamine) to afford 1.25 g of mono-SNAR product 14, racemic-(2-exo,3-exo-)-N6[3-(dimethylamino)carbonylbicyclo-[2.2.1]hept-5-en-2-yl)]-2-chloro-1H-purine-6-amine, in 70% yield. 1H NMR (300 MHz, CD3OD) δ: 8.05 (s, 1H), 6.35 (m, 2H), 4.68 (m, 1H), 3.00 (s, 1H), 3.04 (s, 1H), 3.00 (s, 3H), 2.95 (s, 1H), 2.83 (s, 1H), 2.68 (s, 3H), 2.39 (d, J=8.7 Hz, 1H), 1.69 (d, J=9.0 Hz, 1H), 1.33 (m, 1H); LC-MS: purity: 90.51%; MS (m/e): 333.43 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[C:45](=[O:50])[CH2:46]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1=O
Solvent: COCCO
Solvent: CCN(CC)CC
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 7 h
Yield: 50.3 %

Procedure:
A mixture of N-[5-chloro-7-(3-isopropoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.22 g, 0.43 mmol), triethylamine (0.29 ml, 2.13 mmol), 1-methylpiperazin-2-one (0.24 g, 2.13 mmol) in 2-methoxyethanol (3 ml) was heated to 80 C for 12 hours and then at 100 C for 7 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 2-8% methanol in dichloromethane to give the product as an light orange solid (0.129 g, 51%). NMR Spectrum: (DMSOd6) 1.18 (d, 6H), 1.98 (m, 2H), 2.52 (t, 2H under DMSO), 2.72 (t, 2H), 2.88 (s, 3H), 3.04 (s, 2H), 3.34 (t, 2H under H2O), 3.83 (m, 1H), 3.97 (s, 3H), 4.22 (t, 2H), 4.42 (s, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H), 7.83 (s, 1H), 8.34 (s, 1H), 9.52 (s, 1H). Mass Spectrum: M+H+ 596 and M+H− 594.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1.CCN(CC)CC.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH3:32][C:31]([Si:28]([CH3:30])([CH3:29])[O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
To cis-(3RS,5RS)-5-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (0.78 g; 2.8 mmol) in CHCl3 was added Et3N (2.0 ml; 15 mmol), and tert-butyldimethylsilyl chloride (1.06 g; 7.0 mmol). The reaction was allowed to stir for 14 hours under N2 at room temperature. The reaction was diluted with 200 ml of CHCl3 and washed with saturated aqueous NaHCO3, 0.1 N aqueous HCl, saturated aqueous NH4Cl, and brine. The organic layer was dried with Na2SO4, and the solvents were removed to provide the desired compound (0.80 g; 73%) as a colorless oil.
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].[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[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:41](=[O:42])[NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=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=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)NCc1ccccc1
Yield: 48 %

Procedure:
A solution of 0.28 g of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, and 0.083 g of benzyl isocyanate in 5 ml of dichloromethane was stirred at 20° C. for 2 hours. The solvent was then removed by evaporation and the residue was triturated with diethyl ether to give 0.174 g of N-[3(S)-[[N-(benzylcarbamoyl)-L -asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white solid; MS: m/e 582 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([NH:27][C:28](N1C=CC=N1)=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25](=[O:26])[NH:27][CH:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)Nc1nc(CCc2ccc(CN)cc2)cs1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A mixture of N-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (20 mg) prepared in a similar manner according to Production Example 12, N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (23 mg) and tetrahydrofuran (0.5 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica-gel with chloroform as an eluent. The crystalline residue was collected and washed with diisopropyl ether to give di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate (22 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])(C[Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[C:40](=O)([O-])[OH:41].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])([CH2:40][OH:41])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 68.9 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.88 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 10 ml), to which 1.57 ml of 30% aqueous hydrogen peroxide and 0.128 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of water, an aqueous solution of Na2S2O3 (25 ml×2) and 25 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 0.5 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 69%) as colorless powdery crystals.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(OCC)(=O)C.O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in ethyl acetate (90 ml), a solution of NaOH (0.2 g) in water (1 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ethyl acetate (50 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.52 g (49.7%) of fluvastatin sodium crystal Form LXXVII.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.CC1(C)[O:40][C:39](=O)[CH:38]([C:42]2[CH:46]=[CH:45][S:44][CH:43]=2)[C:37](=[O:47])[O:36]1>O1CCCC1>[C:37]([CH:38]([C:42]1[CH:46]=[CH:45][S:44][CH:43]=1)[C:39]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:40])([OH:47])=[O:36]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC1(C)OC(=O)C(c2ccsc2)C(=O)O1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccsc3)[C@H]2SC1

Procedure:
To a suspension of 656.7 mg (2 mmol) of 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (as prepared in example 9) in 25 ml. of anhydrous tetrahydrofuran there is added 1.6 ml. of bis-trimethylsilylacetamide. The mixture is stirred to give a solution to which there is added at once 452.5 mg (2 mmol) of 2.2-dimethyl-5-(3-thienyl)-1.3-dioxane-4.6-dione as prepared in example 6, the mixture being stirred at 25° C for 8 hours. Tetrahydrofuran is removed under reduced pressure and the residue is taken up with 30 ml. of water, brought to pH 2.5 with 0.5 ml. 6N HCl, stirred for 15 minutes and extracted three times with 25 ml. of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and filtered over DARCO G60 (a product manufactured and sold by Atlas Chem. Ind.)-charcoal. Most of the solvent is evaporated under reduced pressure and 100 ml. of petroleum ether (50°-70° C) is added thereto. The suspension is stirred for 30 minutes and filtered. The precipitate is washed with 20 ml. of petroleum ether (50°-70° C) and dried over anhydrous P2O5 under reduced pressure to yield DL-7-[α-carboxy-α-(3-thienyl)-acetamido]-3-(1-methyl-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (RIT 3838).