Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].O[CH2:23][CH2:24]/[CH:25]=[CH:26]\[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:32]([O:31][P:27](/[CH:26]=[CH:25]\[CH2:24][CH2:23][O:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O:28][CH2:29][CH3:30])=[O:34])[CH3:33]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Reactant: CCOP(=O)(/C=C\CCO)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C\CCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a mixture of 9-hydroxy-6-phthalimidopurine (320 mg, 1.14 mmol) , diethyl (Z)-4-hydroxybut-1-enylphosphonate (250 mg, 1.20 mmol) and triphenyl phosphine (448 mg, 1.71 mmol) in dry tetrahydrofuran (11 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (296 mg, 170 mmol). The mixture was allowed to warm to r.t. and stirred for 2.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with acetone-hexane (1:1, 4:3) to give (Z)-9-[4-(diethoxyphosphoryl)but-3-enyloxy]-6-phthalimidopurine as a light brown gum (320 mg, 60%); λmax (EtOH) 271 (14,680)nm; υmax (KBr) 2980, 1735, 1595, 1575, 1360, 1330, 1245 and 1025 cm-1 ; δH [(CD3)2SO] 1.23 (6H, t, J 7 Hz, CH3), 3.05 (2H, m, CH2), 3.98 (4H, dq, J 7 Hz and 8Hz, CH2CH 3), 4.63 (2H, t, J 6 Hz, CH2O ), 5.90 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.75 (1H, ddt, J 7 Hz, 14 Hz and 52 Hz, PCH=CH), 8.05 (4H, m, C6H4), 9.05 (1H, s, H-2/H-8), 9.10 (1H, s, H-2/H-8) (Found: C, 53.77; H, 4.87; N, 14.52%; MH+ 472.1384. C21H22N5O6P requires C, 53.50; H, 4.70; N, 14.86%; MH+ 472.1386).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([O:19]C)=[O:18])=[CH:11][C:12]=3[F:16])[N:7]=2)[CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH:1]1([CH2:4][NH:5][C:6]2[N:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][C:12]=3[F:16])[N:7]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(cyclopropylmethylamino)-5-fluoro-quinazoline-7-carboxylate (40 mg, 0.15 mmol) in THF (1.3 mL) and water (0.4 mL) was treated with LiOH (10.4 mg, 0.44 mmol) and stirred at ambient temperature for 1 h. The mixture was acidified with 1M aqueous citric acid and the resulting precipitate collected via centrifugation, washed with water, and then dried under high vacuum to afford 2-(cyclopropylmethylamino)-5-fluoroquinazoline-7-carboxylic acid as a yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)(O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1.N1C=CN=C1.S(Cl)([Cl:30])=O>C(#N)C>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:30])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cn1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: Cl
Product: Clc1ccc(C(Cl)(Cn2cncn2)c2ccc(Cl)cn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.0 g (5.95 mmoles) of 1,1-bis(5-chloropyrid-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol and 2.4 g (35.3 mmoles) of imidazole in 60 ml. of acetonitrile was added with stirring 2.1 g (17.65 mmoles) of thionyl chloride, the reaction mixture stirred for 2 hrs at room temperature and the solvent allowed to evaporate. Dilute sodium bicarbonate solution (30 ml) was added to the residue and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were dried over magnesium sulfate, concentrated to dryness and the residue chromatographed on 230-400 mesh silica gel using ethyl acetate-petrol (b.p. 60°-80° C.) (1:1, v:v) as the eluent. The fractions containing the product were combined and concentrated in vacuo to a colorless oil. Treatment of the residue with ethereal hydrogen chloride gave 1.4 (60% yield) of the desired product as a white solid, m.p. 115°-125° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:1]#[CH:2])[CH:4]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethynylaniline (2.61 g, 22.3 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (3.1 mL, 22.3 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (2.21 mL, 23 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid (m.p. 99-100° C.). NMR (300 MHz, CDCl3): 8.05 (broad s, 1H, NH), 7.69 (s, 1H), 7.62 (m, 1H), 7.33 (m, 2H), 6.04 (s, 1H), 3.10 ppm (s, 1H, acetylenic).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Yield: 48.5 %

Procedure:
A mixture of 60.9 g. (0.293 mole) of 4-(4-fluorobenzoyl)piperidine, 46.0 g. (0.31 mole) of 3-bromopropanol and 41.4 g. (0.30 mole) of anhydrous potassium carbonate in 750 ml. of 1-butanol was stirred at reflux for 15 hours. The mixture was filtered, the filtrate concentrated under vacuum and the residual oil was dissolved in acid solution and extracted with benzene. After discarding the benzene layer, the aqueous acid layer was made basic and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, the mixture filtered and the filtrate concentrated under vacuum. Anhydrous ether was added to the oily residue and the oil crystallized. The solid which weighed 57.0 g. was washed with ether and filtered. Upon recrystallizing from isopropanol and isopropyl ether, 38.5 g. (48.5%) of product was obtained. A portion (4.0 g.) was recrystallized from petroleum ether to give 2.4 g. of product melting at 105°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([CH3:31])([C:15]2[N:19]([CH3:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:17][N:16]=2)[CH3:14])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].C(N(CC)CC)C.Cl[C:40](=O)[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([CH3:31])([C:15]2[N:19]([CH3:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])=[N:17][N:16]=2)[CH3:14])=[C:6]([C:7]2[O:8][C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:10][N:9]=2)[CH:11]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NN
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc(-c2cc(Cl)ccc2OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (782 mg) was dissolved in THF (10 ml), and triethylamine (0.510 ml) was added thereto, followed by ice-cooling. Ethyl chloro(oxo)acetate (0.200 ml) was added thereto, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether. The resulting solid (650 mg) was dissolved in dichloromethane (10 ml), and pyridine (0.385 ml) was added thereto, followed by cooling to −78° C. Trifluoromethanesulfonic anhydride (0.385 ml) was added to the reaction solution and was elevated to room temperature, followed by stirring for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether, to obtain, as a yellowish white solid, ethyl 5-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3,4-oxadiazole-2-carboxylate (240 mg).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[NH:17][C:16]=3[C:15](=[O:26])[N:14]([CH2:27][CH2:28][CH3:29])[C:13]2=[O:30])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[CH:33]1(C(O)=O)[CH2:37]CC[CH2:34]1.[O:41]1CCOCC1>O>[NH2:19][C:20]1[N:12]([CH2:11][CH2:10][C:9]2[CH:31]=[CH:32][C:6]([NH:5][C:1]([CH:2]3[CH2:37][CH2:33][CH2:34][CH2:3]3)=[O:4])=[CH:7][CH:8]=2)[C:13](=[O:30])[N:14]([CH2:27][CH2:28][CH3:29])[C:15](=[O:26])[C:16]=1[NH:17][C:18]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:41]
Reactant: CCCn1c(=O)c2[nH]c(C3CCCC3)nc2n(CCc2ccc(NC(=O)CC)cc2)c1=O
Reactant: C1COCCO1
Reactant: O=C(O)C1CCCC1
Solvent: O
Product: CCCn1c(=O)c(NC(=O)C2CCCC2)c(N)n(CCc2ccc(NC(=O)C3CCCC3)cc2)c1=O
Yield: 41 %

Procedure:
Compound k obtained in Reference Example 2 (10.8 g, 35.3 mmol) was dissolved in a mixture of 100 ml of dioxane and 100 ml of water, and 3.86 ml (35.5 mmol) of cyclopentanecarboxylic acid was added to the solution. Then, 1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride (11.2 g, 56.8 mmol) was added slowly at room temperature at pH 5-6 over a period of five minutes. The crystals formed were collected by filtration to give 7.13 g (yield: 41%) of 6-amino-1-[4-(cyclopentanecarbonylamino)phenethyl]-5-(cyclopentanecarbonyl) amino-3-propyluracil (Compound x) as white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13]([NH:23][CH2:24][C:25]([OH:27])=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CN(C)C=O>[C:13]([NH:23][C@H:24]([C:25]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:27])[CH2:16][CH:17]([CH3:22])[CH3:18])([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
1.74 g (10.00 mM) of arginine are suspended in 25 ml of dimethylformamide, the solution is added with 4,25 g (11.00 mM) of p-nitrophenyl ester of carbobenzoxy-glycine, the mixture is stirred at room temperature for one day. Dimethylformamide is evaporated, the residue is dissolved in 5 ml of methanol and added with 300 ml of ether. The resulting precipitate is filtered-off, washed with ether on the filter and dried in a vacuum desiccator to give 4.05 g (96%) of carbobenzoxy-leucyl-arginine, m.p. 126°-130° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([Cl:38])[CH:17]=1.CCCCCC.C(OCC)(=O)C>C(#N)C>[Cl:38][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:37]=[CH:36][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(Cl)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
2-Phenylacetyl chloride (0.93 ml) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (137 mg) was added thereto at 60° C., followed by stirring at the same temperature for 3 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-amino-2-chlorophenoxy)-2-[(morpholin-4-yl)carbonylamino]pyridine (164 mg) in acetonitrile (5 ml) was added thereto, followed by stirring at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:4, then ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which hexane/ethyl acetate (1/5) was added to suspend. The resultant solid was filtered off and dried under aeration to provide the titled compound (115 mg, 47%) as pale yellow powder.
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[CH2:17]([N+:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>O.CC(O)C>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O-:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:17]([N+:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=P([O-])(c1ccccc1)c1ccccc1

Procedure:
To a flask were added 1.0 g diphenylphosphinic acid, 3.2 g of a 20% solution of tetraethylammonium hydroxide in water and 20 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, an oil was obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].O.O.[Cl:18][Sn]Cl>O.Cl.CC(O)=O>[ClH:18].[NH:5]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])[NH2:1]
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C(=O)O)cc1NN
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.74 g of NaNO2 in 28 ml of water is added over 30 minutes to a solution, cooled to -5° C., of 5 g of 3-amino-4-methylbenzoic acid in 120 ml of concentrated HCl and 40 ml AcOH, and the mixture is left stirring for 1 hour 20 minutes at 0° C. After cooling to -10° C., a solution of 27.6 g of SnCl2.2H2O in 28 ml of concentrated HCl is added slowly. After stirring for 1 hour at RT, filtration, washing of the precipitate with 5 ml of 1N HCl and drying over P2O5 under vacuum, 6.15 g of the expected product are obtained.
Reaction SMILES: N[C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[BrH:12].N([O-])=O.[Na+]>O>[Br:12][C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Br)C1CCCCC1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
The (R)-2-amino-2-cyclohexylacetic acid (H-Cyclohexyl-D-Gly-OH, 1 g, 6.36 mmol), which is commercially available from Bachem California Inc., Torrance, Calif. 90505, was dissolved in a mixture of HBr 48% (5.8 niL, 50.9 mmol) and H2O (20 mL). At 0° C., a solution of NaNO2 (1.4 g, 20.4 mmol) in H2O (10 mL) was added over a period of 30 min. The reaction was stirred for two hours. The reaction mixture was degassed in vacuo and extracted with EtOAc (2×2mL). The extracts were washed with water (15 mL), dried (Na2SO4), filtered and evaporated to give 1.3 g (92% yield) of the (R)-2-bromo-2-cyclohexylacetic acid as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]([C:14]([O:16][CH2:17][CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)=[O:15])=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].O.NN>C(O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:8]([C:14]([O:16][CH2:17][CH2:18][NH2:19])=[O:15])=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1ccccc1OCc1ccccc1

Procedure:
A solution of 11.0 g (18.97 mmol) of N-ethyl 4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-3-(2-phthalimido-ethoxycarbonyl)-pyridine-5-carboxamide (Example 28) and 95.0 mmol of hydrazine hydrate are heated under reflux in 100 ml of ethanol for 2 h. The solution is then cooled and the residue is filtered. The latter is subsequently washed with methylene chloride and the filtrate is concentrated in vacuo. The concentrated residue is then washed once with a 2 N solution of potassium hydroxide and then 3 times with water. The product is purified on a silica gel column using methylene chloride/methanol mixtures.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:36][CH3:37])=[O:16])[CH2:10][CH2:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)CC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A suspension of 23.6 g of N-triphenylmethyl-4-piperidineacetic acid, 16.9 g of potassium carbonate and 5.0 ml of ethyl bromide in 230 ml of dried N,N-dimethylformamide was stirred at 90° C. for 5 hours. After cooling, the reaction mixture was added with water and ethyl acetate, and the precipitated crystals were collected by filtration and washed with water to give 20.6 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having the melting point of from 165 to 166° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].C(C1NC=CN=1)(C1NC=CN=1)=O.[C:26]([O:30][C:31]([CH2:33][C:34](=[N:36]O)[NH2:35])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[NH2:36][C:34](=[N:35][O:10][C:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:12])[F:13])=[O:11])[CH2:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32]
Reactant: CC(C)(C)OC(=O)CC(N)=NO
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(N)=NOC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
30 g of 4-trifluoromethyl-3-pyridinecarboxylic acid is initially charged in 150 ml of dry THF and, a little at a time, admixed with 25.3 9 of carbonyl-diimidazole. The mixture is stirred at room temperature for 30 min. 27.2 g of tert-butoxycarbonylacetamide oxime dissolved in 150 ml of THF are then added dropwise. The mixture is stirred overnight, the solvent is evaporated and the residue is taken up in ethyl acetate, washed three times with 1 M sulfuric acid and once with saturated sodium bicarbonate solution. Concentration of the ethyl acetate phase gives 28 g of the product as a pale yellow solid.
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]>CC(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: CC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) and NaOH (0.29 g) partially dissolved in acetone (0.75 ml) was added. The mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.31 g (76.2%) of fluvastatin sodium crystal Form I.
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C1CCCCC1.[Li]C(CC)C.C[O:24][B:25](OC)[O:26]C>C1COCC1>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([B:25]([OH:26])[OH:24])[C:5]=2[O:6]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to −78° C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at −78° C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to −30° C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl.C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][S:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1nnc(S)s1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(=O)CSc1nnc(C)s1
Yield: 91.3 %

Procedure:
A solution of 5-methyl-1, 3,4-thiadiazole-2-thiol (264 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (10 mL) and acetonitrile (10 mL) was stirred at 20° C. for 3 hours under nitrogen. The precipitates were filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (450 mg, yield 69%) as a solid. 1H-NMR (300 Hz, D3COD and d6-DMSO) δ (ppm): 4.22 (q, J=7.1 Hz, 2H), 3.78 (d, J=14.1 Hz, 1H), 3.71 (d, J=14.1 Hz, 1H), 2.74 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).