Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@:24]([CH3:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@@:24]([CH3:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide (460 mg, 0.99 mmol) and 10% Pd/C (100 mg) are evacuated in a flask. To this is added methanol (10 mL) and a hydrogen atmosphere is introduced. The reaction is allowed to stir at room temperature for 2 hours at which time the reaction appears complete by TLC. The mixture is filtered through celite; the filtrate is collected and evaporated to give a white glassy solid. The hydroxamic acid is crystallized by dissolving in ethyl acetate and adding hexane dropwise until the solution becomes cloudy. N-Hydroxy-2(R)-[[(R)-methylphenyl-phosphinyl]benzylamino]-4-methylpentanamide is obtained as a white crystalline solid: MS-IS m/z 375 [M+H]+, 397 [M+Na]+, 413 [M+K]+. (R2 =isobutyl, R1 =benzyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:5]1[C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cccc(-c3cccc4ccccc34)c2C1
Yield: 4030.6 %

Procedure:
The crude product was taken up in 200 cm3 of toluene, 0.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO, solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 10 g (86%) of 22 as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(C)C=CC(S(O[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)(=O)=O)=CC=1.C(N(CC)CC)C.O>C(Cl)Cl>[OH:36][CH:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OCc1ccc2ccccc2n1
Reactant: CCCCCC(O)c1cccc(COS(=O)(=O)c2ccc(C)cc2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1cccc(COCc2ccc3ccccc3n2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
A mixture of 2-hydroxymethylquinoline (8 g, 0.05 mol) and 3-(1-hydroxyhexyl)benzyl p-toluenesulfonate (18.2 g, 0.05 mol; prepared as in Example 17) in methylene chloride (200 ml) containing triethylamine (15 ml) was stirred at 0° C. for 4 hours, and then allowed to warm up to room temperature. This mixture was stirred for two more hours at this temperature, and then poured into water. The organic layer was separated and washed with dilute sodium hydroxide solution, water and brine. After drying the organics, all volatiles were removed to obtain the crude product as a yellowish brown liquid. This was purified by chromatography on silica gel using 15% ethyl acetate in hexanes to get the pure product as a clear, light yellow liquid (9 g, 52% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23](O)=[O:24].[CH2:26]([S:33][CH:34]([CH:37]([O:40][CH3:41])[O:38][CH3:39])[CH2:35][NH2:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:26]([S:33][CH:34]([CH:37]([O:38][CH3:39])[O:40][CH3:41])[CH2:35][NH:36][C:23]([C:5]1[N:4]([CH2:3][O:2][CH3:1])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCn1c(C(=O)O)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCn1c(C(=O)NCC(SCc2ccccc2)C(OC)OC)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Yield: 105.2 %

Procedure:
A solution of 1-(methoxymethyl)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.94 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (0.70 g), N-ethyldiisopropylamine (1.0 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 20 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4) to give the title compound (1.6 g, yield: 100%) as a pale-yellow oil. MS: 553(MH+).
Reaction SMILES: C([O-])=O.C([NH+](CC)CC)C.C(O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[CH:24]=1>O>[CH2:23]([C:24]1[C:25](=[O:26])[O:33][C:20]2[C:15]([C:14]=1[OH:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:32]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=Cc1ccccc1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O
Solvent: O=CO
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylammonium formate (TEAF) was prepared by adding TEA (20.0 mL) to formic acid (16.5 mL) with ice cooling. To TEAF was added benzaldehyde (3.78 mL) and 4-hydroxy-chromen-2-one (6.0 g) and the resulting mixture was heated to 130–140° C. for 3 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to give a light yellow solid. The crude solid was recrystallized from EtOH to give 3-Benzyl-4-hydroxy-chromen-2-one as a white solid (1.95 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](=[O:12])([O-:11])[O-].[K+:13].[K+].[CH:15]([O-:17])=[O:16].[K+]>>[OH:2][C:1]1[CH:8]=[C:7]([C:15]([O-:17])=[O:16])[C:5]([OH:6])=[CH:4][C:3]=1[C:9]([O-:11])=[O:12].[K+:13].[K+:13]
Reactant: O=C[O-]
Reactant: Oc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C([O-])c1cc(O)c(C(=O)[O-])cc1O
Temperature: 200 °C

Procedure:
Dipotassium 2,5-dihydroxyterephthalate was prepared in the known “Kolbe-Schmidt” type reaction from hydroquinone. Hydroquinone was mixed with potassium carbonate and potassium formate, the latter which acted as a solvent when molten. The mixture was heated to 200° C. with stirring to provide a homogeneous solution. Excess carbon dioxide was bubbled through the stirred solution for about 8 h. Excess carbon dioxide optionally may be recycled. The reaction mass was drowned in water, and filtered. When the drowned and stirred reaction mass was filtered, the sparingly soluble dipotassium 2,5-dihydroxyterephthalate was separated from water-soluble potassium formate and potassium carbonate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>O1CCCC1.C(N(CC)CC)C>[N+:22](=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:12])=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Yield: 70.6 %

Procedure:
To a 100 ml round-bottom flask fitted with a mechanical stirrer, nitrogen inlet and bubbler was charged 4-hydroxycoumarin (3.1 g, 18.8 mmol) dissolved in dry terahyrofuran (THF) (21.6 g) and triethylamine (1.8 g). A solution of p-toluenesulfonyl azide (5.3 g, 28.3 mmol) in dry THF (14.4 g) was then added to this solution dropwise over a period of 15 minutes. The reaction was continued until all of 4-hydroxycoumarin had reacted as monitored by high pressure liquid chromatography (HPLC) (ca. 2.0 hours). The precipitated reaction product was filtered in a small Buchner funnel and the filtrate was packed in powdered dry ice to produce a second crop of crystals, which was also isolated by filtration. The combined filtercakes were dried overnight under house vacuum at 60° C. to obtain orange colored crystals of 3-diazo-4-oxocoumarin; yield 2.5 g (70.6% yield). The crude product was further purified by dissolving it in 75.0 g of acetone and precipitating by pouring into 150.0 g ice-water yielding pale yellow crystals.
Reaction SMILES: [IH:1].CS[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1.O.[NH2:11][NH2:12]>C(O)C>[IH:1].[NH:11]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1)[NH2:12]
Reactant: CSC1=NCCCC1
Reactant: NN
Agent: I
Solvent: O
Solvent: CCO
Product: NNC1=NCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 6.43 g portion of 3,4,5,6-tetrahydro-2-(methylthio)-pyridine, hydroiodide was added to an ice-cold solution of 1.25 ml of hydrazine hydrate in 35 ml of ethanol. The suspension was stirred at ice bath temperature for 30 minutes, then the solid was collected, washed with ethanol and ether and dried, giving 3.5 g of 2-hydrazino-3,4,5,6-tetrahydropyridine, hydroiodide, which was converted to the monohydronitrate by treatment with silver nitrate in water.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14]C(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: COC(Cl)Cl
Reactant: COc1cccc2cc(C)oc12
Solvent: ClCCl
Product: COc1ccc(C=O)c2cc(C)oc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
To a well stirred solution of 7-methoxy-2-methylbenzo[b]furan (from step 2) (6.5 g, 40.07 mmol) in DCM (70.0 mL) was added stannous chloride (17.7 g, 68.26 mmol) followed by slow addition of 1,1-dichloromethyl methyl ether (4.6 g, 40.07 mmol) at −10-0° C. and stirred for 1-2 hrs. Ice cold water (100 mL) was added with vigorous stirring, the organic layer was separated and washed with water (2×50 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (7.0 g). The crude product was purified by silica gel column using petroleum ether: ethyl acetate (9:1) as an eluent to afford the product as pale yellow oil (2.3 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.CCOC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Sc2ccccn2)nc1
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 2-mercaptopyridine (6.39 g, 57.4 mmol) in DMF (100 mL) was added NaH (60% dispersion in oil, 2.29 g, 57.2 mmol) in portions and the mixture was stirred for 15 min. 6-Bromo-3-pyridine carboxaldehyde (9.28 g, 49.9 mmol) was added and the resultant mixture was stirred for 1 h. Water was added followed by the addition of EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by flash column chromatography (eluents: 20% EtOAc in hexanes and 30% EtOAc in hexanes). Evaporation of the appropriate fractions gave a white solid, which was further purified by recrystallization from diethyl ether to give the product as a white solid (9.66 g, 90% yield). 1H NMR (CDCl3) δ 10.00 (s, 1H), 8.89-8.84 (m, 1H), 8.67-8.64 (m, 1H), 8.01 (dd, J=2.2, 8.9 Hz, 1H), 7.76 (dt, J=2.2, 8.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.35-7.29 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][CH2:23][C@@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC[C@@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-2-amino-1-phenylethanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>C(Cl)Cl>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:21]
Reactant: CCOC(=O)c1csc(CO)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(hydroxymethyl)-thiazole-4-carboxylate 33 (38.4 g) and pyridine (41 mL) in 100 mL of CH2Cl2 is slowly added 2,2,2-trichloroethyl chloroformate (32 mL, 0.23 mol) at 0° C. After the resulting mixture is stirred for 30 minutes, the reaction is quenched by the addition of 10% aq NaHCO3. The organic layer is separated, and the aqueous layer is extracted with CH2Cl2. The combined organic extracts are washed with 2 N HCl, 10% aq NaHCO3, and brine, dried (Na2SO4), and concentrated. The residue is then recrystallized in ethanol (50 mL) to yield a light yellow solid. The mother liquor is concentrated and chromatographed to afford an additional amount of product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH2:28](O)C>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCO
Reactant: C1CCNCC1
Product: O=C1SC(=Cc2ccccn2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.54 g (5.0 mmol) of pyridine-2-a!aldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 6 hours. To the reaction mixture, 0.02 ml (0.2 mmol) of piperidine was added, followed by refluxing for 12 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.483 g (72.2%, light yellow crystal) of the desired product.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[F:26][C:27]1[CH:28]=[C:29]([NH:37][CH:38]=[C:39]([C:45]([O:47]CC)=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34].C([O-])(=O)CC([O-])=O.FC1C(OC)=C(OC)C=C2C=1C(=O)C(C(OCC)=O)=CN2>CCCCCC>[F:26][C:27]1[CH:28]=[C:29]2[C:30]([C:45](=[O:47])[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][NH:37]2)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34]
Reactant: CCOC(=O)C(=CNc1cc(F)c(OC)c(OC)c1)C(=O)OCC
Agent: CCOC(=O)c1c[nH]c2cc(OC)c(OC)c(F)c2c1=O
Agent: O=C([O-])CC(=O)[O-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(F)c(OC)c(OC)c2c1=O
Temperature: 250 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To Dowtherm (150 mL) heated at 250° C. was added diethyl 2-(((3-fluoro-4,5-dimethoxyphenyl)amino)methylene)malonate (30 g, 87 mmol). The mixture was stirred at 250° C. for 30 min. LCMS indicated completion of the reaction. The reaction mixture was allowed to cool a bit and was then added to cold hexane, the precipitates were collected by filtration, washed with hexane and then allowed to dry in the air. Similar scale reactions were repeated several times. From a total amount of the malonate (148 g, 434 mmol), a mixture of ethyl 5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate and ethyl 7-fluoro-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained as brown solid without further purification (103 g, 349 mmol, 80% yield). LCMS: (M+H)+: 296.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[N:17][CH:18]=2)[N:3]=1.CCN([CH2:27][CH3:28])CC.C[N:30]([CH:32]=[O:33])C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:16]1[N:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]#[C:19][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][C:27]=3[CH2:28][C:32]([NH2:30])=[O:33])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cn1
Temperature: 120 °C
Yield: 79 %

Procedure:
1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)ethanone (A141) (0.313 g, 0.988 mmol) and I8 (0.189 g, 1.18 mmol) were added to a solution of PdCl2(PPh3)2 (0.017 g, 0.025 mmol), CuI (0.010 g, 0.049 mmol) and PPh3 (0.013 g, 0.049 mmol) in DMF (3 mL) and Et3N (0.552 mL, 3.95 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes. The reaction mixture was diluted with water and then filtered. The solid was washed with water and dried before being suspended in EtOAc, ultra sonicated for 20 seconds, filtered and dried to give the title compound (A142) as a light brown solid (0.347 g, 79%). LCMS-B: rt=6.78 min; m/z=440 [M+H]+.
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].CO.[OH-].[Na+:35]>CC(O)C>[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+:35]
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: CO
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
Yield: 30.1 %

Procedure:
In a 100 ml flask were placed Fluvastatin methyl ester (3.0 g), MeOH (20 ml) and NaOH (0.29 g). After a clear solution was obtained propan-2-ol (80 ml) was added and the solution was stirred at room temperature over night. A little precipitation occurred, propan-2-ol (40 ml) was added and the solution was stirred at room temperature for another night. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried at 50° C. in a vacuum oven for 22.5 h to obtain 0.92 g of fluvastatin sodium crystal Form LXV.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ccc(-c2ccc(C(=O)C3CC=CC3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(-c2ccc(O)cc2)cc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of (3-cyclopenten-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)-methanone (42 g) in methylene dichloride (400 ml) was added over 1 h. to a solution of boron tribromide (30 ml) in methylene dichloride (200 ml) at -70° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm up slowly at room temperature and was stirred overnight. The solution was poured into water and the mixture was stirred for 10 min. The organic layer was washed twice with water, once with brine and dried (MgSO4). Removal of the solvent gave (3-cyclopenten-1-yl) (4'-hydroxy-[1,1'-biphenyl]-4-yl)-methanone (38.5 g). A small sample recrystallised from ethanol had m.p. 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH2:34]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:34][CH:33]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: OCC=C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCC=C(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
308 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 348 mg (1.65 mmol) of 3,3-diphenyl-2-propene-1-ol, 260 mg (1.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 26 mg (0.21 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:33][N:34]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:34][CH3:33])=[O:26])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC)s3)C[C@H]2OC)nc1Cl
Yield: 75.6 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (40 mg, 0.09 mmol), methylamine hydrochloride (7 mg, 0.11 mmol), WSC hydrochloride (59 mg, 0.31 mmol), HOBT (21 mg, 0.15 mmol), diisopropylethylamine (0.020 mL, 0.11 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 30 mg of the title compound as a white solid (73%).