Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C:23]23[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][O:16][CH2:15][C@H:14]13>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:17][O:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1CCC23O[C@H]2COC[C@@H]3C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O[C@]12CCCC[C@@H]1COC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoroaniline (0.721 g, 6.48 mmol) in CH2Cl2 (6 mL) at 0° C. was added trimethylaluminum (2M in toluene, 3.24 mL) dropwise. The mixture was warmed to rt for 30 min. A mixture of both cis and trans octahydrooxireno[d]isochromene (0.200 g, 1.30 mmol) in CH2Cl2 2 mL+0.5 mL rinse) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). The mixture was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.94 (1, 2H, J=8.6 Hz), 6.78 (dd, 2H, J=4.2 Hz, 8.8 Hz), 4.14 (dd, 1H, J=1.5 Hz, 12.0 Hz), 3.64 (d, 1H, J=11.5 Hz), 3.56 (dd, 1H, J=4.6 Hz, 11.0), 3.48 (t, 1H, J=11.5 Hz), 3.10 (s, 1H), 1.17-2.00 (m, 9H). HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1554
Reaction SMILES: [C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:16][CH:15]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCOc1ccc(C=O)cc1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)C(=O)c1ccccc1

Procedure:
A mixture of 4-[2-(N-benzoyl-N-methylamino)ethoxy]benzaldehyde (3.94 g), 2,4-thiazolidinedione (1.79 g), benzoic acid (0.2 g) and piperidine (0.2 ml) were heated at reflux in toluene (250 ml) in a Dean and Stark apparatus. After 5 hours at reflux the mixture was allowed to cool and crystallise overnight. The title compound, mp 178-180° C., was filtered off, washed with cold toluene and dried under vacuum.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.CC1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N+:10]=1[O-].[OH-].[Na+].ClCCl>O>[CH3:15][C:12]1[CH:13]=[CH:14][C:6]([CH2:5][OH:7])=[N:10][CH:11]=1
Reactant: Cc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CO)nc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To acetic anhydride (1.61 L) at 90° C. was added 2,5-dimethyl-pyridine 1-oxide (1000 g) dropwise over 3 hours, maintaining a temperature between 90-100° C. The reaction was stirred at 90° C. for 1.5 hours, and then cooled with stirring overnight. The mixture was slowly poured into aqueous 25% sodium hydroxide (3 L) over 4 hours, and then dichloromethane (8 L) and water (8 L) were added, and the mixture was allowed to separate for 2 days. The aqueous layer was separated and extracted separately with dichloromethane and ethyl acetate, and the combined organic layers were concentrated to dryness. The crude material was applied to the top of a pad of silica (˜1 kg) and eluted with ethyl acetate until no product was observed in the eluant. The filtrate was concentrated under vacuum to give the desired product (320 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 195 mg (0.325 mmol) of (2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 26 mg (0.649 mmol) of sodium hydroxide in 2 ml of methanol and 2 ml of tetrahydrofuran is left to stir at 0° C. for 18 hours. The reaction mixture is then concentrated, taken up in methylene chloride and washed with water and brine. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (800:50:1). The title compound ##STR66## is obtained (157 mg, 96%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =503,505.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[F:30][C:31]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:32]=1[NH2:43].COCC(O)C>>[F:30][C:31]1[CH:36]=[C:35]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[CH:34]=[CH:33][C:32]=1[NH:43][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(N2CCOCC2)cc1F
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3F)nn12
Yield: 20 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.250 mL, 0.00144 mol) and 2-Fluoro-4-morpholin-4-yl-phenylamine (0.171 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 0.00512 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 36.52 mg of (2-Fluoro-4-morpholin-4-yl-phenyl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilized powder. (M+H)=420.1. 1H NMR (400 MHz, DMSO, d6) δ 8.90 (s, 1H), 8.48 (s, 1H), 7.84 (d, 1H, J=7.56 Hz), 7.56 (t, 1H, J=9.00 Hz), 7.38 (m, 1H), 7.14 (m, 1H), 7.01 (m, 2H), 6.88 (m, 2H), 6.67 (m, 1H), 3.78 (s, 3H), 3.74 (m, 4H), 3.09 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:21]([C:33]([F:35])([F:34])[F:36])[CH:20]=2)=[O:17])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: CN1CCN(Cc2ccc(NC(=O)c3cccc(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1cnc2cccnn12
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 519 m/z (M+H).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=1>O1CCCC1>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[CH:7]=1
Reactant: CC(=O)c1cc(C)on1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 50 mL, 25 mmol) maintained under nitrogen below 0° C. was added a solution of 1-(5-methyl-1,2-oxazol-3-yl)ethan-1-one (2.5 g, 19.98 mmol) in tetrahydrofuran (20 mL) dropwise over 5 min. The resulting solution was warmed to room temperature and then stirred for a further 3 hr. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) then extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with brine (200 mL), dried with anhydrous sodium sulphate and concentrated in vacuo. The residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:4) afforded the title compound (2.3 g, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 6.12 (s, 1H), 3.47 (s, 1H), 2.63 (s, 1H), 2.42 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1cc(Oc2ccccc2Br)ccn1
Product: Nc1cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ccn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)pyridin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H16FN5O, 373.13; m/z found, 374.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 7.77 (d, J=6.3, 1H), 7.65-7.48 (m, 3H), 7.45-7.32 (m, 3H), 7.25 (d, J=8.0, 1H), 6.88 (s, 2H), 6.52 (s, 2H), 6.23 (dd, J=6.3, 2.2, 1H), 5.87 (d, J=2.2, 1H).
Reaction SMILES: [CH2:1]([N:7]1[C:11](=O)[C:10]2=CC=CC=[C:9]2[C:8]1=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C=O.[NH:20]1CCC[CH2:21]1.O.NN>>[N:7]1([CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:21][NH2:20])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Reactant: C1CCNC1
Agent: C=O
Agent: NN
Solvent: O
Product: NCCCCC#CCN1CCCC1

Procedure:
In a manner similar to Description 1 (iii) and (iv), reaction of N-5-hexynylphthalimide, paraformaldehyde and pyrrolidine, followed by treatment with hydrazine hydrate gives 7-pyrrolidinohept-5-ynylamine.
Reaction SMILES: [C:1]1([C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)(=[O:12])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].O.C(O)C>[C:1]1([C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)(=[O:12])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(S(=O)(=O)NC(=O)c2ccccc2)c1
Yield: 90 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(phenylcarbonylaminosulphonyl)-3-nitrobenzene (5.3 g, 17.3 mmol), 10% palladium on carbon (0.5 g, 9% (w/w)) in water (3 ml) and ethanol (100 ml), the title compound (4.3 g, 90%) was afforded as a yellow solid. mp 160°-162° C. 1H NMR (360 MHz, D6 -DMSO) δ 6.81 (1H, m), 7.07 (1H, m), 7.22 (2H, m), 7.48 (2H, m), 7.60 (1H, dd, J=7.4 and 7.4 Hz), 7.87 (2H, m).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].BrC(C)(C)C([NH2:24])=O>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[NH2:24][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)(Br)C(N)=O
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Product: Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
To a solution of 5-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 7:3 EtOAc/hexane to obtain 5-aminoquinoline as a brown solid (90 mg, 0.62 mmol, 16.8% yield).: mp 98-100° C. (lit. 108-109° C., Akita, Y., et. al., Synthesis, 1977, 792); 1H NMR (300 MHz, CDCl3) δ8.89 (dd, 1 H, J=4.13, 2.06 Hz), 8.18 (dd, 1 H, J=8.49, 0.93), 7.60-7.48 (om's, 2 H), 7.35 (dd, 1 H, J=8.56, 4.26), 6.83 (dd, 1 H, J=7.13, 1.31), 4.21 (br s, 2 H, N--H2); 13C NMR (75 MHz, CDCl3) δ150.2, 149.1, 142.2, 130.0, 129.5, 120.1, 119.6, 118.7, 110.0; MS (CI/CH4) 145.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN1C(=O)CCC1.O>[C:29]([Si:26]([O:25][CH2:24][CH2:23][O:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([CH3:9])=[C:7]([F:8])[C:2]=1[F:1])([CH3:28])[CH3:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1c([N+](=O)[O-])cc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c([N+](=O)[O-])cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c1F
Temperature: 100 °C
Yield: 61.9 %

Procedure:
To a solution of 2,3-difluoro-4-methyl-5-nitro-phenol (1.02 g, 5.39 mmol) in NMP (10 ml) was added cesium carbonate (2.28 g, 7.01 mmol), sodium iodide (0.807 g, 5.39 mmol) and 2-bromoethoxy tertbutyldimethylsilane (1.5 ml, 7.01 mmol). The mixture was heated at 100° C. for one hour, then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 9:1) gave 1.16 g (62%) of tert-butyl-[2-(2,3-difluoro-4-methyl-5-nitro-phenoxy)-ethoxy]-dimethyl-silane as a tan solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH2:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: C1COCCN1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 83 %

Procedure:
Morpholine (2.152 mL, 24.71 mmol) was added to a stirred suspension of 2-amino-4-nitrobenzoic acid (1.5 g, 8.24 mmol) and HATU (3.44 g, 9.05 mmol) in acetonitrile (15 mL) at room temperature. After 1 h at room temperature, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (100 mL). The EtOAc layer was washed with saturated NH4Cl (10 mL) and brine (10 mL), dried (MgSO4), and concentrated. The resulting syrup was triturated with hot CH2Cl2 and a yellow solid precipitated out. The solid was washed with CH2Cl2 and collected by filtration (1.7195 g, 83% yield). LCMS: (M+H)+=252.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (1H, d, J=2.26 Hz), 7.35 (1H, dd, J=8.28, 2.26 Hz), 7.24 (1 H, d, J=8.53 Hz), 5.86 (2H, s), 3.60 (8H, br. s.).
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[N:31][OH:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>O.O1CCCC1.CO>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH:31][OH:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(C=NO)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(CNO)cc2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Hydrochloric acid (4 N, in dioxane, 10 mL) was added dropwise into a mixture of 4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehyde oxime (1.5 g, 3.56 mmol), sodium cyanoborohydride (1.1 g, 17.81 mmol), methyl alcohol (100 mL), and tetrahydrofuran (100 mL). The reaction mixture was stirred for 1 hour poured into water, basified with sodium hydroxide (2 N), and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (EtOAc/MeOH 20:1) gave an off-white solid (1.21 g, 80% yield); MS m/e 424 (M+);
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]>C1COCC1>[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: C1CCOC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 39 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in THF (30 ml) and the NaOH (1 eq.) was added. After 2.5 h hexanes (60 ml) was added and the slurry stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with hexanes (30 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.2 g (39%) of fluvastatin sodium Form CIV.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: COc1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1ccccc1OCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C19H22O6 [M+Na]+: 369.4.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CO
Reactant: O=S(Cl)Cl
Product: Cc1ncccc1CCl

Procedure:
1.00 g (8.12 mmol) 3-(hydroxymethyl)-2-methylpyridine are initially introduced into the reaction vessel and 5.9 ml (81.2 mmol) thionyl chloride are slowly added at 0° C. The mixture is stirred under reflux for 3 h. It is concentrated, saturated sodium bicarbonate solution is added to the residue and the mixture is extracted several times with diethyl ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Ca+2].[OH-].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.CCCCCC>O1CCOCC1.O>[OH:13][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[N:9]=[C:10]([CH3:14])[C:11]=1[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2nc(C)cc2O)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2O)cc1
Temperature: 110 °C

Procedure:
A solution containing 1.0 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazol-3-ol in 30 ml of dioxan was treated with 679 mg of calcium hydroxide and 800 μl of benzoyl chloride, then heated at 110° C. for 2 h. To the mixture was added 20 drops of water and the mixture heated for a further 2 h. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane/10% citric acid. The organic phase was washed with brine, then dried over anhydrous magnesium sulphate, filtered and evaporated to give yellow oil. The oil was purified twice by flash chromatography on silica gel, initially using methanol/dichloromethane (1:49) to give a red solid, then ethyl acetate/hexane (1:1 to 2:1) for the elutions to give 400 mg of [5-hydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow gum. Mass spectrum (ES) m/z 323 [M+H]+.
Reaction SMILES: C[N:2]([CH3:22])[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC(C(N)=O)[C:25]([NH2:27])=[O:26]>CC(O)=O>[NH2:27][C:25]([C:22]1[NH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)=[O:26]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)C(N)C(N)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A 50 mL round bottomed flask was charged with of ethyl 3-(dimethylamino)-2-(3-fluoro-4-nitrobenzoyl)acrylate (51.74 g, 166.75 mmol) and 2-aminomalonamide (23.4 mg, 200 mmol) and AcOH (1 L). The reaction mixture was heated to 80° C. over night. The starting material appeared consumed by TLC. The AcOH was removed under reduced pressure and TFA (300 mL) was added. The mixture was heated over night at 60° C. The reaction was cooled to room temperature and the TEA was removed under reduced pressure. The orange oil was treated with saturated aqueous NaHCO3 (1 L), then solid NaHCO3 was added until the solution was neutral. The solids were filtered and placed in a 1 L erlenmeyer flask. The solids were washed with H2O (3×1 L) and the water was decanted off through the filter. On the last washing the solids were poured onto the filter and allowed to air dry. The solids were once again removed from the filter and washed with Et2O (4×500 mL). The Et2O was decanted off through the filter and on the final washing the solids were transferred to the filter. An addition portion of Et2O (200 mL) was used to wash the flask and the filter cake. The desired product was dried in a vacuum oven at 40° C. to provide a light tan solid (36.8 g, 114.5 mmol, 69% yield). 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 8.07 (app t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (dd, J=12.6, 1.6 Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (br s, 1H), 6.72 (br s, 1H), 4.01 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H); LCMS* RT=4.45 min; MS {M−H]+=320.1.