Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[N:20]1([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8](=[O:16])[C:7]3=[CH:17][S:18][CH:19]=[C:6]23)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2)c2cscc21
Yield: 90.3 %

Procedure:
1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 3.7 g of piperidine and 15 ml of dioxane are stirred at 80° C. for 1 hour; the resulting mixture is concentrated in vacuo, and the obtained residue is recrystallized from isopropanol/water. 2.0 g of 9,10-dihydro-4-(piperidinoacetyl)-4H-thieno[3,4-b][1,5]benzodiazepin-10-one are thus obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][C:24]([OH:26])=[O:25])=[CH:13][CH:12]=2)[C:8]2[CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[Br:33]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:33][CH:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][C:24]([OH:26])=[O:25])=[CH:15][CH:16]=2)[C:8]2[CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C=O)cc2n1Cc1ccc(-c2ccccc2CC(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1nc2ccc(C=O)cc2n1Cc1ccc(-c2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a mixture 0.55 g of 2-butyl-1-[(2'-carboxymethylbiphenyl-4-yl)methyl]benzimidazole-6-carboxaldehyde in 30 mL of carbon tetrachloride was added 0.23 g of N-bromosuccinimide and a catalytic amount of azobisisobutyronitrile. The reaction was stirred at room temperature until the reaction went to completion and then concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried and concentrated. Flash column chromatography (silica gel; 1:1 hexane/ethyl acetate to 1:3 hexane/ethyl acetate) afforded 0.45 g of the product as a thick clear oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([F:18])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:15][C:10]1[CH:9]=[C:8]([C:3]([F:18])([C:2]([F:1])([F:19])[F:20])[C:4]([F:5])([F:6])[F:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Yield: 78.1 %

Procedure:
A mixture of 2.95 g of 4-(heptafluoroisopropyl)-2-nitrophenol, 20 ml of ethyl acetate and 0.30 g of 5% palladium on carbon was stirred in a hydrogen atmosphere at room temperature for four hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.08 g of 2-amino-4-(heptafluoroisopropyl)phenol.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:7]([C:10](=[N:16][O:17][CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)C(C)=O
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
6.1 kg of potassium carbonate were added at 20°-25° C. to a mixture of 4.69 kg of ethyl 2-acetyl-2-hydroxyiminoacetate (equal to 4.21 kg of pure product) in 21 liters of anhydrous pure acetone and after stirring the suspension for 10 minutes, 3.72 kg of dimethyl sulfate were added at 20°-25° C. The mixture was poured into 126 liters of demineralized water and was extracted 4 times with 5 liters and then with 2 liters of methylene chloride. The combined extracts were washed with 10 liters of demineralized water, were dried and vacuum filtered. The filter was rinsed with 2 liters of methylene chloride and the filtrate was evaporated to dryness under reduced pressure to obtain 4.88 kg of ethyl 2-acetyl-2-methoxyiminoacetate with an RF=0.7 (thin layer chromatography-9-1 methylene chloride-ethyl acetate eluant). The product was identical to that product in Step A of Example 3.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)[C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:19]1[CH:20]=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=1)[C:8]([NH:10][NH2:11])=[O:9]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (30 mL) was added to tert-butyl N′-[6-chloro-2-(3,4,5-trifluorophenyl)hexanoyl]hydrazinecarboxylate synthesized according to the method described in Examples 112 and 113 (ESI-MS; m/z 417 [M++Na], 2.08 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (1.81 g). IPEA (1.5 mL), (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid (450 mg) and BOPCl (0.53 g) were added to a solution of 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (612 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the resulting residue in phosphorus oxychloride (8 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 430 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)CCC>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Reaction time: 3 h

Procedure:
A mixture of 24.3 g. (0.1 mole) of 4-(p-fluorobenzoyl)-piperidine hydrochloride, 12.5 g. (0.125 mole) of 3-chloropropanol and 42.0 g. (0.5 mole) of sodium bicarbonate in 500 ml. of n-butanol was stirred at reflux for 15 hours. An additional 3.0 g. (0.025 mole) of 3-chloropropanol was added after thin layer chromatography showed incomplete reaction and the reaction was continued for 3 hours. The cooled reaction mixture was filtered, the filtrate concentrated at reduced pressure and the residual oil crystallized by trituration in isopropyl ether. The tan solid weighed 23 g. (87%) and melted at 107°-109° C. Recrystallization from benzene-isooctane gave 17.7 g. of material melting at 111°-112° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12](OCC)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]([OH:13])=[CH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cccc(Cl)c1
Reactant: Cc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(=Cc1ccncn1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 4-methylpyrimidine (4.56 mL 50.1 mmol) and ethyl 3-chlorobenzoate (7.90 mL 50.1 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)amide (100 mL, 1.0M in tetrahydrofuran, 100 mmol) dropwise over 30 minutes. The resultant mixture was warmed to room temperature and stirred 16 hours. The reaction mixture was concentrated in vacuo. The resultant oil was diluted with methanol. Upon standing, a solid precipitated, which was collected on a filter to provide 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (11.2 g, 93%) as a yellow solid. Rf 0.31 (3:1 hexanes:ethyl acetate); 1H NMR (d6-DMSO) δ 8.37 (s, 1H), 7.98 (m, 1H), 7.81–7.76 (m, 2H), 7.38–7.32 (m, 2H), 6.71 (br, 1H), 5.65 (s, 1H); MS m/z 233 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)[OH:32]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:34]4[CH2:35][CH2:36][CH2:37][C@@H:33]4[C@@H:31]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Reactant: OC(c1ccccn1)C1CCCN1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC[C@@H]3[C@@H](O)c3ccccn3)sc21

Procedure:
Analogous to the procedures described in Example 2, N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1) is treated with pyridin-2-yl(pyrrolidin-2-yl)methanol (Preparation 3) to afford the title compound. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.62, 8.70, 8.50, 7.78, 7.54, 7.41-7.33, 7.30, 7.24, 5.13, 4.67, 4.55, 4.04, 3.96, 3.73, 3.15-3.10, 2.94-2.86, 2.33-2.27, 1.84-1.77, 1.64-1.46; MS (ESI+) m/z 523 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])/[CH:10]=[C:11](\[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)/[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](#[N:25])[CH2:23][CH3:24]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:8][C:9]([C:10]1[C:22]([CH2:23][CH3:24])=[N:25][N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC#N
Reactant: C/C(=C/C(=O)OCc1ccccc1)Nc1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccc(F)cc2)c(C)c1C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
According to AVV A, (Z-3-(4-fluorophenylamino)-but-2-enoic acid benzylester (285.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After purification by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), the product was obtained in the form of a yellow oil (283.0 mg, 0.84 mmol, 84%).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>Br>[ClH:1].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2CCN(CCCc3ccccc3)CC2)c1
Agent: Br
Agent: Cl
Product: Oc1cccc(C2CCN(CCCc3ccccc3)CC2)c1

Procedure:
) 6.7 g 4-(3-methoxyphenyl)-1-(3-phenylpropyl)piperidine hydrochloride was refluxed with 80 ml 48% HBr for an hour. The products were cooled, the aqueous layer decanted and concentrated in vacuo. The resulting residue and insolubles were treated with excess saturated sodium bicarbonate and extracted with methylene chloride twice. The methylene chloride layer was washed twice with saturated bicarbonate and dried over magnesium sulfate and concentrated in vacuo. The resulting viscous oil was taken up in 50 ml acetone and HCl was added, resulting in precipitation. The precipitate was filtered off affording 8.6 g of crude product. The product was recrystallized from 110 ml absolute ethanol and 50 ml ether, yielding 4-(3-hydroxyphenyl)-1-(3-phenylpropyl)piperidine hydrochloride, melting point 211°-213° C.
Reaction SMILES: C(NC(CC1C=CC(N(C(=O)C(OC(C)(C)C)=O)C2C=CC=CC=2C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)=C(CC)C=1)C(NCCCCC(N[C@@H](CC1C=CC(OC(C)(C)C)=CC=1)C(O)=O)=O)=O)(=O)C.C([O:86][C:87]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=1[N:95]([C:132](=[O:140])[C:133]([O:135]C(C)(C)C)=[O:134])[C:96]1[C:105]2[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=2)[C:99]([CH2:106][C@@H:107]([C:113]([NH:115][CH2:116][CH2:117][CH2:118][CH2:119][C:120]([NH:122][C@H:123]([C:128]([O:130]C)=[O:129])[CH2:124][CH2:125][S:126][CH3:127])=[O:121])=[O:114])[NH:108][C:109]([O:111][CH3:112])=[O:110])=[CH:98][CH:97]=1)=[O:88])(C1C=CC=CC=1)C1C=CC=CC=1>>[C:133]([C:132]([N:95]([C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][C:89]=1[C:87]([OH:88])=[O:86])[C:96]1[C:105]2[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=2)[C:99]([CH2:106][C@@H:107]([C:113]([NH:115][CH2:116][CH2:117][CH2:118][CH2:119][C:120]([NH:122][C@H:123]([C:128]([OH:130])=[O:129])[CH2:124][CH2:125][S:126][CH3:127])=[O:121])=[O:114])[NH:108][C:109]([O:111][CH3:112])=[O:110])=[CH:98][CH:97]=1)=[O:140])([OH:135])=[O:134]
Reactant: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)c2ccccc12)C(=O)NCCCCC(=O)N[C@@H](CCSC)C(=O)OC
Agent: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)O)c2ccccc2C(=O)O)c2ccccc12)C(=O)NCCCCC(=O)N[C@@H](CCSC)C(=O)O

Procedure:
The titled compound was prepared according to the procedure described in Example 1L, substituting the ester from Example 1K with the ester from Example 7L. MS (ESI+) m/e 711 (M+H)+, 1H NMR (300 MHz, DMSO-d6) 1.23-1.64 (m, 4H), 1.71-2.22 (m, 4H), 2.03 (s, 3H), 2.35-2.56 (m, 2H), 2.97-3.59 (m, 7H), 4.00-4.67 (m, 2H), 6.70-7.80 (m, 6H), 7.86 (d, J=6.3 Hz, 1H), 7.92-8.34 (m, 4H), 8.43 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([NH2:10])[CH:4]=1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COc1ccc(O)c(N)c1
Reaction time: 2 h

Procedure:
193.1 g of 7A was mixed with 1400 ml of water. 513 ml of ammonium hydroxide was added. 595 g of powdered sodium dithionite was added in portions over a period of 50 minutes. The resulting mixture was stirred for 2 hours. The solid product was collected and dried under vacuum over P2O5 to give 4-methoxy-2-aminophenol (7B), mp: 134°-136° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21]>CCOCC>[ClH:21].[ClH:21].[N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCCCC2)nc1
Agent: Cl
Solvent: CCOCC
Product: Nc1ccc(N2CCCCC2)nc1
Temperature: 25 °C

Procedure:
The product from Example 144B (1.00 g, 3.62 mmol) was added slowly to 4 M hydrochloric acid (10 mL, 40 mmol) and stirred at room temperature. After stirring overnight, ether was added and the solid filtered. Dried in vacuum oven to a white solid (0.817 g; 84%). 1H NMR (400 MHz, methanol-d4) δ 1.77 (s, 6H), 3.65 (s, 4H), 7.41 (d, J=9.8 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.79 (dd, J=2.7, 9.8 Hz, 1H).
Reaction SMILES: C[C:2]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10]C(=O)OCC3C=CC=CC=3)[CH2:8][C:4]=2[CH:3]=1>[Pd]>[O:6]1[CH:7]([CH2:9][NH2:10])[CH2:8][C:4]2[CH:3]=[CH:2][C:25]3[CH2:24][CH2:23][CH2:22][C:21]=3[C:5]1=2
Reactant: Cc1cc2c(c3c1CCC3)OC(CNC(=O)OCc1ccccc1)C2
Agent: [Pd]
Product: NCC1Cc2ccc3c(c2O1)CCC3
Yield: 110.6 %

Procedure:
Treatment of (−)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (1.39 g, 4.12 mmol) with palladium on carbon (10 wt. %, 0.139 g) generally according to the procedure described for Example 2 afforded 0.862 g (87%) of (−)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. [α]D25=+48.6 (c 10.0 in methanol); mp>220° C.; Anal. calcd. for C13H17NOHCl.0.1H2O: C, 64.64; H, 7.59; N, 5.80. Found: C, 64.62; H, 7.66; N, 5.77.
Reaction SMILES: C(P(=O)C(C)(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1.[CH3:28][NH:29][CH:30]=[O:31].CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:26][C:24]1[CH:25]=[C:20]([N:29]([CH3:28])[CH:30]=[O:31])[CH:21]=[C:22]([CH3:27])[CH:23]=1
Reactant: CNC=O
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: CC(C)(C)[PH](=O)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), di-tert-butylphosphine oxide (16.5 mg, 0.102 mmol), K3PO4 (430 mg, 2.03 mmol), evacuated, backfilled with Ar. 5-Iodo-m-xylene (145 μL, 1.00 mmol), N-methylformamide (72 μL, 1.23 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL) and ethyl acetate (2 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide a 46% yield of N-(3,5-dimethylphenyl)-N-methylformamide.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19](O)=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[NH2:31][OH:32].O.CO>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH:2]([CH3:3])[CH3:1])[C:12]=2/[CH:13]=[CH:14]/[C@@H:15]([OH:23])[CH2:16][C@@H:17]([OH:22])[CH2:18][C:19]([NH:31][OH:32])=[O:20])=[CH:25][CH:26]=1
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Reactant: NO
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)NO)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of fluvastatin (100 mg, 0.25 mmol, in the lactone form) in THF (1 mL) was added 50% hydroxylamine in H2O (0.12 mL, 1.91 mmol). The mixture was stirred at ambient temperature for 16 h, and concentrated under reduced pressure. The residue was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; CH2Cl2/MeOH/NEt3 (89:1:9 to 5:5:1)) to give fluva-HA (30 mg, 30%). C24H27FN2O4; white foam; TLC (CH2C1-2/MeOH (9:1)) Rf=0.13; 1H NMR (CDCl3, 400 MHz) δ 7.57-7.59 (1H, d, J=8.4 Hz), 7.41-7.44 (3H, m), 7.13-7.19 (3H, m), 6.99-7.03 (1H, t), 6.69-6.73 (1H, d, J=14.8 Hz), 5.74-5.79 (1H, dd, J=16.4 Hz), 4.95 (1H, br s), 4.39-4.42 (1H, m), 4.21-4.24 (1H, m), 2.24-2.25 (2H, m), 1.64-1.73 (6H, m), 1.32-1.36 (2H, m) ppm; ESI-HRMS calcd for C24H28FN2O4: 427.2033. found: m/z 427.2034 [M+H]+.
Reaction SMILES: C(OP([CH:9]([C:21]#[N:22])[CH:10]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH2:11][CH2:12][CH:13]=[CH2:14])(=O)OCC)C.[N+:23]([C:26]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][C:27]=1[CH:28]=O)([O-])=O.[Cl-].[NH4+]>C1COCC1>[O:34]([C:31]1[CH:30]=[C:27]2[C:26](=[CH:33][CH:32]=1)[N:23]=[C:21]([NH2:22])[C:9]([CH:10]([CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:28]2)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the oil isolated in Step B (23.28 g, 70.7 mmol) in THF (100 mL) at −78° C., LHDMS (1.0 M, 84.8 mL, 84.8 mmol) was added slowly. The reaction mixture was then stirred at room temperature for 1 hour. A solution of 2-nitro-5-phenoxybenzaldehyde (20.63 g, 75.5 mmol) in THF (100 mL) was added. The reaction mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (200 mL) was added. The reaction mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with brine and dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a colorless oil which was a mixture of cis-[2-(2-nitro-5-phenoxy-benzylidene)-3-(tetrahydro-pyran-4-yl)-hept-6-enenitrile] and trans-[2-(2-nitro-5-phenoxy-benzylidene)-3-(tetrahydro-pyran-4-yl)-hept-6-enenitrile].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[NH2:31][C:32]1[C:33]([CH3:38])=[CH:34][CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]1([CH3:38])[C:32]([NH:31][C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Nc2ccccc2C)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.06 g, 0.11 mmol), o-toluidine (0.061 ml, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.005 g, 0.005 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (0.011 g, 0.02 mmol) and potassium carbonate (0.063 g, 0.46 mmol) in DMF (1.5 ml) was degassed and heated in the microwave at 150° C. for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water (×2). The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 10-90% EtOAc in hexane as gradient to afford tert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.030 g, 0.06 mmol, 52%). LCMS (1) Rt: 2.63 min; m/z (ES+) 507.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([O:13]C)=[O:12].[Li+].[OH-].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc2cc[nH]c2cc1Cl
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc[nH]c2cc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A solution of Example 58B (1.17 g, approximately 5.6 mmol) in THF (50 mL) was treated with 1M LiOH (56 mL, 56 mmol), heated at 50° C., stirred for 18 hours, treated with 1M NaOH, washed with diethyl ether, acidified with HCl, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified on silica gel with 50% ethyl acetate/hexanes to provide of 660 mg of the desired product.