Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[O:9])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCNC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(3-aminoprop-1-yloxy)phenyl]benzamide (422 mg) and triethylamine (130 mg) in dichloromethane (10 ml) was added phenyl chloroformate (201 mg) and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and then the organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 1% methanol in chloroform) to give 4-nitro-N-methyl-N-[2-(3-phenoxycarbonylaminoprop-1-yloxy)phenyl]benzamide (383 mg) as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=3)[CH2:9][CH2:10]2)[C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1cc(N2CCC3(CC2)CO3)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3cc(Cl)ncn3)CC2)C(=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 6-(6-chloropyrimidine-4-yl)-1-oxa-6-azaspiro[2,5]octane (4.00 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.38 g) in tert-butylalcohol (50 ml) was added potassium tert-butoxide (0.57 g), and the mixture was stirred at 80° C. overnight. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (100 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (eluent:ethyl acetate) and crystallized from a mixture of ethyl acetate and diethylether to give colorless crystals of 4-(tert-butoxycarbonyl)-1-[1-(6-chloro-4-pyrimidinyl)-4-hydroxypiperidin-4-ylmethyl]piperazin-2-one (5.51 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]([C:23]#[N:24])=[C:8]([NH2:25])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[NH2:25][C:8]1[N:7]=[C:6]([CH:5]([CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]=1[C:23]#[N:24]
Reactant: CCOC(=O)Cc1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Reaction time: 0.75 h

Procedure:
Ethyl[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]acetate (step 1) (2.00 g, 5.71 mmol) is initially charged in 40 ml of DMF. Sodium hydride (0.37 g, 9.19 mmol) is added and the mixture is stirred for 45 minutes. Methyl iodide (0.40 ml, 6.39 mmol) is then added, the color of the yellow reaction solution turning to orange. After five hours, a further 0.2 ml of methyl iodide is added and the mixture is stirred at room temperature overnight. The mixture is poured into water (50 ml), and an emulsion is formed. The emulsion is extracted three times with ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The mixture is chromatographed by RP-HPLC using an acetonitrile/water gradient. The product is obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[CH2:11][O:10]1)[CH:2]=[CH2:3].[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:19][CH2:18]1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(C)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:16][C@@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:21][CH2:22]1)[CH:2]=[CH2:3].[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:16][C@@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:21][CH2:22]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC1CO1
Reactant: N[C@H]1CC[C@@H](N2CCNC2=O)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CN[C@H]1CC[C@@H](N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 657.6 g of 92% pure o-(allyloxy)phenoxymethyloxirane (U.S. Pat. No. 3,483,221) and 512 g of cis-1-(4-aminocyclohexyl)-2-imidazolidinone is stirred and refluxed for 6 hours in 6,000 ml of isopropanol. To the above reaction mixture, while still hot, is added 162.1 g of fumaric acid. The resulting mixture is allowed to stir at room temperature overnight. The crude product is filtered and washed with 1000 ml of isopropyl alcohol. The thus obtained wet solid is first recrystallized from 5000 ml of isopropyl alcohol and then dried in a vacuum oven at 65° to constant weight to give a white crystalline product, m.p. 154°-155°. Recrystallization of 1781 g of the resulting salt from 9700 ml of anhydrous ethanol yields cis-1-{4-[3-(o-allyloxyphenoxy)-2-hydroxypropylamino]-cyclohexyl}-2-imidazolidinone hemifumarate salt, m.p. 156°-7°, being the cis compound of formula III wherein R3 represents hydrogen and R7 represents allyloxy, as the hemifumarate salt.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@@H:18]([C:20]([F:23])([CH3:22])[CH3:21])[CH3:19])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]([CH3:19])[C:20]([F:23])([CH3:22])[CH3:21])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C#N)c3)cc12)C(C)(C)F
Agent: [Ni]
Solvent: CCO
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C(C)(C)F
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A suspension of (R)-6-(3-cyanophenyl)-4-(3-fluoro-3-methylbutan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 53, 110 mg, 0.301 mmol) and Raney 3201 Nickel (17.67 mg, 0.301 mmol) in ethanol (5 mL) was bubbled with ammonia gas for 3 minutes then stirred under a balloon of hydrogen for 6 hrs. The reaction mixture was filtered and concentrated to yield the title compound (108 mg, 97%). HPLC (condition G): retention time=2.330 minute. LC/MS (M+H)+=370.3. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (1 H, s), 8.01 (1 H, d, J=1.8 Hz), 7.78-7.84 (2 H, m), 7.50 (1 H, t, J=8.0 Hz), 7.35 (1 H, d, J=7.7 Hz), 7.28 (1 H, d, J=1.8 Hz), 4.45-4.61 (1 H, m), 4.18 (2 H, s), 1.52 (3 H, d, J=2.4 Hz), 1.45-1.49 (6 H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[N:24]1([S:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([S:29]([C:32]2[CH:38]=[CH:37][C:35]([NH:36]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(S(=O)(=O)N2CCCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(pyrrolidin-1-ylsulphonyl)-aniline.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[C:30](=[O:31])[C:29]5[C:28]([C:32]#[N:33])=[CH:27][CH:26]=[CH:25][C:24]=5[CH2:23]4)=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[NH2:33][CH2:32][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[C:30](=[O:31])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=4)[N:14]=3)[NH:19][CH:20]=1)[CH2:23]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc(C#N)c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cccc(CN)c5C4=O)c3n2)cc1
Reaction time: 3 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-3-oxo-isoindoline-4-carbonitrile (150 mg, 0.2143 mmol) dissolved in a mixture of DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (55.65 mg, 0.4286 mmol) added then the reaction mixture cooled in an ice bath. NaBH4 (81 mg, 2.143 mmol) added in one portion. Ice bath removed and mixture stirred for 3 h then cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to a black foam. This material deprotected using Method E Step 2 to give the title compound after purification by hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, d), 3.50 (1H, sep), 4.17 (2H, s), 5.50 (2H, s), 7.51-7.53 (1H, m), 7.62-7.65 (3H, m), 8.00 (2H, d), 8.51-8.54 (3H, m), m 9.09 (1H, s) ppm; MS (ES+) 462.0.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C1C=CN=CC=1>[CH2:1]([N:5]([C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)CC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 106.5 %

Procedure:
A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10% palladium on carbon (2.5 g) as catalyst. The reaction mixture was filtered through celite pad and the filtrate was concentrated down to give a white solid (11.46 g, 100%). This material was taken onto next step immediately. To a stirred mixture, under N2 atmosphere, of the aniline (11.46 g, 49 mmol), butryaldehyde (4.43 mL, 49 mmol) in tetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.62 g, 68.6 mmol), and glacial acetic acid (2.82 mL, 49 mmol). The reaction was stirred for two hours. The reaction was quenched with 1N NaOH (50 mL), diluted with water, extracted with ether 3 times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give an oil (5.80 g, 41%). This material was immediately taken onto next step. A solution of the N-butyl aniline (5.80 g, 19.9 mmol) in a 1:1 mixture of perchloric acid and hydrochloric acid (100 mL) was stirred at room temperature for three days. The reaction mixture was poured onto ice and made basic with concentracted ammonium hydroxide, extracted with ether four times, dried over sodium sulfate and concentrated to give a yellow oil. The yellowish oil was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 1-[4-(butylamino)phenyl]-4-piperidineone as an oil (3.84 g, 82%). To a stirred mixture of 1-[4-(butylamino)phenyl]-4-piperidineone (2.46 g, 10 mmol), triethylamine (1.81 mL, 13 mmol), and 4-(dimethylamino)pyridine (DMAP) (catalytic amount) was added ethyl 3-chloro-3-oxopropionate (2.18 g, 13 mmol) dropwise. The reaction was stirred for 18 hours. The reaction mixture was filtered, concentrated in vacuo, taken up in methylene chloride, and washed with saturated sodium bicarbonate two times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give a yellow oil (3.84 g, 68%); MS (ES) m/z: 361.3 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH2:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-:20].[Na+]>O>[NH2:15][C:16]1[C:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:20])=[O:17]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(C(=O)c3ccc(F)cc3)c2N1
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(F)cc1

Procedure:
A mixture of 1.5 g. (0.006 mole) of 7-(4-fluorobenzoyl) indolin-2-one in 50 ml. of 3N sodium hydroxide was refluxed under nitrogen for 45 min. The solution was cooled, diluted with an equal volume of water, filtered, and the filtrate was extracted two times with 50 ml. of ether. The aqueous basic solution was treated dropwise with glacial acetic acid until a heavy yellow precipitate formed. The precipitate was filtered off, washed thoroughly with water and air-dried. The yeild was 1.1 g. (68%); m.p. 136°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[CH3:19][O:20][C:21]1[N:22]=[CH:23][C:24]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:3]=2)=[CH:25][CH:26]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cn1

Procedure:
The title compound was prepared from the product of Example 65A and 2-methoxypyridin-5-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 337.0 (M+H)+, retention time 1.23 minutes.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([O:30][CH2:31]C)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[CH3:31][O:30][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(N3CCOCC3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(N3CCOCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-ethoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester (Step A) by standard hydrolysis procedure C (NaOH). 1H-NMR (CDCl3, 200.15 MHz): δ 9.90 (s, 1H), 7.30 (d, 2H, J=9.1), 7.10 (d, 2H, J=8.4), 6.91 (d, 2H, J=9.1), 6.75 (d, 2H, J=8.8), 4.18–3.90 (m, 9H), 3.43–3.33 (m, 7H), 3.02 (dd, 1H, J=14.3, 4.8), 2.90 (dd, 1H, J=14.3, 7.0), 2.18 (qn, 2H, J=5.9).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]=[CH:5][CH:6]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][C@H:6]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: COC(=O)C=CC(Cc1cn(CC=Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC[C@@H](Cc1cn(CCCc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Yield: 93.4 %

Procedure:
5-[1-(3-Phenyl-allyl)-1H-indol-3-yl]-4-(7-phenyl-heptanoylamino)-pent-2-enoic acid methyl ester (118 mg, 0.215 mmol) in MeOH (60 mL) was hydrogenated at 15 psi for 15 minutes using 10% Pd/C. The solution was filtered and the solvent removed to afford the title compound (111 mg, 93%). ESMS 553 (M+H+), mp 79.4-81° C. 1H NMR (CDCl3) δ 7.62 (1H, d, J=7.74 Hz). 7.31-7.07 (13H, m), 6.93 (1H, s), 5.43 (1H, d, J=8.37 Hz), 4.32-4.22 (1H, m), 4.08 (2H, t, J=6.96 Hz), 3.62 (3H, s), 2.97 (1H, dd, J=5.37, 14.43 Hz), 2.91 (1H, dd, J=6.54, 14.43 Hz), 2.62 (2H, t, J=7.62 Hz), 2.57 (2 h, t, J=7.73 Hz), 2.41-2.10 (4H, m), 2.06 (2H, t, J=7.62 Hz), 1.97-1.26 (10H, m). 13C NMR (CDCl3) δ 174.3, 172.9, 142.7, 140.9, 136.2, 132.1, 128.5, 128.4, 128.3, 128.2, 126.4, 126.1, 125.6, 121.6, 119.1, 119.0, 110.2, 109.4, 51.6, 49.5, 45.5, 36.9, 35.8, 32.9, 31.5, 31.2, 31.0, 30.6, 29.1, 28.9, 25.6. ISMS: 553 (M+H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=4)[CH2:21]3)[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:53]CC1>>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH2:29][CH:28]([OH:53])[C:27](=[O:30])[CH:26]=4)[CH2:21]3)[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)C(O)C3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 20 mg (0.07 mmol) of 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (Example 7) and 170 mg (0.39 mmol) MoOPH in ˜2 mL dry THF under nitrogen atmosphere at −78° C. was added ×0.076 mL (0.15 mmol) of 2.0 M solution of KHMDS. The resulting mixture was stirred at −78° C. for 2 hr then quenched by the addition of sat. aq. NH4Cl. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over drying agent and filtered. The residue was purified by prep TLC eluting with CHCl3/2N NH3 in MeOH (9/1) to afford the title compound as a mixture of diastereomers. 1H-NMR (CDCl3): δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.85, 4.71 (1H, s), 4.47 (1H, m), 4.20 (1H, m), 3.80–3.65 (1H, m), 3.37 (1H, m), 3.25–3.08 (1H, m), 3.10–2.80 (3H, m), 2.58 (1H, m), 2.50–2.30 (1H, m), 2.15 (1H, m), 1.95 (2H, m), 1.35 (3H, d, J=6.0 Hz). MS: (MH)+572.5. The diastereomers were separated by HPLC on CHIRACEL AS column eluting with hexanes/EtOH (85/15) to afford the individual diastereomers.
Reaction SMILES: [CH2:1]([CH:3]1[C:7]2=[N:8][C:9]3[C:10]([F:17])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([OH:16])=[C:6]2[C:5](=[N:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:4]1)C.Cl.[OH2:25]>>[F:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([CH:3]([OH:25])[CH3:1])[C:6]([C:5]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:4])=[C:15]2[OH:16]
Reactant: O
Reactant: CCC1OC(=Nc2nccs2)c2c1nc1c(F)cccc1c2O
Agent: Cl
Product: CC(O)c1nc2c(F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 50 °C

Procedure:
A mixture of 5 g of the product of Step F and 50 ml of 6N hydrochloric acid was heated at 50° C. for 5 hours and after addition of 50 ml of water, the mixture was cooled to 0° to 5° C. for 30 minutes and was vacuum filtered. The product was washed with water and dried under reduced pressure at 80° C. The product was successively chromatographed over silica gel twice and eluted with a 9-1 chloroform-methanol mixture to obtain 1.15 g of 8-fluoro-4-hydroxy-2-(1-hydroxyethyl)-N-(2-thiazolyl)-3-quinoline-carboxamide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]([CH3:16])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:4].[N+:19]([O-])([OH:21])=[O:20].C(OCC)(=O)C>C(O)(=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]([CH3:16])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]acetamide (26.9 g) in acetic acid (85 mL) was added dropwise 70% nitric acid (6.78 mL) at room temperature with stirring. The mixture was stirred for 15 minutes at that temperature. The resulting mixture was poured into ice-water (500 g), and ethyl acetate was added. The organic layer was separated, washed successively with saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to afford the title compound (33.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.7 %

Procedure:
A solution of 5-hydroxy-1H-indole (0.13 g, 1.0 mmol) in acetonitrile (10 mL) was successively added with N-(2-chloroethyl)morpholine hydrochloride (0.19 g, 1.0 mmol), and potassium carbonate (0.28 g, 2.0 mmol), and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure, then the residue was added with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (50:50→20:80)) to obtain 4-[2-(1H-indol-5-yloxy)ethyl]morpholine (0.12 g, 50%).