Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1)NO
Reaction time: 22 h

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (30 mg, 0.07 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a white wax (15 mg, 79%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:43](OC(=O)C)(=[O:45])[CH3:44]>C1COCC1>[C:43]([NH:22][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])/[CH:13]=[CH:12]/[C:10]2[CH:11]=[C:6]([C:5]3[S:1][C:2]4[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=4[CH:4]=3)[C:7]([O:27][CH3:28])=[CH:8][C:9]=2[O:25][CH3:26])=[CH:17][CH:18]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(N)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)NC(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A suspension of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide (Ex-93, 0.5 g, 1.13 mmol) in THF (15 mL) was cooled to −78° C. followed by addition of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.3 mL, 2.3 mmol). The mixture was stirred at this temperature for 1 hour and warmed up to 0° C. Acetic anhydride (0.48 mL, 6.8 mmol) was then added dropwise. After the addition was complete the reaction mixture was warmed up to ambient temperature and stirred for 2 hours. The reaction was quenched with water. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NH4Cl, brine, dried and concentrated. The residue was purified by flash chromatography. Elution with 50% EtOAc/hexane gave the title compound as yellow solid (0.16 g, 29%), mp 228–229° C. 1H-NMR (CCDl3) δ 8.52 (s, 1H), 8.15–8.10 (m, 3H), 7.96 (d, J=7.6 Hz, 2H), 7.85–7.77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J=16.7 Hz, 1H), 7.34–7.29 (m, 3H), 6.58 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 2.65 (s, 3H). MS m/z=485 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:34]1([O:33][C:31]([N:26]2[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]3[C:6](=[O:29])[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:8]=3)=[O:21])[CH2:24][CH2:25]2)=[O:32])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 20 mL round-bottomed flask, 1-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)-3-(piperidin-4-yl)urea (intermediate N) (0.100 g, 0.243 mmol), phenyl chloroformate (38.1 mg, 30.6 μL, 0.243 mmol) and N,N-diisopropylethylamine (157 mg, 213 μL, 1.22 mmol) were combined with CH2Cl2 (5 ml). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated. The crude product was purified using preparative reverse-phase HPLC to give 4-[3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-piperidine-1-carboxylic acid phenyl ester. MS calcd. for C29H28ClN4O4 [(M+H)+] 531.2, obsd. 531.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[N+]=[N-])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N=[N+]=[N-])c2)COC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(N)c2)COC1

Procedure:
A solution of 740 mg (2.118 mmol) [5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester (Example 31h) in 5 ml THF and 5 ml EtOH was stirred in the presence of 35 mg 10% Pd—C under hydrogen. After 3 h the mixture was filtered over celite, concentrated and crystallized from EtOAc/hexane to give a beige solid. The racemic product was separated via prep HPLC on Chiralpak AD-H 250×4.6 mm column using heptan/EtOH 1:1 as an eluent. The desired compound was the slower eluting (R)-enantiomer. TLC: Rf (Hexane/EtOAc 2:1)=0.15. HPLC: RtH4=1.764 min; ESIMS [M+H]+=324.11 1H-NMR (CDCl3, 360 MHz, broad signals due to hindered rotation): 10.5 (br, 1H), 7.12 (br, 1H), 6.69 (d, 1H), 6.59 (br d, 1H), 4.8-4.0 (m, 8H), 1.48 (br s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(Br)c(OC2CCNCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol (36 mL, 324 mmol). The mixture was cooled to −78° C. and a solution of triphenylphosphine (81.5 g, 311 mmol) in CH2Cl2 (130 mL) was added via a cannula. The reaction was then warmed to room temperature and stirred overnight. The solvents were removed under vacuum and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to −78° C. and treated with 4 M HCl in 1,4-dioxane (450 mL). The reaction was warmed to room temperature and stirred 24 h. After this time, the solvents were removed under vacuum. The salts were neutralized with 1 N NaOH (750 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined and concentrated to dryness. The crude material was treated with heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with Et2O and treated with 4 M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with Et2O:hexanes (1:1). The salts were again neutralized with 1 N NaOH (500 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO4). The organic layer was filtered and concentrated to dryness to afford the title product as a colorless oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[O:9]>>[OH:9][CH2:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: O=C1CCCCC1
Reactant: C=O
Product: O=C1CCCCC1CO

Procedure:
By condensing cyclohexanone (2) with formaldehyde, the 2-hydroxymethylcyclohexanone (3) is obtained, wherefrom, by reaction with phenylmagnesium bromide, 1-phenyl-cis-2-hydroxymethyl-r-1-cyclohexanol (4) is prepared, the latter being subsequently oxidized with potassium permanganate into the acid (1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1O
Reactant: Nc1ccccc1
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccccc1
Reaction time: 0.25 h

Procedure:
o-Hydroxybenzaldehyde (0.20 mole) was treated with aniline with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 min., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 min. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice-bath for 0.5 hour. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol yielded N-(o-hydroxybenzylidene)aniline. m.p. 47°-49° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][N:35]=1)CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:32]1[CH:33]=[CH:34][N:35]=[C:31]1[C:2]1[C:3]2[N:4]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2c(Br)cccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2c(-c3ncco3)cccn12
Temperature: 125 °C
Yield: 16.4 %

Procedure:
A solution of bromide 1-6 (43 mg, 0.116 mmol) in THF (2 mL) in a microwave vial was sparged with N2 gas for 5 min, and 2-(tributylstannyl)oxazole (83 mg, 0.233 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol) were added. The vial was capped and heated at 125° C. under microwave irradiation for 20 min, then another 30 min at 130° C. An additional portion of 2-(tributylstannyl)oxazole (50 mg, 0.140 mmol) was added, and the vial was heated at 85° C. in an oil bath for 16 h. After cooling, the reaction mixture was directly purified by silica gel flash column chromatography (12 g cartridge), eluting with 40-100% EtOAc/hexanes then 2% EtOH/EtOAc. The fractions containing the desired product (4-1) were pooled, and after solvent removal in vacuo, 6.8 mg (16%) of a yellow solid were obtained. 1H NMR (300 MHz, CHCl3-d): δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.92 (dd, J=6.9, 1.2 Hz, 1H), 7.88 (dd, 6.9, 1.2 Hz, 1H), 7.80 (d, J=0.6 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.68 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 7.50 (ddd, Jr=7.8, 6.6, 1.2 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 6.64 (t, J=7.2 Hz, 1H), 4.69 (t, J=7.5 Hz, 2H), 3.61 (t, J=7.5 Hz, 2H). HRMS (ES) 358.1299 (M+H) found, 358.1302 required.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3].[CH3:13][C:14]1([CH3:22])[C:19]([CH:20]=[CH2:21])=[CH:18][CH2:17][CH2:16][CH2:15]1>CO>[CH2:1]([O:4][C:5]1[C:6](=[O:12])[C:7]2[C:8](=[CH:21][CH:20]=[C:19]3[C:18]=2[CH2:17][CH2:16][CH2:15][C:14]3([CH3:22])[CH3:13])[C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CC1=CCCCC1(C)C
Reactant: C=CCOC1=CC(=O)C=CC1=O
Solvent: CO
Product: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3(C)C
Yield: 36 %

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 60.9 mM) and 6,6-Dimethyl-1-Vinylcyclohexene (19.8 g, 183 mM) were dissolved in 100 ml of MeOH, and refluxed for 3 hours. 3-Allyloxy-8,8-dimethyl-5,6,7,8-tetrahydro-1,4-phenanthrenequinone (6.5 g, 22.0 mM) was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([NH2:20])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[S:30])[NH2:20])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(N)=O)cnn2C(C)(C)C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(N)=S)cnn2C(C)(C)C)cc1
Yield: 52.8 %

Procedure:
A solution of the compound (1.45 g, 5.30 mmol) obtained in step 10 and Lawesson's reagent (2.146 g, 5.30 mmol) in THF (25 mL) was stirred at 60° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→60% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carbothioamide (0.81 g, 2.80 mmol, 53%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@:10]([C:26]#[C:27][CH2:28]O)([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([SnH:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:26]=[C:27]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][O:25]3)[C@:9]1([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:15][C@H:14]2[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CC[C@H]3[C@H](S(=O)(=O)c4ccccc4)C[C@]2(c2ccccc2)N3Cc2ccccc2)OC1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol) was added to a degassed solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-(3-hydroxypropynyl)-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 1.8 g, 3.7 mmol) in tetrahydrofuran (50 ml). The mixture was cooled to +5° C. before tri-n-butyltin hydride (1.3 g, 4.4 mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 18 hours before triphenylphosphine (1 g, 3.7 mmol) and diethyl azodicarboxylate (0.65 g, 3.7 mmol) were added. After 3 hours the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% ethyl acetate/iso-hexanes to give the title compound (154 mg, 5.5%).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15](OCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[F:14])=[CH2:15])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Product: C=C(C(=O)OCC)c1c(F)cnc2ccc(OC)nc12
Yield: 44.5 %

Procedure:
Starting from 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (10 g, 38.9 mmol) and diethyl malonate (17.9 mL, 116.7 mmol), the title compound (4.8 g, 17.3 mmol) was prepared as described in WO 2007/122258 for the analogous methyl ester. The purity of the material was around 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:7]1.[C:41](OC(=O)C)(=[O:43])[CH3:42].CO>N1C=CC=CC=1>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:7]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1N
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(3-amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (50.5 mg)in pyridine (1 mL) was added acetic anhydride (1 mL). The reaction mixture was stirred at room temperature overnight and methanol was added. The mixture was evaporated, and 1 N NaOH solution was added. The mixture was extracted with ethyl acetate and the organic layer was concentrated. Preparative TLC gave (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si](C(C)(C)C)(C)C)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCOCC1.Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
To solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.12 g, 4.54 mmol) in dioxane (25 mL) was added TBAF (75% wt in water) (2.375 g, 6.81 mmol). The mixture was stirred at rt for 4 h then was diluted with 1N HCl (25 mL) and water (5 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4, filtered, and partially concentrated under reduced pressure to about 10 mL in volume. To the partially concentrated mixture was added 1N HCl (50 mL). The solids that formed were collected by filtration and were washed with water. The expected product, (1R,3aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (2.58 g, 99% yield), was isolated as a white solid. LCMS: m/e 571.47 (M−H)−, 3.60 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.80 (br. s., 1H), 7.92 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.32-5.26 (m, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.90 (s, 3H), 3.07-2.99 (m, 1H), 2.33-2.21 (m, 2H), 2.10 (dd, J=17.09, 6.10 Hz, 1H), 2.06-1.94 (m, 2H), 1.70 (s, 3H), 1.01 (br. s., 3H), 1.00 (br. s., 3H), 0.98 (s, 3H), 0.91 (s, 6H), 1.79-0.89 (m, 17H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([O:27]CC)=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37].[OH-].[Na+]>O1CCCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(O)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(O)cc12
Temperature: 70 °C

Procedure:
To a solution of EXAMPLE 149B (22 mg) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 10% NaOH 0.3 ml. The reaction was heated at 70° C. for 24 hours, cooled, acidified with diluted aqueousHCl and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.83 (s, 1H), 8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45-7.55 (m, 5H), 7.34-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7.17 (td, J=7.36, 1.23 Hz, 1H), 7.04 (dd, J=7.52, 1.38 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.75 (dd, J=8.90, 2.45 Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.84 (t, J=7.52 Hz, 2H), 4.15 (t, J=5.68 Hz, 2H), 2.63-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J=6.75 Hz, 3H), 0.96 (d, J=7.06 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([CH2:7][C@@H:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CN[C@H](CN1CCOCC1)C2

Procedure:
To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL of ethanol there is added 0.980 g of palladium dihydroxide (20% by weight) at ambient temperature. The reaction mixture is placed under 1.2 bars of hydrogen at ambient temperature for 4 hours. It is then passed through a Whatman filter and the palladium is then rinsed several times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:16][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)c2ccccn2)oc1C
Reactant: N
Solvent: CO
Product: Cc1cc(O)c(-c2ccccn2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(2-pyridyl)-methanone (1.6 g), methanol (15 ml), and a 28% aqueous ammonia solution (15 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-[2,2′]-bipyridin-3-ol (1.2 g, yield 75%).