Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:35])[CH2:33][OH:34])=[CH:28][CH:27]=1>CN(C=O)C>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:35][C@@H:32]([C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[CH2:33][OH:34])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1O
Reactant: N[C@H](CO)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-hydroxyphenyl]methanesulfonamide (J. Med. Chem. 1967, 10, 462-72) (1.15 g) in dry DMF (30 mL) was treated with diisopropylethylamine (1.06 mL) and (S)-phenylglycinol (474 mg) and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue re-suspended in methanol (50 mL). The reaction mixture was cooled to 0° C. and treated with CaCl2 (1.27 g). The reaction mixture was stirred at 0° C. for 30 min prior to portionwise addition of NaBH4 (218 mg) ensuring that the temperature did not rise above 10° C. After complete addition the reaction mixture was allowed to warm to room temperature and stirred for a further 74 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was dried and concentrated in vacuo. The mixture was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) afforded the title compound (85 mg). LCMS RT=2.48 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:17][CH2:18][OH:19])[CH2:8][C@@H:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:17][CH2:18][O:19][C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)C[C@@H](O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccccc2)C1
Reaction time: 8 h

Procedure:
3 g of (S)-(2-Hydroxy-ethyl)-(2-hydroxy-2-phenyl-ethyl)-carbamic acid tert-butyl ester and 0.327 g of triphenylphosphine were dissolved in 53.3 mL toluene. 0.217 g of diethylazodicarboxylate in 5.4 mL toluene was added dropwise to the resulting solution at room temperature under argon atmosphere and the mixture was stirred overnight. The solvent was removed in vacuo and the material purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20].O>CCCCCC>[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1ccc(CO)cc1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
4-Methoxybenzyl alcohol (603 mg, 4.35 mmol), 8-methylnonanoic acid (750 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 4-methoxybenzyl 8-methylnonanoate (1.15 g, yield 90.2%) as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].C(O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>>[C:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6])#[N:2]
Reactant: OCc1ccccc1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Product: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To the microwave vial was charged with isomer methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (+ve) (0.5 g, 2.4 mmole) & benzyl alcohol (0.5 mL, 4.8 mmol), was added tributyltinoxide (0.03 g, 5% W/W). Temperature was set 90° C. & energy is fixed at 250 W for 30 mins. After completion of the reaction (monitored by TLC), the RM mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (0.040 g, yield: 6.0%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[C:30]1([C:36]2[N:37]=[CH:38][NH:39][C:40]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:37]1[C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:39]=[CH:38]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(-n4cnc(-c5ccccc5)c4-c4ccccc4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 84 %

Procedure:
A solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (0.45 g, 1.0 mmol) and 4,5-diphenylimidazole (2.21 g, 10 mmol) in DMF (15 mL) was stirred at 65° C. under N2 for 67 h (reaction almost complete, TLC). Volatiles were evaporated in vacuo, and the residue was chromatographed (MeOH/CH2Cl2, 1:90) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (0.53 g, 83%) and a mixture of 4,5-diphenylimidazole (19 mg) and the title compound (52 mg, 91% total). Recrystallization (iPrOH) gave 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(4,5-diphenylimidazol-1-yl)purine: mp 146-146.5° C.; UV (MeOH) max 279 nm (∈ 18 300), min 267 nm (∈ 16 800); 1H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 8.22 (s, 1H), 7.55-7.57 (m, 2H), 7.35-7.40 (m, 4H), 7.21-7.27 (m, 4H), 6.21 (d, J=5.5 Hz, 1H), 5.80 (“t”, J=5.6 Hz, 1H), 5.58 (“t”, J=5.1 Hz, 1H), 4.41-4.48 (m, 3H), 2.16 (s, 31), 2.15 (s, 3H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.2, 169.5, 169.4, 154.3, 153.5, 147.4, 142.9, 140.5, 139.2, 133.5, 131.1, 131.0, 128.33, 128.28, 128.17, 127.5, 127.2, 124.1, 86.4, 80.7, 73.2, 70.5, 62.9, 20.8, 20.5, 20.4; HRMS m/z 631.1694 (MNa+[C31H28ClN6O7Na]=631.1708). Anal. Calcd for C31H28ClN6O7: C, 59.00; H, 4.31; N, 13.32. Found: C, 58.89; H, 4.45; N, 13.24.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>CO>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Reactant: CC(C)c1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Cl
Temperature: 45 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of 7G (6.4 g, 26.7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (4.8 g, 30.92 mmol, 1.16 eq) and NaOH (4.27 g, 106.8 mmol, 4 eq) in MeOH (200 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The yellow precipitates were collected by filtration and dried to give product 10A (9.96 g, 98.9% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]5[CH2:18][CH2:9][CH:10]([OH:27])[CH2:11][CH2:16]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:31][CH2:30]1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Reactant: OC1CCNCC1
Product: O=C(CCN1CCC(O)CC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCC(O)CC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 4-hydroxypiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-08 (776 mg, 58%) as a pale yellow/green solid.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in toluene (81.2 mL). Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3 mmol) was added to the mixture. Reaction was stirred at room temperature for 14 hours. Mixture was quenched with water. Mixture was extracted with ethyl acetate (30 mL). Mixture was washed 2× saturated aqueous sodium bicarbonate. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 80% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H), 3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0, J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8, 1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)+=411.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:44][O:45][C:46](Cl)=[O:47]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:46]([O:45][CH3:44])=[O:47])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole in THF was added triethylamine, followed by methylchlorocarbonate. The mixture was stirred at room temperature for 20 min. After a routing aqueous work up, the crude product was purified by prep HPLC to give methyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.2 (s, 3H), 3.4 (m, 1H), 3.7 (m, 4H), 4.6 (m, 1H), 5.1 (m, 1H), 6.9 (m, 1H), 7.2 (m, 6H), 7.7 (m, 3H), 7.95 (m, 2H), 8.2 (m, 1H); LC/MS M+H 578 (observed).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: O=C(Oc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of 6-chloronicotinic acid (68.0 g, 0.431 mol), phenol (40.6 g, 0.431 mol), DCC (93.6 g, 0.453 mol), and DMAP (1.60 g, 0.0129 mol) in ether (1 L) was stirred at room temperature overnight. The solvent was evaporated and the residue was stirred in CH2Cl2. The solid was filtered and the filtrate was purified by flash chromatography eluted with CH2Cl2 to give 88.0 g (88%) of the desired product. MS (DCI/NH3) m/z: 234.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=8.14 Hz, 2H) 7.31 (t, J=7.29 Hz, 1H) 7.47 (dd, J=17.12, 7.97 Hz, 3H) 8.40 (m, 1H) 9.17 (d, J=1.70 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1.CO.CC[O:30]C(C)=O>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:30])[CH2:5][CH2:4]1
Reactant: CCOC(C)=O
Reactant: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Solvent: CO
Product: COC1CCN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)CC1

Procedure:
H2O2 (70%, 3.1 mL, ca. 62.6 mmol) was added dropwise to a stirred solution of TFAA (8.8 mL, 62.6 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 42 (2.15 g, 6.3 mmol) and TFA (2.4 mL, 31.3 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give (i) starting material 42 (204 mg, 9%); and (ii) 1,4-dioxide 43 (1.0 g, 44%) as a red solid: mp (MeOH/EtOAc) 148-151° C.; 1H NMR δ 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.44 (br s, 1H, NH), 3.61-3.66 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.22-3.29 (m, 1H, CHO), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.75-2.81 (m, 2H, CH2N), 2.68 (br t, J=6.0 Hz, 2H, CH2N), 2.27-2.34 (m, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.87-1.95 (m, 2H, CH2), 1.61-1.70 (m, 2H, CH2); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.7, 115.7, 111.6, 75.8, 56.3, 55.5, 50.7 (2), 38.3, 33.4, 32.4, 30.6 (2), 25.6. Anal. calcd for C18H25N5O3.¼H2O: C, 59.4; H, 7.1; N, 19.2. Found: C, 59.2; H, 6.8; N, 19.1%.
Reaction SMILES: CN1C=C(C2C=CN=CC=2)C(C2C=CC(O)=CC=2)=N1.C([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:38]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[CH:37][N:36]([CH3:45])[N:35]=2)=[C:30]([F:46])[CH:29]=1)C1C=CC=CC=1>>[F:46][C:30]1[CH:29]=[C:28]([OH:27])[CH:33]=[CH:32][C:31]=1[C:34]1[C:38]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)=[CH:37][N:36]([CH3:45])[N:35]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2F)n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2F)n1

Procedure:
Following the procedure for the preparation of 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol but substituting 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine provided the title compound. MS: (M+H m/z=270.1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][O:19][C:20]([CH3:22])=[O:21].[C:25](O)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40]CC>C1(C)C=CC=CC=1>[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:22][C:20]([O:19][CH2:18]/[CH:17]=[C:16](\[CH:15]=[CH:14]\[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:24])/[CH3:23])=[O:21]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC/C=C(C)\C=C\C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 6 h

Procedure:
Retinyl acetate (22.0 g; 80% in oil; 53.6 mmol) and linoleic acid (Pamolyn 200; 15.0 g; 53.6 mmol; 1.0 equiv) were dissolved in 160 mL of toluene in a 500 mL flask. A dip tube in the flask was connected through a peristaltic pump to a column containing 6.0 g of Novozyme 435 which was connected in sequence to a second column containing 6.0 g of dried Amberlyst A-21. A tube from this second column returned to the original flask. The pump was started (flow rate 6 mL/min) sending the reaction mixture through the two columns and then back to the pot. After 6 h conversion had reached 71%, and the pump was stopped and the Amberlyst resin was regenerated by removing the column and washing the contents with 100 mL of 10% triethylamine in toluene (with 100 mL of toluene chaser). The apparatus was reassembled and the pump re-started. After 3 more hours conversion had reached 75% and the pump was stopped. Approximately 50% of the contents of the pot (80 mL) was removed and a mixture of 11.0 g of 80% retinyl acetate and 7.5 g of linoleic acid in 80 mL of toluene was added to the pot to serve as a first reactant replenishment. The Amberlyst resin was regenerated as above, the apparatus reassembled, and the pump started. After 9 h 73.6% conversion had been achieved and the pump was stopped. Approximately 50% of the contents of the pot (80 mL) was removed and a mixture of 11.0 g of 80% retinyl acetate and 7.5 g of linoleic acid in 80 mL of toluene was added to the pot to serve as a second replenishment. The Amberlyst resin was regenerated as above, the apparatus reassembled, and the pump started. After 12 h 75.0% conversion had been achieved and the reaction was stopped.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:43][C:39]4[C:38]([CH3:57])=[N:37][N:36]([CH3:35])[C:40]=4[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2cc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)sc12
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (119 mg, 0.238 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476 mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (101 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (d, J=9.60 Hz, 1H), 2.02-2.22 (m, 1H), 2.33 (br s, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.62 Hz, 1H), 3.90 (br s, 3H), 3.97-4.13 (m, 2H), 4.27-4.40 (m, 1H), 4.41-4.53 (m, 2H), 7.24-7.44 (m, 1H), 7.84-8.04 (m, 3H), 8.63 (br s, 1H), 9.22 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([NH2:14])[CH2:4]1.[O-:15][C:16]#[N:17].[K+]>Cl>[CH3:2][N:3]1[CH2:7][C@@H:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([NH:14][C:16]([NH2:17])=[O:15])[CH2:4]1
Reactant: N#C[O-]
Reactant: CN1C[C@@H](N)[C@H](c2ccccc2)C1
Agent: Cl
Agent: [K+]
Product: CN1C[C@@H](NC(N)=O)[C@H](c2ccccc2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(3S,4R)-1-Methyl-4-phenylpyrrolidin-3-amine hydrochloride (556 mg, 2.231 mmol) was dissolved in HCl (2 N, 4 mL) and potassium cyanate (905 mg, 11.16 mmol) was added. The reaction mixture was stirred at 80° C. for 3 h. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc followed by 3:1 chloroform/IPA. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-((3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl)urea, which was carried onto the next step without further purification. MS ESI calc'd. For C12H17N3O [M+1]+ 220. found 220.