Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]([CH2:40][CH:41]=[CH2:42])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=O)C>[OH-].[Na+].CCO>[CH2:40]([NH:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:41]=[CH2:42]
Reactant: C=CCN(C(C)=O)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCNS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solid of 1-(4-{[acetyl(allyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (360 mg, 0.6 mmol) was dissolved in 0.5 N solution of NaOH in EtOH (10 mL) and stirred at room temperature for overnight. The mixture was concentrated. It was purified by HPLC to give the desired compound (210 mg, 62%.) IKK-2 resin IC50≦1 μM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 519.9 %

Procedure:
Combine tyramine (3.0 g, 3.3 mmol), benzaldehyde (3.0, 2.2 mmol), 3 Å molecular sieves (5 g), ethanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (2.5 g) to the reaction at 0° C. then stirred at room temperature overnight. Concentrate on a rotary evaporator, take up residue in water, and then extract with dichloromethane (3×100 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 4.3 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 4-(2-benzylamino-ethyl)-phenol (2.6 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.17 (s, 1H), 7.31 (m, 5H), 6.99 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.64 (m, 4H), 2.11 (s, 1H). Step 2 Benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([C:24]2[CH:29]=[N:28][CH:27]=[N:26][CH:25]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(-c2cncnc2)c1
Temperature: 77.5 °C
Yield: 116.3 %

Procedure:
To a solution of 18 (62.0 mg; 0.14 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous sodium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white oil (68.0 mg).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([OH:3])=[O:2].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][C:14]1[C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(CC(=O)O)cc1OC

Procedure:
To 300 mg of methyl 4-carboxymethyl-2-methoxy-benzoate from preparation 1 placed in 6 mL of acetic acid, are added 110 μL of sulfuryl chloride (1 equivalent). The whole is refluxed for 6 hours. After evaporation of the solvent, the reaction crude product is purified on silica gel (petroleum ether/ethyl acetate: 80/20 then 60/40) leading to 165 mg of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].[C:15]([N:23]=[C:24]=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.CCOC(C)=O>[C:4]([C:3]1[C:6]([O:10][CH:11]2[CH2:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:24]([NH:23][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])#[N:5]
Reactant: N#Cc1c(N)cccc1OC1CCC1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)cccc1OC1CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To a solution of 2-amino-6-cyclobutoxybenzonitrile (example 162b) (30 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was added benzoyl isocyanate (23 mg, 0.16 mmol). The reaction was stirred at rt under Na for 19 hours. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO3 (2×), water, brine, dried over MgSO4, filtered and concentrated to provide N-(2-cyano-3-cyclobutoxyphenylcarbamoyl)benzamide (38 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 1.64 (m, 1H), 1.81 (m, 2H), 2.05 (m, 1H), 2.42 (m, 2H), 4.71 (pent, J=7.1 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 6.33 (d, J=8.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.56 (m, 2H), 7.87 (m, 1H), 8.05 (m, 1H), 11.35 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=[S:15])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([S:15][CH3:18])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CSC1=Nc2ccc(F)cc2Nc2sc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Stir 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (61.5 g, 0.233 mol) and DMF (310 mL) under nitrogen for 15 minutes at ambient temperature. Add powdered potassium carbonate (67.7 g, 0.490 mol); stir 15 minutes at ambient temperature. Add iodomethane (22 mL, 0.35 mol); stir 4 hours at ambient temperature. Cool to 0-5° C. and add deionized water (150 mL) dropwise, keeping the temperature below 15° C. Extract the product with ethyl acetate. Wash the organic solution with brine four times, then dry over magnesium sulfate, filter and concentrate under reduced pressure to give 74.0 g of crude product. Purify by flash chromatography, eluting with 2:1/methylene chloride:heptane, then methylene chloride to give 55.0 g (85%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.11 (bs, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 6.50 (s, 1H), 6.44 (m, 1H), 2.41(s, 3H), 2.25 (s, 3H). HRMS (ES) exact mass M+H calcd for C13H11FN2S2 279.0426; found 279.0416.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[C:7]([CH3:22])=[CH:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[Al+3].[Cl-:26].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)([CH3:22])[CH2:6][C:5]1([CH3:23])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CC(=O)N1c2ccc(N)cc2C(C)(c2ccc(Cl)cc2)CC1(C)C
Reaction time: 1 h

Procedure:
A mixture of 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) and AlCl3 (35 mg) in chlorobenzene (2 ml) was stirred for 1 h. The reaction mixture was quenched with water and in addition a solution of 2 M NaOH and ethyl acetate were added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1.C(OC(N1CCC(C2NC(C3C=CC=CN=3)=C(C3C=CC4OCOC=4C=3)N=2)CC1)=O)C1C=CC=CC=1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:36][CH2:37][N:38]([S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:39][CH2:40]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: c1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)nc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.9 %

Procedure:
α-Toluenesulfonyl chloride (0.023 g, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol, in 3 mL of anhydrous THF), which was prepared with 4-(4-benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester in a similar manner as described in Example 9. The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (10%) of the title compound as a yellow solid. MS (ESP+) m/z 503.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.67 (m, 1H), 7.82 (m, 1H), 7.42 (m. 7H), 7.02 (m, 3H), 6.07 (s, 2H), 4.38 (s, 2H), 3.81 (m, 2H), 3.17 (m, 1H), 2.85 (m, 1H), 2.10 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][C:22]([OH:29])([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]3)=[O:18])[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.O[C:52]1[CH:57]=[CH:56][C:55]([C:58]([CH3:70])([CH3:69])[C:59]([O:61]CC2C=CC=CC=2)=[O:60])=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][C:22]([OH:29])([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:24]3)=[O:18])[CH:15]=2)[C:10]([O:12][C:52]2[CH:57]=[CH:56][C:55]([C:58]([CH3:70])([CH3:69])[C:59]([OH:61])=[O:60])=[CH:54][CH:53]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(C(=O)O)c2)CC1
Reactant: CC(C)(C(=O)OCc1ccccc1)c1ccc(O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(C(=O)Oc3ccc(C(C)(C)C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Under an argon atmosphere, the compound prepared in Example 37 (75 mg) was dissolved in DMF (1 mL), added with EDC (55.5 mg), HOBt (39.1 mg), diisopropylethylamine (0.05 mL) and benzyl 2-(4-hydroxyphenyl)-2-methylpropanoate (56.5 mg) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, sequentially washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was dissolved in methanol (1 mL) and ethyl acetate (1 mL), added with 5% palladium carbon (50 mg) and stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction solution was filtered with celite and the solvent was distilled off. The resulting residue was purified by thin layer chromatography (chloroform:methanol=5:1) to give the titled compound (59.1 mg) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH:10]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[CH:10]([N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C(NCc2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a cooled to 0° C. solution of 3-benzylamino-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 11.4 mmol) and triethylamine (4.77 mL, 34.2 mmol) in THF (60 mL), was added drop-wise methane sulfonyl chloride (1.7 g, 14.8 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h, then Cs2CO3 (5.0 g, 15.4 mmol) was added. The reaction mixture was heated to 60° C. for 18 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was washed with H2O (2×100 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the crude title compound (3.38 g). The crude product was purified (FCC, SiO2, 4% acetone, dichloromethane) to yield pure title compound (2.88 g, 84%). MS (ESI) mass calcd. for C18H26N2O2, 302.42; m/z found, 303.2 [M+H]+. 1H NMR (CDCl3): 7.35-7.15 (m, 5H), 4.02-2.80 (m, 9H), 2.48-2.36 (m, 1H), 1.95-1.65 (m, 2H), 1.56-1.32 (m, 10H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:12][C@@H:13]2[NH:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2)cc1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(SC[C@H]2CCC(=O)N2)cc1
Reaction time: 72 h
Yield: 98.3 %

Procedure:
To a solution of (R)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Helvetica Chimica Acta 1990, 73, 122-32; Tetrahedron: Asymmetry 2007, 18, 664-670) (1.05 g, 3.9 mmol) in CH3CN (30 mL) was added 4-methoxybenzenthiol (0.55 g, 3.9 mmol) and Cs2CO3 (5 g, excess). The reaction mixture was stirred for 3 days. To the solution was added EtOAc (50 mL) and H2O (30 ml). The organic phase was separated. The solvents were removed by evaporation to give the title compound as an oil (0.91 g, 98%). TLC and NMR indicated that the product was pure enough for the next step.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc(-c2ccc(F)cn2)cc1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2ccc(F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A mixture of 2-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-5-fluoropyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.3 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (285 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([C:22]#[N:23])(C)C.C(Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:22]#[N:23])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cc2cc[n+]([O-])cc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: N#Cc1cc(Cc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.3 %

Procedure:
To a solution of 4-(4-nitro-benzyl)-pyridine 1-oxide (1.0 g, 4.3 mmol) in dichloromethane (9 mL) was added-trimethylsilyl cyanide (2.3 mL, 17 mmol). After 5 min, benzoyl chloride (1.0 mL, 8.7 mmol) was added dropwise and the mixture was stirred at rt for an additional 30 min. Water (10 mL) was carefully added, followed by solid potassium carbonate (2.1 g). After 30 min, the aqueous phase was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography, eluting with 5-25% ethyl acetate in hexanes, gave an orange oil. This oil was subsequently triturated with toluene to afford 4-(4-nitro-benzyl)-pyridine-2-carbonitrile as a tan solid (353 mg, 34%). 1H NMR (CHCl3-d) δ 8.63 (d, J=4.8 Hz, 1H), 8.21 (m, 2H), 7.49 (m, 1H), 7.32 (m, 3H), 4.15 (s, 2H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[F:32][C:33]([F:43])([F:42])[O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(C)(C)C.[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([O:34][C:33]([F:32])([F:42])[F:43])[CH:36]=2)=[CH:13][CH:14]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Nc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.196 mmol, Intermediate 14) in toluene (30 mL) was added 3-(trifluoromethoxy)aniline (45 mg, 0.254 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol), X-phos (10 mg, 0.021 mmol) and potassium tert-butanolate (45 mg, 0.402 mmol). The mixture was degassed and refilled with nitrogen 3 times. The reaction was stirred at 100° C. overnight under nitrogen. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (3:1 to 3:2). The product was collected, concentrated, and dried in vacuo to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione (70 mg, 57.6%) as a yellow solid. LCMS MH+-THP 524.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[N:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: BrCc1cnc2ccccc2c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-(bromomethyl)quinoline, 6-methyl-2-sulfanylpyrimidin-4-ol (853 mg, 6 mmol) and triethylamine (1 mL, 7 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.7 g, 99% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.54 (s, 2H), 6.01 (s, 1H), 7.58 (m, 1H), 7.70 (m, 1H), 7.94 (m, 2H), 8.35 (s, 1H), 8.96 (s, 1H); M+ 284.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1.O.O.[Cl-].[Ca+2:37].[Cl-]>O>[Ca:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [Ca+2]
Agent: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: [Cl-]
Solvent: O
Product: [Ca]
Reaction time: 1 h

Procedure:
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid TRIS salt (17.7 g) was dissolved in degassed water (120 ml) at 20° C. A solution of calcium chloride dihydrate (2.6 g) in water (25 ml) was added dropwise at about 20° C. over 20 minutes. The mixture was stirred for 60 minutes and the resultant solid filtered. The solid was washed with water (140 ml) and dried under a flow of nitrogen to give non-crystalline calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid.