Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C(NC2C3NC=NC=3N=CN=2)=[O:8])=CC=1.C(N[C:23]1[CH:44]=[CH:43][N:26]([C@@H:27]2[O:42][C@H:36]([CH2:37][O:38]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@H:28]2[O:29]C)[C:25](=[O:45])[N:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.ClCCl>[C@@H:27]1([N:26]2[CH:43]=[CH:44][C:23](=[O:8])[NH:24][C:25]2=[O:45])[O:42][C@H:36]([CH2:37][OH:38])[C@@H:31]([OH:32])[C@H:28]1[OH:29]
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc(NC(C)=O)nc1=O
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 75 °C
Yield: 50 %

Procedure:
A solution of N6-benzoylaminopurine (Lancaster) (1.23 g, 5.16 mmol) stirring in anhydrous acetonitrile under an argon atmosphere was treated with BSA (3.82 ml, 15.48 mmol) at reflux for 3 hours. Upon cooling, a solution of N4-acetyl-5′,3′-di-O-acetyl-2′-O-methyl cytidine (2) (see above) (0.66 g, 1.72 mmol) in 20 ml anh. acetonitrile was added to the reaction mixture followed by TMStriflate (1.03 ml, 5.16 mmol). The reaction mixture was then heated to 75° C. for 16 hours while stirring under positive pressure argon. Upon cooling, an additional 1.03 ml (5.16 mmol) of TMStriflate was added, and the reaction heated to 75° C. for an additional 20 hours. Once cool, the reaction mixture was diluted with two volumes of dichloromethane and washed with sat. NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. Flash chromatography employing a gradient of 10 to 80% ethyl acetate/hexanes afforded (1) as a white foam; 0.403 g, 50% yield. 1H NMR (CDCl3): 8.88 (br s, 1H, NH), 8.81 (s, 1H, H8), 8.31 (s, 1H, H2), 8.11-7.53 (m, 5H, benzoyl), 6.18 (d, J1′,2′=4.8, 1H, H1′), 5.41 (t, J3′,2′=4.8, J3′,4′=4.8, 1H, H3′), 4.75 (t, J2′,1′=4.8, J2′,3′=4.8, 1H, H2′), 4.50-4.34 (m, 3H, H4′, H5′, H5″), 3.44 (s, 3H, OCH3), 2.19 (s, 3H, OAc), 2.14 (s, 3H, OAc).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:19])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyanuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(F)cc4)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccc(F)cc1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.1 mg, 0.056 mmol) (from Example 8 supra) in methyl sulfoxide (0.5 mL) and ethanolamine (1.5 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the crude product was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 80/20) to give two products. The faster eluting material gave 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 7.3 mg, 28%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])[NH2:4].[F:14][CH:15]([F:21])[C:16](OCC)=O>>[F:14][CH:15]([F:21])[C:16]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[N:7][CH:8]=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])[N:4]=1
Reactant: NC(=NO)c1cncc(C(=O)O)c1
Reactant: CCOC(=O)C(F)F
Product: O=C(O)c1cncc(-c2noc(C(F)F)n2)c1
Yield: 30 %

Procedure:
This compound was synthesized from 5-(N′-hydroxycarbamimidoyl)nicotinic acid using ethyl difluoroacetate as described in example 1 step 5 (100 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 13.94 (br s, 1H), 9.40 (d, J=2.1 Hz, 1H), 9.28 (d, J=2.1 Hz, 1H), 8.76-8.75 (t, J=2.1 Hz, 1H), 7.73-7.47 (m, 1H). MS (ESI) m/z: Calculated for C9H6F2N3O3: 241.03. found: 241.8 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25]O.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([OH:9])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OO
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](CO)CC1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(4S)-3-[(2R)-3-Cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 0.1 mol) was stirred in a mixture of THF (330 mL) and water (55 mL) and cooled to 0° C. 30% Hydrogen peroxide (96 mL, 1 mol) was added, followed by lithium hydroxide monohydrate (8.4 g, 0.2 mol). The reaction was warmed to room temperature, and then stirred overnight. The THF was removed by rotary evaporation. The aqueous residue was washed with dichloromethane (3×100 mL), was acidified with 6N HCl, and was extracted with ethyl acetate (4×100 mL). The organic extracts were dried (MgSO4) and were evaporated to provide (2R)-3-cyclopentyl-2-(hydroxymethyl)propanoic acid as a clear, colorless oil (18.5 g, >100%). LCMS: (M+H)+: not detected. 1H NMR (400 MHz, CDCl3): δ 7.3 (br s, 1H), 3.79 (d, J=5.83 Hz, 2H), 2.64-2.71 (m, 1H), 1.45-1.87 (m, 9H), 1.05-0.14 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]1
Reactant: Cc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 25 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and charged with tert-butyl 4-[[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (1.50 g, 3.57 mmol, 1.00 equiv), 2-bromo-6-methylpyridine (0.916 g, 5.32 mmol, 1.49 equiv), Tetrakis(triphenylphosphine)palladium (0.413 g, 0.360 mmol, 0.10 equiv), potassium carbonate (1.50 g, 10.8 mmol, 3.04 equiv), dioxane (15 mL) and water (3 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.10 g (80% yield) of tert-butyl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C(c1ccc(F)cc1)C1CCN(c2ccncc2)CC1
Temperature: 145 °C
Yield: 41.5 %

Procedure:
A stirred mixture of 4-(4-fluorobenzoyl)piperidine, hydrochloride salt (3.90 g), 4-chloropyridine, hydrochloride salt (2.85 g) and triethylamine (4.90 ml) in xylene (75 ml) was heated at 145° C. for 27 hours. The solvent was evaporated and the residue partitioned between methylene chloride (150 ml) and water (100 ml), the pH being adjusted to ˜10 with 0.880 ammonia. The aqueous phase was extracted with a further methylene chloride (50 ml). The combined organic phases were washed with water, dried (Mg SO4) and evaporated. The residue was purified by column chromatography using a 19:1 mixture of methylene chloride and methanol as eluent to give 4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine (1.89 g);
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2Z,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1742 cm-1, 1671 cm-1, 1634 cm-1, 1442 cm-1, 1367 cm-1, 951 cm-1.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28].C(#N)CC.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:55]([O:59][CH2:60][CH3:61])(=[O:58])[CH:56]=[CH2:57]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[CH2:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28])[CH3:61]
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1ccc(Br)c(F)c1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(F)c1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A 150 mL sealed tube was charged with a stirring bar, (R)-1-(4-Bromo-2,3-difluorophenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol (3.06 g) 1 and propionitrile (70 mL). To this was added Pd(OAc)2 (0.151 g), P(O-tol)3 (0.82 g), ethyl acrylate (1.35 g), triethylamine (2.73 g) sequentially and deoxygenated the reaction by bubbling nitrogen for 15 minutes. The sealed tube was capped tightly and immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 12 hrs. Cool to ambient temperature and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting initially with 50% EtoAc in hexanes and 100% EtOAc. At this time the eluting solvent mixtures were switched to 100% dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOH in dichloromethane. The product was collected and concentrated to get the desired product (2.40 g, 75%) as pale yellow foam. MS (ES) m/z 474 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[C:6]([O:13][C:14](=[O:16])[CH3:15])=[C:5]([CH3:17])[C:4]=1[CH3:18].[H][H]>C(O)C.C(OCC)(=O)C.[Pt]=O>[C:14]([O:13][C:6]1[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]([NH:2][CH3:1])=[C:8]([NH2:9])[C:7]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 55.7 %

Procedure:
A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline (prepared as described in Preparation 18) in a mixture of 20 ml ethanol and 20 ml of ethyl acetate was shaken at room temperature for 3.5 hours and then at 40° C. for 3 hours in an atmosphere of hydrogen and in the presence of 0.2 g of platinum oxide. At the end of this time, the reaction mixture was filtered to remove the platinum oxide and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.3 g of title compound, melting at 113°-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.[OH-].[Na+]>C(O)CCC>[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:26][C:27]=2[CH:33]=1
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl) carbonyl]cyclobutane-carboxylate (100 mg, 0.32 mmol) in n-butanol (15 mL) was added 2,6-dichloro-1,3-benzothiazole (396 mg, 1.94 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was brought up in MeOH. Then 1 N aqueous NaOH (1.0 mL, 1.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was suspended in water. Concentrated HCl was added to adjust the acidity to pH 1, and the precipitate that formed was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylic acid (16 mg, 10%). LC-MS ret. time 3.69; m/z 463.1 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 2.01-2.23 (m, 3H), 2.32 (m, 1H), 3.43 (m, 1H), 4.32 (m, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.62 (d, 1H), 7.81 (m, 4H), 7.90 (d, 2H), 7.98 (m, 3H), 10.77 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: O=C(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCSc1nnc(S)s1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 1.3 g of anhydrous potassium carbonate, and 20 ml of N,N-dimethylformamide was added 1.6 g of 3-bromopropionic acid, whereby the red color of the reaction mixture began to gradually fade and the reaction mixture became yellow. Then, the reaction mixture was poured into 100 ml of ice water and extracted with 30 ml of ethyl acetate three times. The extract thus obtained was washed with water and extracted with 20 ml of an aqueous solution of 5% sodium hydrogen carbonate two times. The extract was washed with ethyl acetate, acidified with diluted hydrochloric acid, and extracted with 30 ml of ethyl acetate three times and the extract thus obtained was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide 0.76 g of 3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:18][CH3:19])C(=O)OC(C)(C)C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:18][CH3:19])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNc1cc(Br)cn(C)c1=O
Temperature: 30 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate (99.0 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30° C. The reaction mixture was stirred for 30 min at 30° C. Then the mixture was filtered and the filter cake collected. The filtrate was adjusted to pH=9 with saturated aqueous NaHCO3, extracted with EA (20 mL), dried over Na2SO4, filtered and concentrated to give a light green solid which is combined with the filter cake to give the title compound (46.0 mg) which was carried forward without purification. 1H NMR (CDCl3 400 MHz): δ 6.72 (d, J=2.4 Hz, 1H), 6.20 (d, J=1.6 Hz, 1H), 3.51 (s, 3H), 3.09 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 231.
Reaction SMILES: [CH2:1]([CH:3]([CH2:30][CH3:31])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=2[O:28][CH3:29])=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl.CN(C)CCCN=C=NCC.[C:44]1([CH3:54])[C:45]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:47]=[CH:48][CH:49]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:3]([CH2:30][CH3:31])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:53][S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH3:54])(=[O:51])=[O:52])=[O:25])=[CH:21][C:20]=2[O:28][CH3:29])=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)O)cc3OC)c2c1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoic acid (189 mg), 4-dimethylaminopyridine (110 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg), and o-toluenesulfonamide (96 mg) in methylene chloride (2 ml) was stirred for 18 h. Methylene chloride (25 ml) was added, and the solution was washed (1N hydrochloric acid, brine), dried (MgSO4) and evaporated. The residue was recrystallized from 21 ml of 1:0.5:1 methylene chloride:methanol:hexane, ground to a powder and vacuum dried at 100° C. to give the title compound (179 mg, 70%) as a colorless solid; mp 126.0°-128.0° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[OH:28][C:27]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:33])[N:23]1[CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: Brc1cccnc1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −70° C., a 1.6 M butyllithium solution (3.99 mmol) in absolute diethyl ether was admixed dropwise with a solution of 0.56 g (3.56 mmol) of 3-bromopyridine in absolute diethyl ether. The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at −70° C., a solution of 0.5 g (1.78 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide in 10 ml of absolute tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature, stirred for another 1 h and then admixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted three times with diethyl ether. The combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. The colorless oily crude product was purified by chromatography. Elution was carried out using a dichloromethane/methanol gradient (0 to 3% methanol). The resulting colorless oil solidified on standing at room temperature. Yield: 0.34 g. M.p.: 97° C.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=1[Cl:32]>>[C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:22][C:23]3[C:24]([Cl:32])=[CH:25][C:26]([O:30][CH3:31])=[CH:27][C:28]=3[Cl:29])[C:14]2=[O:18])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Product: COc1cc(Cl)c(CC2CCN(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(Cl)c1
Yield: 49 %

Procedure:
Using the procedure to synthesize Example 202 and using the reagents of cis-1-[4-(tert-butyl-dimethyl-silanoxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17) and 2-Bromomethyl-1,3-dichloro-5-methoxy-benzene (Preparation 62). Warm reaction to room temperature, quench with NH4Cl (sat), dilute with diethyl ether, wash with brine, dry over sodium sulfate, filter and evaporate to an oil. Chromatography (silica, 100% hexanes to 75:25 hexanes/EtoAc) yields 1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-methoxy-benzyl)-pyrrolidin-2-one in 49% yield. The silylether is dissolved in THF, treated with 10.0 equivalents of HCl (conc) and allowed to stir at room temperature for 3 h, quench reaction with water, dilute with EtOAc, adjust pH to 7.0, separate, dry over sodium sulfate, filter and evaporate provides the titled compound in 84% yield: Mass spectrum (API-ES positive) m/z=372 (M+H).
Reaction SMILES: O=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2C(=O)[O:3]1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C1COCC1.O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]([CH:6]2[NH:5][CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]2)=[O:3])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(=O)C2C1
Reactant: Nc1cccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)Nc2cccnc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
tert-Butyl 1,3-dioxotetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (1.50 g, 5.85 mmol) and 3-aminopyridine (1.10 g, 11.7 mmol) were heated to reflux in THF (20 mL). After 4 h, the reaction mixture was cooled to rt, diluted with H2O (50 mL), and was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% MeOH in CH2Cl2 with 0.5% NH4OH gradient), yielding 0.740 g (44%) of the title compound. LC-MS: RT=4.14 min, [M+H]+=307.1.