Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52]>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH:52][C:29]([C:23]1[C:22]2[CH2:21][CH2:20][N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)=[O:12])[CH:14]=3)[CH2:28][C:27]=2[CH:26]=[N:25][CH:24]=1)=[O:30]
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Reactant: COC(=O)CN
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 64.2 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.067 mL, 0.39 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, glycine methyl ester hydrochloride (18.1 mg, 0.144 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (30 mg, 64%). 1H NMR (CDCl3) δ: 8.55 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.53 (d, J=11.4 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.33-7.40 (m, 1H), 7.20-7.32 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.62 (t, J=5.1 Hz, 1H), 4.47 (s, 2H), 4.24 (d, J=5.3 Hz, 2H), 3.81 (s, 3H), 3.56-3.61 (m, 2H), 3.20 (t, J=5.6 Hz, 2H), 2.85-2.99 (m, 1H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=1[F:60]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=3[F:60])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(O)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.9 %

Procedure:
To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].C([OH:24])C.Cl>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:24])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(F)c1

Procedure:
A 5.5 g. portion of ethyl 5-cyano-1-(3-fluorophenyl)-4-pyrazolecarboxylate and 4.7 g. of potassium hydroxide were dissolved in 100 ml. of ethanol at the reflux temperature and the mixture was stirred at that temperature for 2 hours. The mixture was then diluted to 350 ml. with cold water, and was heated slightly to obtain a solution which was made acid with concentrated hydrochloric acid. The product was precipitated by adding small amounts of ice, and the precipitated product was then collected by filtration and crystallized from ethanol-water to obtain 3.6 g. of the desired product, m.p. 215°-216°, having the following elemental analysis.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2(CO2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.1 %

Procedure:
To a 0° C. solution of tert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115 ml, CHCl3 was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches. Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred. After 19 hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropyl alcohol was added (reaction mixture clarified), and another 1 equivalent of mCPBA was added. The reaction mixture was warmed to ambient temperature and stirred 2 hours, then another 1 equivalent mCPBA was added portionwise. After a total of 40 hours, the reaction mixture was cooled to 0° C., and 200 mL of 1:1 saturated Na2S2O3/saturated NaHCO3 was added slowly by pouring portionwise through ice (internal temperature was monitored; an initial 10° C. exotherm was observed). The mixture was stirred for 30 minutes, then extracted with CHCl3, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (1.0 g, 26.1% yield) as a clear colorless oil.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12](=[S:35])[NH:13][C:14]1[S:15][C:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:18]=1)(=O)C1C=CC=CC=1.O>CO>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([NH:13][C:12]([NH2:11])=[S:35])[S:15][C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2nc(NC(=S)NC(=O)c3ccccc3)sc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(NC(N)=S)sc2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution of sodium hydroxide (0.36 g) in methanol (4.1 ml) was added to a solution of 2-(3-benzoylthioureido)-4,5-bis(4-methoxyphenyl)thiazole (4.3 g) and water (0.5 ml) in methanol (25 ml). The resulting mixture was stirred for 3 hours at 55°~60° C. The methanol was evaporated in vacuo and the residue was triturated with water. The precipitates were collected by filtration and dried to give 4,5-bis(4-methoxyphenyl)-2-thioureidothiazole (3.20 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc([C@@H]2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 94° C. and MS: m/e=350.3 (M+) was prepared in accordance with the general method of example 1e from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[N:30]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC1CCN(C(=O)c2ccc(-c3ccc(OCCCCl)cc3)cc2)CC1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: Cl
Product: CC1CCN(C(=O)c2ccc(-c3ccc(OCCCN4[C@H](C)CC[C@H]4C)cc3)cc2)CC1

Procedure:
The product from Example 9A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][N:14](C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:19]N>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)CCN(C)C)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNCC2)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(3,4-dimethoxyphenyl-3-(dimethylamino)propan-1-one (2.9 g, 0.0122 moles, 1 equiv.) in absolute ethanol was added hydrazine hydrate (99%-100%) (1.18 ml, 0.0244 moles, 2 equiv) drop wise. After that the reaction mixture was refluxed for 4 h at 80° C. under inert atmosphere. Consumption of starting materials was confirmed by LC-MS analysis and TLC. Ethanol and excess hydrazine hydrate was evaporated under reduced pressure and to the crude product was stirred with diethyl ether at RT for 30 mins, filtered washed with ether and finally dried under vacuum to get 2.4 g (95% yield) of the title product as yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:14]=1)=[N:8][CH:9]=[C:10](Br)[C:11]=2[CH3:12])[CH2:2][CH3:3].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>C1COCC1>[CH2:1]([C:4]1[N:5]=[C:6]2[CH:11]([CH3:12])[C:10]([CH:22]=[O:23])=[CH:9][N:8]=[C:7]2[N:14]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCc1nc2ncc(Br)c(C)c2[nH]1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC1=NC2=NC=C(C=O)C(C)C2=N1
Temperature: -78 °C

Procedure:
To a cooled (-78° C.) stirred solution of 2-propyl-6-bromo-7-methylimidazo[4,5-b]pyridine (540 mg, 2.15 mmol) in THF (20 mL) was added tert-butyl-lithium (4.40 mL, 1.7M/pentane) over 30 seconds After 45 minutes, dimethylformamide (0.665 mL) was added and after 10 additional minutes the reaction was warmed to RT and quenched with 20% aqueous 4 NH4Cl. Extractive workup EtOAc (4×10 mL) and purification (SiO2, 4% MeOH/EtOAc) gave 2-propyl-7-methylimidazo[4,5-b]pyridine-6-carboxaldehyde (350 mg). To a stirred, cooled (0° C.) methanolic (15 mL) solution of the aldehyde (300 mg) was added NaBH4 (84 mg). After 30 minutes HOAc (0.1 mL) was added, the mixture was warmed (RT), concentrated, and purified (SiO2, 10% MeOH/CH2Cl2) to give 190 mg of 6-hydroxymethyl-7-methyl-2-propylimidazo[4,5-b]pyridineas an oil. The title compound was prepared by using a similar method to that described in Example 7, Part B.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[I-].[I-].[Na+].[S:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1cscn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCOc1c(OCCc2nccs2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O

Procedure:
trans-2-[3-(2-Hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy) phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (50 mg, 0.08 mmol)(Example 12) was converted into the corresponding iodide by treatment with sodium iodide in DMF. The iodo intermediate and thiazole (0.17 mL, 2.4 mmol) in toluene (5 mL) was heated under reflux overnight. The solution was evaporated to dryness, and the product was isolated by preparative TLC (chloroform-methanol; 9:1, v/v), Rf 0.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[SH:72][CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76].C(N(C(C)C)C(C)C)C>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].O1CCOCC1>[C:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:12]2[N:13]=[C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]([S:72][CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])=[CH:3][C:4]=3[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:10][CH:11]=2)[CH2:15][CH2:16]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C

Procedure:
A mixture of 1-(4-(2-(5-Bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (40.0 g, 84.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (2.44 g, 4.22 mmol), Pd2dba3 (1.93 g, 2.11 mmol), methyl 3-mercaptopropanoate (18.7 mL, 169 mmol), N-ethyl-N-isopropylpropan-2-amine (15.4 mL, 88.7 mmol), and dioxane (250 mL) was heated to 95° C. under nitrogen for 2 hours. The reaction was cooled to ambient temperature and the resultant solids were filtered through celite washing with CH2Cl2. The filtrate was concentrated to a yellow oil and purified on silica eluting with 3%-5% MeOH/EtOAc to afford methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([O:18]CC)=[O:17].[OH-].[K+]>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)O)sc2ncc(-c3ccco3)nc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylate 58 (100 mg, 0.346 mmol) and potassium hydroxide (97 mg, 1.728 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 70° C. for 1 h. Quenched in ice cold citric acid solution. The resulting precipitate was collected, washed with water and dried to 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylic acid 59 (66 mg, 73.1%). (m/z)=262 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: N#Cc1ncc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3cc(Br)cnc3C#N)cc2)CC1

Procedure:
A solution of 5-bromo-3-fluoropicolinonitrile (1 g, 5 mmol), from EXAMPLE 49A, and 4-(4-methylpiperazin-1-yl)aniline (1.24 g, 6.5 mmol) in isopropanol (15 mL) was treated with triethylamine (0.76 mL, 7.5 mmol) was subjected to microwave irradiation (Biotage, Initiator) at 180° C. for 2 hours. The reaction mixture was concentrated and purified on silica gel with 2-25% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:31]=[N:32][NH2:33])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:34][Si](C(C)(C)C)(C)C)[CH:17]=[CH:16][C@@H:15]35)[Si](C(C)(C)C)(C)C.C(#N)C>O1CCCC1>[O:23]1[C@@H:19]2[C@@:20]34[CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:31]=[N:32][NH2:33])[C@@H:14]([C@@H:15]3[CH:16]=[CH:17][C@@H:18]2[OH:34])[CH2:13][C:12]2=[C:21]4[C:22]1=[C:9]([OH:1])[CH:10]=[CH:11]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCNC=NN)CC[C@]314
Solvent: CC#N
Solvent: C1CCOC1
Product: NN=CNCCCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Yield: 73 %

Procedure:
3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(N-aminoiminomethyl-aminopropyl)morphinan was deprotected using 40% HF in a 10:1 mixture of acetonitrile and tetrahydrofuran as described before. The precipitate was filtered and washed with acetonitrile, methylenechloride followed by methanol. KRS-2-47 was obtained as a white powder in 73% yield (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[OH:31]O.[OH-].[Na+].Cl>C1COCC1.O>[OH:31][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=1)[O:11][CH:10]([C:13]([F:14])([F:16])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: OO
Reactant: CCOC(=O)C1=Cc2cc(B3OC(C)(C)C(C)(C)O3)cc(OC)c2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2cc(O)cc(OC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 424.6 %

Procedure:
The ethyl 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.21 g, 0.49 mmole) was dissolved in THF (3 mL) and cooled to 0° C. (ice bath). Hydrogen peroxide (0.25 g, 0.074 mmole) followed by 2.5N sodium hydroxide (0.20 mL) was added dropwise and the resulting solution was stirred for 3 hours. The contents were poured into water (20 mL) and acidified using 2.4 N HCl to pH around 1 and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to flash chromatography (silica gel) and eluted with 0-35% EtOAc/ hexanes to give yellow solid (0.1 g, 65%). LCMS m/z 319.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.66 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 3.86 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [NH3:1].[F:2][CH:3]([F:20])[C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][C:10]=2[O:18][CH3:19])[CH:8]=1>>[F:20][CH:3]([F:2])[C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:1])=[S:17])=[CH:11][C:10]=2[O:18][CH3:19])[CH:8]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-n1cnc(C(F)F)c1
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C(F)F)c1
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Step N (6): Methanolic ammonia (2.0 M, 100 mL, 200 mmol) was added to a flask charged with 4-(difluoromethyl)-1-(4-isothiocyanato-2-methoxyphenyl)-1H-imidazole (2.26 g, 8.1 mmol). After 16 h, the reaction mixture was concentrated in vacuo to afford 1-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (2.08 g, 87% yield). LC-MS (M+H)+ 299.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([C:29]1[C:28]([CH3:35])=[N:1][C:2]2[C:3]([C:25]=1[NH2:26])=[C:4]([O:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12]1)[CH:22]=[CH:23][CH:24]=2)=[O:31])[CH3:34]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCC(NC(=O)c2ccncc2)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC(NC(=O)c4ccncc4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)-isonicotinamide (Example 108b) and ethyl 3-oxobutanoate as a yellow solid (25%). MS 463 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([NH2:14])=[O:13])[CH2:4][CH3:5])[CH3:2].N.CN.C1([NH2:21])CC1>>[NH2:21][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:7]1[C:12]([NH2:14])=[O:13]
Reactant: NC1CC1
Reactant: CCC(CC)c1cc(C)[nH]c1C(N)=O
Agent: CN
Agent: N
Product: CCC(CC)c1cc(C)n(N)c1C(N)=O

Procedure:
By the same procedure as a reaction of Example 5, using 3-(1-ethylpropyl)-5-methyl-1H-pyrrole-2-carboxamide (which was provided by the same procedure as a reaction of Example 4, using a saturated aqueous solution of ammonia instead of an aqueous solution of 40% methylamine) instead of the compound prepared in Example 4, using cyclopropylamine instead of 40% aqueous solution of methylamine, and using the corresponding aldehydes instead of the compound prepared in Example 7, the title compound (1.988 g) having the following physical data was obtained.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH3:10][C:11](=O)[CH:12]=[CH:13][CH3:14].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:10][C:11]1[CH2:12][CH:13]([CH3:14])[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=1
Reactant: CC=CC(C)=O
Reactant: CCOC(=O)CNN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN1N=C(C)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A mixture of ethyl hydrazinoacetate hydrochloride (1.55 g, 10 mmol), 3-pentene-2-one (0.95 mL, 10 mmol) and sodium bicarbonate (1.00 g, 11.9 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting oil was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a yellow oil (0.26 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[CH2:11][O:12][CH3:13].[OH:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH3:13][O:12][CH2:11][O:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COCCl
Reactant: CCOC(=O)C(C)(C)C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)C(OCOC)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Diisopropylethylamine (15.9 ml) and chloro(methoxy)methane (5.48 ml) were added dropwise to a methylene chloride (270 ml) solution of ethyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (13.5 g) under ice cooling, followed by stirring at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and water and the organic layer washed with an aqueous hydrochloric acid solution (1M), a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was subjected to evaporation under reduced pressure and then the residue was purified by silica gel column chromatography to obtain ethyl 3-(methoxymethoxy)-2,2-dimethyl-3-phenylpropanoate (13.1 g).