Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].CC(C)=[O:18].[Mn]([O-])(=O)(=O)=O.[K+].C(O)(C)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([OH:18])=[O:6]
Reactant: CC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Temperature: 50 °C

Procedure:
2,3-Dimethoxy-6-nitrobenzaldehyde (40.0 g, 0.19 mole) was treated with acetone (275 mL) and warmed to 50° C. A solution of potassium permanganate in water (60 g/L) was added slowly at 50°-70° C. over a period of 16-20 hours until thin layer chromatographic analysis revealed complete absence of the starting material. Isopropanol (7.5 mL) was then added and the mixture was heated an additional hour. The precipitated manganese dioxide was removed by filtration and the filter cake was washed with 3% aqueous potassium hydroxide (ca 175-200 mL). The combined filtrates were acidified with hydrochloric acid and the precipitate was collected by filtration and dried in vacuo. The crude product was recrystallized from acetone to give the pure material, 28.3 g (67%), mp 187°-189° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])CCC>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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:25]2[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C#N)c1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc(C#N)c2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 42.6 %

Procedure:
A solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (3 g, 7.75 mmol), tetrakis(triphenylphosphine)palladium (0.446 g, 0.775 mmol), and 3-tributylstannanyl-benzonitrile (3.65 g, 9.3 mmol) in dioxane (100 mL) was heated to 110° C. for 96 h under nitrogen. The mixture was allowed to cool to r.t., and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (silica gel 60, hexanes/DCM 9:1) to give 4-acetylamino-3′-cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.2 g, 3.3 mmol, 43%) as a yellow oil, ESI-MS: m/z 363 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:28]([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[CH2:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[N:30]1(/[CH:28]=[CH:29]/[C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]5)[N:12]=4)=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)ccc34)n2)CC(C)(C)N1
Reactant: C=Cn1ccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(/C=C/n5ccnc5)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 229 and 1-vinyl-1H-imidazole, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]1[CH2:22][CH2:23][CH2:24][C:16]1=[C:15]2[C:25](=[O:27])[CH3:26].[CH3:28][NH:29][CH3:30]>C1COCC1>[CH3:28][N:29]([CH3:30])[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]1[CH2:22][CH2:23][CH2:24][C:16]1=[C:15]2[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)c1c2c(cc3ccc(Cl)cc13)CCC2
Reactant: CNC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1c2c(cc3ccc(N(C)C)cc13)CCC2
Temperature: 85 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
An oven-dried sealed tube (0.5-2 mL) was equipped with a stir bar and charged with the precatalyst (0.003 g, 0.004 mmol). The tube was closed with a septum, then evacuated and refilled with nitrogen three times through a needle. LHMDS (0.3 mL of a 1.0 M solution in THF, 0.32 mmol) and compound 6b (0.038 g, 0.16 mmol) in THF (0.3 mL) were added via syringe. Finally, dimethylamine (0.3 mL of a 2.0 M solution in THF, 0.24 mmol) in THF (0.3 mL) was added at rt via syringe. The resulting solution was heated at 85° C. in an oil bath and stirred for 3 h. The consumption of the starting material was monitored by TLC. Once the reaction was complete, the mixture was cooled rt, diluted with sat'd aq ammonium chloride solution (10 mL), and then extracted with AcOEt (3×12 mL). The combined organic layers were dried over Na2SO4, gravity filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (n-hexane/AcOEt 9.25:0.7) and the pure product was isolated as a yellow solid (70% yield).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=Cc1cc2cnccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2cnccc2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of thieno[3,2-c]pyridine-2-carbaldehyde (720 mg, 4.41 mmol) in a 2.0 M solution of methylamine in methanol (25 mL) was stirred at room temperature for S hours. After this time, the mixture was concentrated to dryness, dissolved in anhydrous methanol (10 mL) then cooled to 0° C. To this solution was added NaBH4 (167 mg, 4.41 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. The mixture was concentrated, dissolved in CH2Cl2 (100 mL) and treated with 1.0 N NaOH (20 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic fractions were washed with brine, dried over Na2SO4 then concentrated to give a yellow residue which was subjected to flash chromatography on silica gel (10% 2M NH3 in MeOH:CH2Cl2). The title compound was obtained as a white solid in 63.6% yield: 1H-NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.29 (s, 1H), 4.10 (s, 2H), 2.54 (s, 3H); MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:20][CH:19]=[N:18][N:17]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2].[Br:31]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(#N)C>>[Br:31][C:19]1[NH:20][C:16]([C:6]2[S:5][C:4]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)=[C:3]([C:1]#[N:2])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:17][N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1cc(-c2sc(-c3nnc(Br)[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A suspension of N-(4-(3-cyano-4-(2,4-dichlorophenyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide (0.0700 g, 0.154 mmol) and N-Bromosuccinimide (33.1 mg, 0.186 mmol) in Carbon tetrachloride (2.5 mL, 26 mmol) was heated to 85° C. in a capped vial for 2.5 hours. To the suspension was added dry Acetonitrile (6.0 mL, 110 mmol) and the mixture was heated at 85° C. (turned into a clear solution) for 2 hours. The mixture was cooled to r.t., evaporated in rotavapor. The residue was dry loaded in a silica column and eluted with MeOH/DCM (0/100 to 5/95) to give a solid product (66.0 mg, yield 80.4%). LCMS: (FA) ES+, 533, 535, 537 and ES− 531, 533, 535. 1H NMR (400 MHz, d1-chloroform) δ: 8.65 (s, 1H), 8.42 (d, J=5.02 Hz, 1H), 8.26 (s, 1H), 7.61 (d, J=2.01 Hz, 1H), 7.56 (dd, J=5.27, 1.76 Hz, 1H), 7.43-7.45 (dd, J=8.28, 2.01 Hz, 1H), 7.37-7.39 (d, J=8.28 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH:40]([C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[C:53](=[O:54])[CH2:52][N:51]([C@@H:55]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C:56](O)=[O:57])[C:50]2=[O:63])[N:47]=1)([CH3:42])[CH3:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:56](=[O:57])[C@@H:55]([N:51]1[CH2:52][C:53](=[O:54])[N:49]([CH2:48][C:46]2[N:47]=[C:43]([CH:40]([CH3:42])[CH3:41])[S:44][CH:45]=2)[C:50]1=[O:63])[CH:59]([CH3:62])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2csc(C(C)C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2csc(C(C)C)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution containing the product from Example 2C (0.030 g, 0.056 mmol) in THF (0.5 mL) was treated with the product from Example 56E (0.026 g, 0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.033 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.66 (d, J=6.62 Hz, 3 H), 0.73 (t, J=7.35 Hz, 3 H), 0.88 (m, 12 H), 1.26 (s, 3 H), 1.29 (s, 3 H), 1.50 (m, 2 H), 1.73 (m, 1 H), 2.69 (m, 4 H), 3.10 (d, J=18.38 Hz, 1 H), 3.50 (s, 3 H), 3.78 (m, 3 H) 4.17 (m, 3 H), 4.66 (m, 3 H), 6.67 (d, J=9.93 Hz, 1 H), 6.99 (m, 3 H), 7.07 (m, 2 H), 7.23 (m, 3 H), 7.31 (m, 1 H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Product from Example 140, step 3 (100 mg, 0.26 mmol) was dissolved in 3 ml EtOH, and NaBH4 (7.5 mg, 0.196 mmol) in 1 ml H2O was added and the mixture stirred at rt for 2 h. The mixture was then quenched with 3N NaOH (5 mL) and ether was added to extract the compound, which was dried over anhy. MgSO4 and concentrated to give a yellow oil (90.1 mg, 90.1%)
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=[S:30])[CH3:2]
Reactant: CNc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CNc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.356 mmol) and Lawesson reagent (0.144 g, 0.356 mmol) in dioxane (3 mL) was stirred at 65° C. for 2 h. Solvent was removed under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a product as foam. Yield 0.097 g (92%). MS (m/z): [M+H]+=298.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.S1(CCCC1)(=O)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([NH:18][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Solvent: O=S1(=O)CCCC1
Product: c1ccc(Nc2c[nH]c3ncccc23)cc1
Temperature: 180 °C

Procedure:
To 10 mg of 3-bromo-1H-pyrrolo[2,3-b]pyridine 582 was added 0.4 mL of sulfolane and aniline (2-3 equiv). The vial was sealed and heated at 180° C. for 10 minutes. After cooling, the desired compound was isolated by preparative HPLC/MS.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[C:24]([NH2:29])[N:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25]2[C:26]([OH:28])=[N:27][C:22]([NH2:21])=[N:23][C:24]=2[NH:29][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: Nc1cc(O)nc(N)n1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc(N)nc(O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
500 mg (1.85 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are mixed with 349 mg (2.77 mmol) of 2,6-diaminopyrimidin-4-ol, dissolved in 10 ml of isopropanol, and heated under reflux under argon for 2 days. The mixture is filtered and the remaining solid is washed with isopropanol. 660 mg (94% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][NH2:14])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:1][C:2]1[C:3]([CH2:13][NH:14][C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CSc1nc2cc(F)c(CN)cc2s1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2cc(F)c(CNc3ncccc3[N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To a stirred mixture of (5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine (128 mg, 0.6 mmol) and DIEA (195 μL, 1.2 mmol) at 0° C. under argon was added 2-chloro-3-nitropyridine (98 mg, 0.7 mmol) in one portion. The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford N-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine (165 mg, 84%) as a yellow oil. LCMS (ESI) m/z 351 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[C:7]([O:32][CH3:33])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (62 mg), morpholine (40 mg), and potassium carbonate (100 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (45 mg, yield 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][NH:47][CH2:48][CH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[O:52][CH2:53][CH2:54][OH:55].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[N:47]([CH2:48][CH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[O:52][CH2:53][CH2:54][OH:55])[CH3:46])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNCCc1ccccc1OCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
(2R)-2-(tert-Butoxycarbonylamino)-3-(2-naphthyl)propionic acid (654 mg, 2.07 mmol) was dissolved in N,N-dimethylformamide (4 ml) and dichloromethane (4 ml). 1-Hydroxy-7-azabenzotriazole (282 mg, 2.07 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (397 mg, 2.07 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of 2-(2-(2-(methylamino)ethyl)phenoxy)ethanol (434 mg, 2.07 mmol) in dichloromethane (4 ml) and ethyldiisopropylamine (0.36 ml, 2.07 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (50 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g), using ethyl acetate/heptane 1:1 as eluent, to give 539 mg of [(1R)-1-(N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: COC(=O)C(C/C=C/c1ccccc1)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C(C/C=C/c1ccccc1)C(C)O

Procedure:
Analogously to Example 30A, 8.00 g (34.44 mmol) of methyl (4E)-2-acetyl-5-phenyl-4-pentenoate are reacted with 0.72 g (18.9 mmol) of sodium borohydride to give methyl (4E)-2-(1-hydroxyethyl)-5-phenyl-4-pentenoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:3]=1[OH:15].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>O1CCCC1>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C:4]1[C:3]2[O:15][C:16](=[O:17])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(OC2CCCCO2)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(OC3CCCCO3)c2o1
Yield: 87.2 %

Procedure:
To a solution of 2-amino-6-(tetrahydropyran-2-yloxy)phenol (2.0 g) in anhydrous tetrahydrofuran (30 ml) was added 1,1′-carbonyldiimidazole (2.03 g), and the mixture was refluxed for 2 hours under nitrogen atmosphere. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (chloroform:methanol=40:1, v/v) and crystallized with diisopropyl ether to give 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (1.96 g).
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[NH:19][C:20]4[C:21]([N:39]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([N:33]5[CH2:37][CH2:36][C@@H:35](O)[CH2:34]5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:26][C:24]1[CH:25]=[C:20]2[NH:19][C:18]([O:17][C@H:16]3[C@H:12]4[O:11][CH2:10][C@@H:9]([OH:8])[C@H:13]4[O:14][CH2:15]3)=[N:39][C:21]2=[N:22][C:23]=1[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:34]=[CH:35][CH:36]=[CH:37]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CC[C@@H](O)C4)cc3)c(Cl)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-n4cccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
(3R)-1-[4-[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]pyrrolidin-3-ol (229.7 mg, 0.401 mmol) and tetrabutylammonium fluoride 1.0 M in THF (4.2 ml, 4.20 mmol) were combined in a 40 ml vial. The reaction mixture was an amber solution that was stirred at room temperature. After 1.25 hours, the reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was separated, and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. This material (loaded in DMSO/MeOH) was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting (20 ml/min) with a 17 minute 10%-60% acetonitrile/water+0.05% TFA gradient followed by a 2 minute 60% acetonitrile/water+0.05% TFA flush. The product fractions were combined, frozen, and lyophilized to give the title compound as a light yellow solid. LC-MS: calculated for C22H19ClN4O4 438.11 observed m/e: 439.18 (M+H)+ (Rt 1.14/2 min); 1H NMR δ (ppm) (500 MHz CD3OD): 7.87 (s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.28 (d, J=2.5 Hz, 2H), 6.33 (d, J=2.5 Hz, 2H), 5.57 (q, J=5.6 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.48 (t, J=5.1 Hz, 1H), 4.28-4.32 (m, 1H), 4.18 (dd, J=10.3, 5.8 Hz, 1H), 4.13 (dd, J=10.6, 4.7 Hz, 1H), 3.91 (dd, J=8.3, 6.7 Hz, 1H), 3.61 (dd, J=9.0, 7.6 Hz, 1H).