Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=O)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=[S:31])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2scc(CC3C(=O)N=C4C=CC=CN43)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc2scc(CC3C(=S)N=C4C=CC=CN43)c12
Temperature: 170 °C

Procedure:
A suspension of 475 mg (1.6 mmol) of 3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-one and 525 mg (1.3 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide in 20 mL of toluene is heated at 170° C. for 90 minutes under microwave condition. The precipitated solid is collected to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:11][C:12]([C:14]#[C:15][C:16](OCCCC)=[O:17])=[O:13])[CH2:8][CH2:9][CH3:10]>C(O)C>[CH2:7]([O:11][C:12]([C:14]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:16](=[O:17])[CH:15]=1)=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOC(=O)C#CC(=O)OCCCC
Reactant: Nc1nccs1
Solvent: CCO
Product: CCCCOC(=O)c1cc(=O)nc2sccn12

Procedure:
The procedure is as in Example 22, except that 5 g of 2-aminothiazole are reacted with 11.3 g of acetylene dicarboxylic acid di-n-butyl ester in presence of 50 ml of absolute ethanol. 7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid n-butyl ester melting at 142°-144° C. is thus obtained in a yield of 8.1 g (64.3% of the theoretical).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C=O)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
In a 250 mL round bottom flask, 2-chloro-4-fluorobenzaldehyde (3.15 g, 20 mmol), 1-ethylpiperazine (2.8 mL, 22 mmol), and potassium carbonate (2.76 g, 20 mmol) were dissolved in anhydrous DMF (20 mL). The mixture was heated at 100° C. for 4 hours. DMF was evaporated under vacuum. The crude product was partitioned between water (100 mL) and DCM (150 mL). The organic phase was separated, washed with water, dried over Na2SO4, and evaporated to provide nearly pure 2-chloro-4-(4-ethylpiperazin-1-yl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH2:19])[C:6]=2[CH:20]=1.O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][C:22](=[O:24])[CH3:23])[C:6]=2[CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Solvent: O
Product: CC(=O)NCCCC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
3-Chloro-5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution heated to refluxing for 20 minutes. The solution then is cooled and poured into a large volume of water. The mixture is stirred until the excess reagent is hydrolyzed. The product then is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:13]
Reactant: NCc1nc2ccccc2o1
Reactant: CCOC=O
Product: O=CNCc1nc2ccccc2o1

Procedure:
A mixture of 4.29 g (28.9 mmol) of 2-(aminomethyl)benzoxazole (PREPARATION 6) and 20 ml of ethyl formate is heated at 80° for 2 hr, after which the excess ethyl formate is removed under reduced pressure. The residue is chromatographed on silica gel (350 ml) eluting with methanol/dichloromethane (2/98), the appropriate fractions are pooled and concentrated to give the product, which is crystallized from dichloromethane/hexane to give the title compound, mp 98°-99°; MS (m/z) at 176; IR 1655, 1621, 1519, 1241, 750 cm-1 ; NMR (CDCl3) 4.81, 6.45, 7.36. 7.53, 7.70, 8.39 δ.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)([CH3:25])([CH3:24])[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27](=[O:33])[NH:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.213 g, 0.71 mmol) and (S)-proline tert-butyl amide (0.133 g, 0.78 mmol) gives the title compound.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:32])([F:31])[F:30])[CH2:23][NH2:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:30])([F:31])[F:32])[CH2:23][NH:24][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 3-fluoro-4-(trifluoromethoxy)benzylamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)[OH:24])[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33].[CH3:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([OH:24])[C:25]4[CH:30]=[CH:29][C:28]([C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:44]=5)=[CH:27][N:26]=4)[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1sc2nc(N3CCC(NCC(O)c4ccc(Br)cn4)CC3)cc(C(F)(F)F)c2c1N
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(C(O)CNC3CCN(c4cc(C(F)(F)F)c5c(N)c(C(N)=O)sc5n4)CC3)nc2)c1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
A N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (60 mg, 0.107 mmol), (3-methylsulfonylphenyl)boronic acid (24 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and potassium carbonate (30 mg, 0.214 mmol) in dry DMF (4 ml) and water (1 ml) was sealed and heated to 85° C. for 18h. The crude reaction mixture was applied to a celite plug and purified by SiO2 chromatography (0–25% MeOH/CH2Cl2 with 1% NH4OH). Fractions containing product were pooled and concentrated. The solid yellow residue was dissolved in 1 ml DMF, applied to a 2 mm prep plate (Merck) and eluted twice with 10% MeOH/CH2Cl2 with 1% NH4OH. The recovered yellow residue was dissolved in 0.5 ml water, 2 ml MeOH, 10 ml CH2Cl2, and 10 ml EtOAc and crystallized by the addition of 50 ml hexanes to give 29.0 mg, 42.3% of 3-Amino-6-(4-{2-hydroxy-2-[5-(3-methanesulfonyl-phenyl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide product. ES+ 635.1 m/z (MH+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH:7]([O:9][C:10]2[C:15]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][C:13]([F:22])=[CH:12][N:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>CO.O>[F:22][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([O:9][CH:7]2[CH2:8][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[N:11][CH:12]=1
Reactant: COC(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methyl ester (3.2 g) in MeOH (60 mL) and water (15 mL) at RT was added lithium hydroxide (1.0 g, 41.6 mmol). The reaction mixture was heated to 50° C. for 2 h and then additional LiOH (400 mg) was added. Stirring was continued at 50° C. for 1 h. The reaction was neutralized with 5 M HCl and concentrated. The concentrated solution was extracted with EtOAc (50 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over MgSO4 and concentrated to give the product (1.5 g), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:20])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
3-Bromo-4-fluorobenzonitrile (100 g) was dissolved in dimethylformamide (DMF) (500 ml), and sodium sulfide nonahydrate (132 g) was added thereto at 0° C. and then stirred overnight at room temperature. The reaction mixture was poured to ice water (1 L) and the insoluble material was filtered off. The filtrate was added to a 1N aqueous hydrochloric acid solution (700 ml) under ice-cooling and the precipitate was collected by filtration. The crystals thus obtained were washed with hexane/diisopropyl ether and water and then dried to obtain 3-bromo-4-mercaptobenzonitrile (95.0 g) as a light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([CH3:32])[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25])[CH2:17][CH2:16]2)[CH:10]=1.[OH-].[Na+]>O>[C:9]1([CH3:32])[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]3[C:24](=[O:25])[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]4=[N:8][C:29]=3[CH3:31])[CH2:19][CH2:20]2)[CH:10]=1
Reactant: CCOC(=O)C(CCN1CCN(c2cccc(C)c2)CC1)C(C)=O
Reactant: Cc1cccnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(N2CCN(CCc3c(C)nc4c(C)cccn4c3=O)CC2)c1
Yield: 15.1 %

Procedure:
A mixture of 0.19 g of 3-methyl-2-aminopyridine, 1 g of ethyl 2-[2-(4-m-tolyl-1-piperazinyl)ethyl]acetoacetate and 1.17 g of polyphosphoric acid was heated at 120° - 130°C for 2 hours. After completion of the reaction, water was added to the reaction mixture. The resulting mixture was made basic by addition of an aqueous sodium hydroxide solution and then extracted with ethyl acetate. After evaporation of the solvent from the extract, the remaining residue was washed with isopropyl alcohol and recrystallized from isopropyl alcohol to give 0.1 g of the desired compound as pale yellow needles, m.p. 106° - 106.5°C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.95 g, 1.9 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.34 g, 1.1 mmol), Na2CO3 (2 M, 4.6 mL), and Pd(PPh3)2Cl2 (226 mg, 0.1 mmol) in toluene/ethanol (1:1, 16 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 3-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine as brown solid in 67% yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: CNCCc1ccccc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)CCc3ccccc3)c2)C[C@H]1C

Procedure:
N-Methylphenethylamine was coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-phenethylbenzamide as a light yellow powder. NMR (300 MHz, DMSO-d6, 80° C.): δ 0.91 (d, J=5.5 Hz, 3H); 1.08 (d, J=6.3 Hz, 3H); 1.87 (dd, J1 =7.1 Hz, J2 =11.2 Hz, 1H); 2.09 (dd, J1 =7.1 Hz, J2 =11.0 Hz, 1H); 2.58 (d, J=11.3 Hz, 1H); 2.67 (m, 1H); 2.76 (dd, J1 =6.2 Hz, J2 =13.2 Hz, 1H); 2.77-2.87 (m, 4H); 2.89 (s, 3H); 3.18 (dd, J1 =5.5 Hz, J2 =14.2 Hz, 1H); 3.55 (br s, 2H); 4.97 (s, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.74-5.89 (m, 1H); 6.65-6.73 (m, 3H); 7.07-7.41 (m, 9H); 7.43 (d, J=7.9 Hz, 1H); 9.07 (s, 1H). Mass spectrum (CI--CH4) m/e: 498 (M+1, 88%), 344 (22%), 153 (100%). [α]D20 =+3.8°0 (ethanol, c=1.25). The free amine (0.232 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.9 followed by precipitation with diethyl ether from dichloromethane to give 0.205 g of the monohydrochloride salt as a hygroscopic light yellow powder. Calc. for C32H39N3O2HCl H2O: C, 69.61; H, 7.67; N, 7.61; Cl, 6.42. Found: C, 69.51; H, 7.73; N, 7.47; Cl, 6.52.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2c(-c3ccccc3)noc2C)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), ethyl isonipecotate (33.8 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C19H22N2O4: 342.1580, found 342.1578.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: O=C(CCl)Nc1ccccc1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccccc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-phenylacetamide according to the method of Example 1; m.p. 125°-127°.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][OH:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:23]([OH:24])[CH3:22])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: CNO
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: CN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 12.00 (br s, 1H), 8.91 (s, 1H), 8.03 (s, 1H), 7.91 (d, 1H, J=2.8 Hz), 7.38 (dd, 2H, J=5.7 Hz, J=8.5 Hz), 7.12 (d, 2H, J=8.5 Hz), 6.71 (d, 1H, J=3.0 Hz), 5.59 (s, 2H), 3.33 (s, 3H). LCMS (API-ES, M+H+): 301.1. HRMS calcd for C16H15FN3O2 (M+H) 300.1148, found 300.1138. HPLC: 100% purity
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:44])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:45].[H][H]>[Pd].CC(O)C>[ClH:45].[NH2:11][CH2:12][C:13](=[O:44])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:17]
Reactant: O=C(CCC(=O)OCCCCCCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Yield: 19.2 %

Procedure:
This compound was prepared from the product of 15b (0.45 g; 0.74 mmol), 12 M HCl (0.062 mL; 0.74 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.06 g (19%) product was obtained (white solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>ClCCl>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:20])=[CH:12][C:11]=1[C:9]1[O:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([NH:1][C:34](=[O:35])[O:36][CH:37]([CH3:39])[CH3:38])[CH:3]=2
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide (1-15) (100 mg, 0.28 mmol, 1.00 equiv), triethylamine (85 mg, 0.84 mmol, 2.98 equiv), chloro(propan-2-yloxy)methanone (70 mg, 0.57 mmol, 2.03 equiv) in dichloromethane (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 10 mg (8%) of propan-2-yl N-[2-[2-chloro-5-(furan-2-amido)phenyl]-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (76) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-3-(carboethoxy)-piperidine (800 mg, 3.11 mmol) in dry THF (10 mL) at −78° C. was added a 0.6M solution of sodium hexamethyldisilazide in toluene (5.7 mL). The reaction was stirred for 1 h when benzyl bromide (559 mg, 3.27 mmol) was added. After 1 h, the reaction was warmed to room temperature for 15 h. The reaction was quenched by the addition of 1M HCl (10 mL). The reaction was extracted with EtOAc (4×20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 5–15% EtOAc in hexanes) to yield 606 mg of the product as a colorless oil. MS (ESI) 348 (M+H).