Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:8]([CH3:25])[CH2:7][C:6]2=[O:26].[CH:27](OCC)=[O:28].[O-]CC.[Na+].[H-].[Na+]>C1C=CC=CC=1.C(O)C>[OH:28][CH:27]=[C:7]1[C:6](=[O:26])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]1[CH3:25]
Reactant: CCOC=O
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O

Procedure:
Following the procedure of Examples 1-E, 16-B and 17-B, 9.5 g. of benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 10.95 ml. of ethyl formate and sodium ethoxide prepared from 2.57 g. of sodium hydride and 3.23 ml. of ethanol in 120 ml. of benzene gave on work-up a yellow oil which on crystallization afforded 6.0 g. of crude product, m.p. 106°-110°C. The analytical same is recrystallized several times from methanol, m.p. 116°-118°C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[H-].[Na+].I[CH3:29]>O1CCCC1.O>[CH3:29][N:22]([C:20]1[CH:19]=[N:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:12][CH:13]=2)[CH:21]=1)[C:23](=[O:25])[CH3:24]
Reactant: CI
Reactant: CC(=O)Nc1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a solution of N-[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]acetamide obtained in Example 37 (0.34 g) in tetrahydrofuran (3.5 mL), sodium hydride (55% in mineral oil, 0.048 g) was added and iodomethane (0.225 g) was then added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: ethyl acetate:hexane=1:1→ethyl acetate), and the resulting crystal was washed with diisopropyl ether to give the titled compound (0.187 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A cooled (0° C.) solution of (4-bromo-3-fluorophenyl)methanol (Intermediate 9; 299 mg; 1.46 mmol) and methanesulfonyl chloride (147 μL; 1.90 mmol) in DCM (3 mL) was treated slowly with a solution of triethylamine (305 μL; 2.19 mmol) in DCM (1.5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes before being quenched by addition of water. The organic phase was washed with HCl (0.1N in water) and brine, dried over MgSO4, filtered and concentrated to dryness affording a residue, which was purified by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([C:28](Cl)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc5ccccc45)cc3c2C1
Yield: 78.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.2 μL (0.051 mMol) 1-naphthoyl chloride, 13.8 mg (78%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17](Br)=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])[CH3:2].[CH2:21]([N:25]1C=CN=C1)CCC>C1(C)C=CC=CC=1.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([C:21]#[N:25])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CCCCn1ccnc1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2c(s1)CCOc1ccc(C#N)cc1-2

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (500 mg), potassium ferrocyanide (dried, 104 mg), copper (I) iodide (27 mg) and 1-butylimidazole (0.37 mL) in toluene (3 mL) was reacted in the microwave at 160° C. for 4 h. The mixture was then partitioned between dichloromethane (30 mL) and water (20 mL). The organic layer was dried (MgSO4), reduced in vacuo and purified on silica to give 9-cyano-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27]O)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:16]2[C:17]3[C:18]4=[C:19]([CH:23]=[CH:24][N:25]4[CH2:26][CH2:27]2)[N:20]=[CH:21][N:22]=3)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCO)c34)cc2C)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Oc2ccc(N3CCn4ccc5ncnc3c54)cc2C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a suspension of 2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol (50 mg) and tributylphosphine (54 mg) in toluene (2.5 mL) was added 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (67 mg), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (36 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.[Cl:13]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Cl:13][C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(O)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.9 %

Procedure:
2-Methylquinolin-7-ol (200 mg, 1.26 mmol) was added to a solution of 1-chloropyrrolidine-2,5-dione (168 mg, 1.26 mmol) and zirconium(IV) chloride (14.6 mg, 0.0628 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with chloroform (30 mL) and washed with an aqueous sodium carbonate solution followed by brine. After drying (MgSO4), the solution was filtered and concentrated under reduced pressure and the residue was purified by reverse phase chromatography (SP4, 25 M, eluting with a gradient of water/ACN 90:10 to 0:100, 30 column volumes) to yield 8-chloro-2-methylquinolin-7-ol (134 mg, 55.1% yield) as a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[NH2:38][CH2:39][C@@H:40]([C:42]1[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=1)[OH:41].CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NC[C@@H](C1C=CC=C(Cl)C=1)O>>[CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][CH:30]([NH:38][CH2:39][C@H:40]([OH:41])[C:42]4[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=4)[CH2:35][CH2:36]3)=[CH:25][CH:26]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: NC[C@H](O)c1cccc(Cl)c1
Product: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)S1)C(=O)OCC

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester(which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.
Reaction SMILES: [OH:1]O.[C:3]([C:5]1[C:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([O:14][C:15]1[CH:27]=[CH:26][C:18]3[C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][O:21][C:17]=3[CH:16]=1)[CH2:9][CH2:8]2)#[N:4]>FC(F)(F)C(O)C(F)(F)F.C(OCC)(=O)C>[C:3]([C:5]1[C:6]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:36])=[O:1])=[CH:33][CH:34]=2)=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([O:14][C:15]1[CH:27]=[CH:26][C:18]3[C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][O:21][C:17]=3[CH:16]=1)[CH2:9][CH2:8]2)#[N:4]
Reactant: OO
Reactant: CSc1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous hydrogen peroxide (35%, 5 μL) is added to a solution of {(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (120 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.5 mL) at room temperature. The mixture is stirred at room temperature for 2 h and then diluted with ethyl acetate. The resulting mixture is washed with aqueous Na2S2C3 solution, 1 M aqueous HCl solution, and brine, and dried (Na2SO4). The solvent is evaporated to give the title compound. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=[NH:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[N:24]=[C:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([OH:11])[CH:7]=2)[N:1]=1)=[O:28])[CH3:20]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: CCOC(=N)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nc(O)c2cc(O)ccc2n1
Temperature: 60 °C

Procedure:
2-amino-5-hydroxy-benzoic acid (15 mmol) are suspended in ethanol (water free, 600 ml) and heated up to 60° C. and stirred. Then triethylamine (30 mmol) is added and a clear solution is formed. Ethoxy-imino-acetic acid ethyl ester (16.5 mmol) is added at 60° C. and after 15 minutes another portion of triethylamine (15 mmol) is added and the mixture stirred for another 30 minutes. The mixture is cooled down to RT and left at RT without stirring over night. The solid material formed was filtered off, washed with ethanol/ether and dried (vacuum). A pale brown powder with mp. 258-260° C. (decomposition) is obtained.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=2[C:15]([NH:17][C:18]2[CH:36]=[CH:35][C:21]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[O:16])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:36]=[CH:35][C:21]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1)=[O:16]
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 85.2 %

Procedure:
A mixture of 1-{4-[2-[6-phthalimidohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (3.75 g), hydrazine hydrate (0.44 ml) and ethanol (30 ml) is refluxed for 3.5 hours. The precipitated crystal is collected by filtration, dried and purified by silica gel column chromatography (eluent; chloroform:methanol:aqueous ammonia=100:10:1), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.52 g) as white powder, m.p. 135.5°-137.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:35]=[O:36])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([C:23]([CH:35]=[O:36])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C1CCc2c(C=O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the product from Step 9 of Example 1 (15 mg) in 2 mL of DMF was added 15 μL of POCl3. After stirring for 10 min, 2 mL of water was added and the reaction mixture was stirred for 24 h. The solid was collected by filtration to give the title compound (˜16 mg). 1H NMR (500 MHz, acetone-d6) δ 10.11 (s, 1H), 8.15 (m, 1H), 8.10 (m, 2H), 7.48 (t, 2H), 7.45 (m, 1H), 7.27 (m, 2H), 4.68 (m, 1H), 4.30 (m, 1H), 4.06 (t, 1H), 3.62-3.68 (m, 1H), 3.18-3.27 (m, 1H), 3.10 (s, 3H), 2.10 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.Cl.[N-:18]=[N+:19]=[N-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]([C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC)CC(=O)Nc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CC(=O)Nc1cccc(N=[N+]=[N-])c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
N-(3-Aminophenyl)-2-(diethylamino)acetamide 5 (0.52 g, 2.35 mmol) was dissolved in THF (6 ml), and cooled in an ice bath. The resulting stirred mixture was treated sequentially with concentrated aqueous HCl (1.08 ml, 12.92 mmol), then with tBuONO (0.61 g, 5.87 mmol). The reaction was stirred in an ice bath for 1.5 hours and after that time NaN3 (0.46 g, 7.05 mmol) was added, followed by careful addition of water, until the reaction ceased to effervesse. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was carefully neutralised with saturated aqueous NaHCO3 solution and THF was evaporated in vacuo. The aqueous solution was extracted three times with EtOAc (75 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo, to give N-(3-azidophenyl)-2-(diethylamino)acetamide 6 as a dark brown oil (0.56 g, 85%) without requiring any further purification; Rf 0.24 [10% MeOH in DCM]; IR (film): 3279.67, 2934.63, 2110.57, 1687.86, 1515.73 cm−1; δH (CDCl3, 400 MHz) 9.43 (1H, s, NH), 7.41 (1H, m, ArH), 7.30-7.23 (2H, m, 2×ArH), 6.76 (1H, td, J1=8.0, J2=2.0 Hz, ArH), 3.13 (2H, s, CH2), 2.64 (4H, m, 2×CH2), 1.08 (6H, m, 2×CH3); δC (CDCl3, 100 MHz) 170.25 (C═O), 140.95 (Ar—C), 139.18 (Ar—C), 130.14 (Ar—CH), 115.60 (Ar—CH), 114.48 (Ar—CH), 109.96 (Ar—CH), 58.11 (CH2), 48.92 (2×CH2), 12.40 (2×CH3); LC-MS (5 min) m/z 248.49 [C12H17N5O+H]+ (25), 220.07 [(C12H17N5O+H)-28]+ (40) Rt 2.05 min; HRMS m/z calc. C12H18N5O [M+H]+248.1506. found [M+H]+ 247.1498.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][NH2:54]>CO.O1CCCC1>[CH3:53][NH:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:51]
Reactant: CN
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CNC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (50 mg, 0.56 mmol, obtained from the synthetic method described in step 1 of example 10) in a methanol/tetrahydrofuran mixture (v/v=2/1, 9 mL) was added methylamine solution (1 mL, 1.25 mmol). The mixture was heated to 55° C. and stirred for 16 h. The resulting mixture was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2) and saturated brine (10 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 11a as a white solid (37.4 mg, 71.6%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.41 (m, 2H), 7.40 (m, 1H), 7.32 (m, 3H), 7.26 (m, 6H), 7.17 (m, 3H), 7.04 (d, 2H), 6.85 (m, 2H), 6.73 (m, 2H), 4.87 (m, 1H), 4.75 (m, 3H), 4.26 (m, 1H), 4.11 (m, 2H), 3.97 (m, 2H), 3.92 (m, 3H), 3.82 (m, 2H), 3.72 (m, 3H), 2.65 (m, 1H), 2.55 (m, 1H), 2.22 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>CCN(CC)CC.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.[Cu]I>[CH3:9][O:8][C:6]1[N:5]=[CH:4][C:3]([NH2:10])=[C:2]([C:14]#[C:13][CH:12]([CH3:15])[CH3:11])[CH:7]=1
Reactant: C#CC(C)C
Reactant: COc1cc(I)c(N)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1cc(C#CC(C)C)c(N)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-iodo-6-methoxypyridin-3-amine (Compound 3, 845 mg, 3.4 mmol) in Et3N (12 ml) in a re-sealable pressure tube was added Pd(PPh3)2Cl2 (24 mg, 0.034 mmol), CuI (7.0 mg, 0.034 mmol), and 3-methyl-1-butyne (0.66 ml, 6.8 mmol). The mixture was stirred at room temperature for 20 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of (4R)-1-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) prepared in Step A in DMF was added K2CO3 (14 g, 101 mmol) and methyliodide (2.6 ml, 51.9 mmol). The reaction mixture was stirred at rt for 5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.0 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)Nc3ccc(C(C)(C)C)cc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 4-t-butylaniline to give N-(4-t-butylphenyl)-7-methoxybenzofuran-2-carboxamide (Compound 389a). Successively, it was formylated to give N-(4-t-butylphenyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 389b), then compound 389b was reacted with cyclobutylamine to give compound 389 as a white solid.