Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:37])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[CH2:30][N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:38](OCC)=[O:39])=[N:10]2)=[CH:5][CH:4]=1.[NH4+:43].[OH-]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:37])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[CH2:30][N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:38]([NH2:43])=[O:39])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3CN(C)C(=O)NC)cc1)C2=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)N(C)Cc1ccccc1-c1ccc(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Ethyl 1-(4-methoxyphenyl)-6-[2′-({methyl[(methylamino)carbonyl]amino}methyl)-1,1′-biphenyl-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (130 mg, 0.2 mmol) was dissolved in 7.5 mL of 1,4-dioxane. Concentrated NH4OH (7.5 mL) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 4 days. The mixture was stripped and chromatographed using 3% MeOH:CHCl3 with 0.1% concentrated NH4OH. The fractions containing desired product were combined and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 71 mg of desired product (48% yield). MS (ES+): 539.4, (M+H)+. 1HNMR (CDCl3) δ 7.48 (t, 2H), 7.39-7.19 (m, 9H), 6.95 (m, 3H), 6.00 (bs, 1H), 4.47 (s, 2H), 4.189 (t, 2H), 3.83 (s, 3H), 3.41 (t, 2H), 2.77 (s, 3H), 2.72 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:31].[OH-]>>[NH2:31][C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2ncsc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2scnc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 140 °C
Yield: 64.7 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL NH4OH and heated to 140° C. for 20 min in a microwave reactor. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated onto silica gel. Purification by ISCO chromatography (0 to 50% EtOAC in DCM) afforded the title compound (62 mg, 0.139 mmol, 64.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.16 (s, 1H), 7.94 (d, J=5.1 Hz, 1H), 7.59-7.69 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.16-7.27 (m, 5H), 6.78 (s, 2H), 5.99 (d, J=5.3 Hz, 1H). MS (ESI): 446 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:8])[C:5]([OH:19])=[CH:4][CH:3]=1.O1CC[CH2:23]OO1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:23][N:9]([CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7](=[O:8])[C:6]=2[CH:18]=1
Reactant: C1COOOC1
Reactant: CCN(CC)CCCNC(=O)c1cc(Cl)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCCN1COc2ccc(Cl)cc2C1=O
Reaction time: 16 h

Procedure:
1.70 Grammes (6.0 mmoles) of 5-chloro-N-[3-(diethylamino)propyl]salicylamide and 540 milligrammes (6.0 mmoles) of trioxane are dissolved in 30 ml of trifluoroacetic acid and thereaction mixture is kept at room temperature for 16 hours.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].CN1CC[O:21]CC1>C(#N)C>[CH:11]1([CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:21])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cc(OCC2CC2)ccc1CBr
Reactant: CN1CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 1-(bromomethyl)-4-(cyclopropylmethoxy)-2-nitrobenzene (11.4 g) in acetonitrile (200 mL) were added molecular sieves 4 Å (55 g) and N-methylmorpholine (9.37 g) at room temperature. Under an argon atmosphere, the reaction mixture was stirred at room temperature for 1 hr, and filtered through celite. The obtained filtrate was concentrated under reduced pressure, and the residue was dissolved in diethyl ether and the solution was washed twice with 6N hydrochloric acid and once with water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (6.39 g).
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([CH3:13])[CH3:12])[C:5]1=[O:18])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:38]([O:1][C@@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([CH3:12])[CH3:13])[C:5]1=[O:18])[CH3:3])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O)[C@H]1SC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)c2ccccc2)[C@H]1SC
Reaction time: 1.5 h
Yield: 83 %

Procedure:
In 2 ml of tetrahydrofuran were dissolved (3S, 4R)-3-[(S)-1-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one (105 mg, 0.38 mmole), triphenylphosphine (201 mg, 2 equivalents) and benzoic acid (94 mg, 2 equivalents). To the resulting solution was added little by little a solution of diethyl azodicarboxylate (134 mg, 2 equivalents) in tetrahydrofuran (1 ml) at 20° C. over 10 minutes and then the mixture was stirred at the same temperature for 1.5 hours. The solvent was then distilled off and the residue was dissolved in 3 ml of a 6:1 by volume mixture of benzene and ethyl acetate and left to stand in a refrigerator. The resulting precipitate was filtered off and the filtrate was subjected to thin layer chromatography developed with a 5:1 by volume mixture of benzene and ethyl acetate to afford 119 mg (yield 82%) of the desired product as an oil, containing a small amount of the 1'S-isomer.
Reaction SMILES: ClCCC[CH2:5][OH:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23]O)[CH2:17][CH2:16]1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][CH2:5][OH:6])[CH2:19][CH2:20]1
Reactant: OCCCCCl
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Product: COc1ccccc1N1CCN(CCCCO)CC1
Yield: 33 %

Procedure:
4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butan-1-ol (30A) is prepared from 4-chloro-butan-1-ol as described for 29A.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][C:33](O)=[O:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[CH2:32][C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1c(Cl)cccc1Cl

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2,6-dichloro-phenyl)-acetic acid to yield (3aR,4S,7aR)-4-[2-(2,6-dichloro-phenyl)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=9.620 min; HPLC Method I
Reaction SMILES: [CH3:1][C:2]1([CH2:17][C:18]([O:20]CC)=[O:19])[C:16]2[C:6]([CH:7]=[C:8]3[NH:13][C:12](=[O:14])[C:11](=[O:15])[NH:10][C:9]3=2)=[CH:5][CH:4]=[CH:3]1.Cl>O1CCOCC1>[CH3:1][C:2]1([CH2:17][C:18]([OH:20])=[O:19])[C:16]2[C:6]([CH:7]=[C:8]3[NH:13][C:12](=[O:14])[C:11](=[O:15])[NH:10][C:9]3=2)=[CH:5][CH:4]=[CH:3]1
Reactant: CCOC(=O)CC1(C)C=CC=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CC(=O)O)C=CC=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Temperature: 40 °C
Yield: 63 %

Procedure:
A mixture of 0.7 g of ethyl (5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno [1,2-b]pyrazin-5-yl)acetate, 40 ml of dioxane and 9 ml of 8N hydrochloric acid is heated to 40° C. for 90 hours. The reaction mixture is then evaporated in a rotary evaporator, and the evaporation residue is triturated in 20 ml of water, filtered off and rinsed with distilled water (2×10 ml) and then with isopropyl ether (10 ml). After drying at 60° C. under vacuum (1 mm Hg; 0.13 kPa), 0.4 g of (5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno [1,2-b]pyrazin-5-yl)acetic acid is obtained in the form of a pale yellow solid melting above 260° C. (Analysis % calculated C: 61.76; H: 4.44; N: 10.29; 0: 23.51; % found C: 61.8; H: 4.6; N: 10.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14]C(=O)OC(C)(C)C.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH2:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)ccc1F
Agent: Cl
Product: Nc1cc(N2CCOCC2)ccc1F
Yield: 56.8 %

Procedure:
A mixture of tert-butyl (2-fluoro-5-morpholinophenyl)carbamate (0.93 g, 3.14 mmol) and a solution of HCl (31 mL, 31 mmol, 1 M in MeOH) was stirred at rt overnight, then concentrated in vacuo. The residue was dissolved in water (150 mL). The soltution was basified with saturated Na2CO3 aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a light brown solid (0.35 g, 57%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=3[C:21](=[O:32])[C:20]=2[CH:33]=1>CC(N(C)C)=O>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:23]2[O:24][CH2:25][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:33][C:20]=3[C:21](=[O:32])[C:22]=2[CH:29]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1ccc2c(c1)C(=O)c1cc(N)ccc1CO2
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)C(=O)c1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1CO2
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
In dimethylacetamide (8 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.73 g, 4.63 mmol), and thionyl chloride (0.36 ml, 4.63 mmol) was added thereto at −15° C., followed by stirring at −15 to −5° C. for one hour. To the reaction mixture was added 9-amino-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 11 (0.59 g, 2.32 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained oily residue was dissolved in ethyl acetate (25 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), followed by trituration with isopropyl ether to give Compound 1-48 (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40]O)=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:42][C:43](=[N:52]C(=O)OC(C)(C)C)[NH:44]C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40][NH:44][C:43]([NH2:52])=[NH:42])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:10])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N=C(N)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCNC(=N)N
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a mixture of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxypropyl)benzoate (90 mg, 0.15 mmol, 1.0 eq), tert-butyl amino(tert-butoxycarbonylamino)methylenecarbamate (76 mg, 0.29 mmol, 2.0 eq) and triphenylphosphine (59 mg, 0.22 mmol, 1.5 eq) in tetrahydrofuran (0.7 mL) was added diisopropylazodicarboxylate (0.04 mL, 0.22 mmol, 1.5 eq). After stirring for 16 h, the reaction mixture was directly poured onto silica gel and purified (0 to 75% ethyl acetate/hexanes). This product was treated with 1:2 trifluoroacetic acid/dichloromethane (2 mL) at room temperature for 16 h. The reaction mixture was concentrated to provide 77 mg (70%) of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-guanidinopropyl)benzoate: MS (EI) m/z 759 [(M-Boc)H+].
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][NH:20][CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][N:20]([C:35]([O:37][CH3:38])=[O:36])[CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CNCC3)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC(C)C)n3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine (96 mg, 0.948 mmol) was added to a solution of 4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-N-(1-methylethyl)-2-pyrimidinamine (i.e. the product of Step E) (0.150 g, 0.426 mmol) and methyl chloroformate (41.1 μL, 0.178 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 25° C. for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 1:4) as eluant to give 25 mg of the title product, a compound of the present invention, as an off-white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23]C)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]>Br.C(O)(=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cn1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Yield: 104.2 %

Procedure:
A solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (1.0 g, 2.97 mmol) in 48% aqueous HBr (5 mL) and acetic acid (5 mL) was heated at 80° C. for 7.5 h before being concentrated in vacuo. The resultant residue was suspended in water (10 mL) and pH adjusted to ˜6 using 5N aqueous NaOH. The precipitate formed was filtered off, washed with water then dried in vacuo to give 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol as a white solid (1.01 g, 100%). LCMS RT=2.01 min, [M+H]+=327. 1H NMR 400 MHz (DMSO-d) δ: 8.42 (1H, s), 7.85 (1H, s), 5.85 (1H, s), 5.69-5.65 (1H, m), 4.55-4.54 (2H, m), 4.50-4.46 (2H, m), 2.27 (3H, s), 1.44 (6H, d, J=6.59 Hz).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:26])[CH2:16][CH2:17][C:18](=[O:19])[OH:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[OH:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Glu-Glu-Phe-Amp was synthesized by a similar method except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the starting drug conjugate was Phe-Amp (see Phe-Amp synthesis).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
The title compound was prepared (0.137 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.125 g, 0.278 mmol) and methylamine (0.086 g, 2.78 mmol). mp 190-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH:32]=C)[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:34]=O.CSC>CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH:32]=[O:34])[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=O
Reactant: C=CC[C@@]1(C(=O)OC(C)(C)C)CN([C@H](C)c2ccccc2)C(=O)[C@@H]1COCc1ccccc1
Solvent: CO
Solvent: CSC
Product: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O

Procedure:
A solution of (3S,4S)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (6.76 g, 15.0 mmol) in methanol (150 mL) was bubbled with oxygen for five minutes. After bubbling with ozone for 1.5 hours with stirring under cooling with dry ice-methanol, ozone was removed by bubbling with nitrogen. Dimethyl sulfide (5.64 mL, 76.8 mmol) was added under cooling, and the mixture was stirred for 19 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→75:25→66:34→50:50) to give 4.58 g of the title compound as a transparent oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][C@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH:36]4[CH2:38][CH2:37]4)=[CH:28][CH:27]=3)[CH:19]=2)([O:16][CH3:17])[C@H:13]([OH:39])[C@@H:12]([OH:40])[C@@H:11]1[OH:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH2:44]([O:41][C@H:11]1[C@H:12]([O:40][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:39][CH2:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][O:35][CH:36]4[CH2:38][CH2:37]4)=[CH:30][CH:31]=3)[CH:19]=2)([O:16][CH3:17])[O:15][C@@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 196.9 %

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 1b (3.0 g, 4.92 mmol) was dissolved in 50 mL N,N-dimethyl formamide and cooled to 0° C. 60% NaH (984 mg, 24.6 mmol) was added. Then the reaction mixture was warmed to room temperature and stirred for 15 minutes before benzyl bromide (2.95 mL, 24.6 mmol) was added. The mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure after 5 mL methanol were added. The residue was dissolved in 100 mL ethyl acetate and partitioned. The organic extracts were washed with water (50 mL×2) and combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure obtain the crude title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dim-ethyl-silane 1c (4.26 g, yellow grease), which was used directly without purification in the next step.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was prepared from norfloxacin (0.5 g, 1.56 mmole) and 2-bromo-4′-fluoroaceto-phenone(0.40 g, 1.86 mmole) by a method similar to that described for Example 4 (61% yield). Mp: 208° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=7.0), 2.73 and 3.3 (two m, 8H), 3.94 (s, 2H), 4.58 (q, 2 H. J=7.0), 7.18 (d, 1H, J=7.0), 7.36 (m, 2H), 7.90 (d, 1H, J=13.2), 8.11 (m, 2H), 8.94 (s, 1H), 15.30 (br s, 1H). Anal. Calcd. for C24H23F2N3O4: C, 63.29; H, 5.09; N, 9.23. Found: C, 62.96; H, 5.19; N, 9.16.