Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)=[O:18])=[O:14].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH2:54][C@@H:55]3[N:61]([CH:62]=2)[C:60](=[O:63])[C:59]2[CH:64]=[C:65]([O:91][CH3:92])[C:66]([O:68][CH2:69][CH2:70][CH2:71][O:72][C:73]4[C:88]([O:89][CH3:90])=[CH:87][C:76]5[C:77](=[O:86])[N:78]6[CH:84]=[C:83]([CH3:85])[CH2:82][C@H:79]6[CH:80]=[N:81][C:75]=5[CH:74]=4)=[CH:67][C:58]=2[N:57]=[CH:56]3)=[CH:49][CH:48]=1>CO.ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH2:54][C@@H:55]3[N:61]([CH:62]=2)[C:60](=[O:63])[C:59]2[CH:64]=[C:65]([O:91][CH3:92])[C:66]([O:68][CH2:69][CH2:70][CH2:71][O:72][C:73]4[C:88]([O:89][CH3:90])=[CH:87][C:76]5[C:77](=[O:86])[N:78]6[CH:84]=[C:83]([CH3:85])[CH2:82][C@H:79]6[CH:80]=[N:81][C:75]=5[CH:74]=4)=[CH:67][C:58]=2[N:57]=[CH:56]3)=[CH:49][CH:48]=1)=[O:23])=[O:18])=[O:14]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(C)=CN1C2=O
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](C)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN5C(=O)C=CC5=O)C(C)C)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To a mixture of carboxylic acid 23 (8 mg, 21 umol) in 5% methanol/dichloromethane was added EEDQ (6.1 mg, 24.6 umol) and the mixture was stirred for 15 minutes under nitrogen at an ambient temperature. The resulting mixture was added to 11 (12 mg, 18.9 umol) and stirred for 3 hours under nitrogen. The reaction mixture was aspirated directly onto a 1 mm radial chromatotron plate and eluted with a gradient of 1 to 4% methanol in dichloromethane. Product containing fractions were concentrated under reduced pressure to give 9.4 mg (50%) of 30 as a yellow solid: MS (ES−) m/z 997.18 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[Br:2][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: OCCCc1c[nH]c2ccccc12
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCCCc1c[nH]c2ccccc12
Temperature: 23 °C
Yield: 14.8 %

Procedure:
Phosphorus tribromide (17.4 g) in Et2O (30 mL) was added dropwise to a Et20 solution (100 mL) containing 3-(3-hydroxypropyl)indole (VI; 7.5 g) at 0° C. with stirring and under N2 atmosphere. After the addition was complete, the reaction was allowed to warm to 23° C. and continuously stirred for 16 h. At the end of this time, the reaction was cooled to 0° C. and ice (ca. 25 mL) added portionwise and stirred an additional 2 h. The organic phase was separated from the aqueous phase and the aqueous layer extracted with Et2O. The combined organic phases were washed with sat. NaCl solution, dried with MgSO4. filtered and concentrated under reduced pressure to afford 3-(3-bromopropyl)indole (V; 1.51 g; 15%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14](F)[C:13]=1[N+:21]([O-:23])=[O:22])[CH3:11]>>[CH2:10]([C:12]1[C:13]([N+:21]([O-:23])=[O:22])=[C:14]([C:15]([F:19])=[C:16]([F:18])[CH:17]=1)[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])[CH3:11]
Reactant: Nc1ccc(I)cc1F
Reactant: CCc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Product: CCc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
2-Fluoro-4-iodoaniline (2.05 g, 10 mmol) and 1-ethyl-3,4,5-trifluoro-2-nitrobenzene (2.37 g, 10 mmol) were reacted using the condition described in example 1 (Step A) to form the title compound (2.47 g, 60%); m/z=407 [M−1]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C1CCC(O)(c2cc(F)cc(Br)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)C1CC=C(c2cc(F)cc(Br)c2)CC1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Combine 1-(3-bromo-5-fluoro-phenyl)-4-dimethylamino-cyclohexanol (14.5 g, 45.9 mmol), p-TsOH (21.8 g, 114.6 mmol) and toluene (200 mL) and heat to reflux for 3 hr. Cool to ambient temperature and partition between ethyl acetate (500 mL) and 1M NaOH solution (250 mL). Wash the organic layer with 1M NaOH solution (200 mL) and saturated aqueous NaCl (200 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by chromatography (silica gel, 10% 2M NH3/MeOH in DCM) to obtain (4-(3-bromo-5-fluoro-phenyl)-cyclohex-3-enyl)-dimethyl-amine (10.8 g, 79%): MS (ES) m/z=298 (M−H)−, 300 (M+H)+; 1H NMR (CDCl3): δ 7.25 (d, 1H, J=2 Hz), 7.02 (dd, 1H, J=8 Hz, J=2 Hz), 6.9 (dd, 1H, J=8 Hz, J=2 Hz), 6.04 (m, 1H), 2.38 (m, 4H), 2.27 (s, 6H), 2.09 (m, 2H), 1.48 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].CN(C=O)C>C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:24]=[CH2:25])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Temperature: 65 °C
Yield: 50 %

Procedure:
A solution of 1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one (1.9 g, 4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (20 0 mL) containing DMF (2.0 mL) was degassed using house vacuum and purged with argon. Then added PdCl2(PPh3)2 (0.3 g) and the mixture was heated at 65° C. under argon atmosphere for 4 h, with stirring. The solvents were distilled in vacuo, and the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes to give the title compound (0.75 g. 50%) as an orange colored solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>C1COCC1>[C:22]1([O:21][C:20](=[O:28])[NH:17][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(OCc2ccc(F)cc2)ncc1F)Oc1ccccc1
Yield: 21 %

Procedure:
To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperature was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH4Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.CS(Cl)(=O)=O.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:55](=[O:56])[N:31]2[C:32]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)=[O:44])=[C:33]([C@@H:36]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:55](=[O:56])[N:31]3[C:32]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)=[O:44])=[C:33]([C@@H:36]4[CH2:40][CH2:39][C:38]([CH3:41])([CH3:42])[O:37]4)[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCC(C)(C)O3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Yield: 69.2 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (13 mg, 0.065 mmol) in DMF (2 ml) was treated with methanesulphonyl chloride (5 μl, 0.064 mmol) and N,N-diisopropylethylamine (11 μl, 0.063 mmol) as described in Example 7 (a). This was then treated successively with a solution of the amine from Example 29 (e) (25 mg, 0.060 mmol) in DMF (2 ml) and pyridine (5 μl, 0.062 mmol). After work-up the product was purified by chromatography on silica gel eluting with 50, 70 and 100% ethyl acetate in hexane to yield the title compound (25 mg, 70%) as a yellow foam; νmax (CH2Cl2) 3389, 1784, 1722, 1690, 1607 and 1516 cm-1 ; δH (CDCl3, 250 MHz) 1.23 (3 H, s), 1.29 (3 H, s), 1.61-1.84 (3 H, m), 2.31 (1 H, m), 3.40 and 3.63 (2 H, ABq, J 18.7 Hz), 3.81 (3 H, s), 4.20 (3 H, s), 4.99 (1 H, d, J 4.8 Hz), 5.05 (1 H, dd, J 8.1, 8.1 Hz), 5.13 and 5.23 (2 H, ABq, J 11.8 Hz), 5.90 (1 H, dd, J 8.9, 4.8 Hz), 6.90 (2 H, d, J 8.7 Hz), 7.23 (1 H, s), 7.34 (2 H, d, J 8.7 Hz), 7.50 (2 H, br s, exch.) and 7.68 (1 H, br d, J 8.9 Hz, exch). [Mass spectrum: +ve ion (ammonia) MH+ (602)].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C@H:32]([OH:34])[CH3:33])=[CH:30][CH:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:34][C@@H:32]([C:31]2[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)[CH3:33])[CH:7]=1
Reactant: C[C@@H](O)c1ccc(F)cc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: C[C@@H](Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccc(F)cc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and (R)-4-fluoro-α-methylbenzyl alcohol (74.4 mg; 0.515 mmol), example 67 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>CC(OC)(C)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 4-methyl-3-nitrophenol (10.0 g), butyl bromide (9.4 g), sodium carbonate (6.9 g) and DMF (50 mL) was heated at 80° C. for 7 hours. The cooled reaction solution was diluted with MTBE and washed twice each with water and sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 209.25 (C11H15NO3) was obtained in this way; MS (ESI): 210 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]([CH2:18][CH2:19]Br)[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:19][CH2:18][N:12]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11]1)=[N+:26]=[N-:27]
Reactant: COC(=O)c1nn(CCBr)c(C(=O)OC)c1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCN=[N+]=[N-])c(C(=O)OC)c1OCc1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1-(2-bromoethyl)-1H-pyrazole-3,5-dicarboxylate (1.0 g, 2.52 mmol) in DMF was added sodium azide. The reaction mixture was stirred at 40° C. overnight and quenched with water (100 mL). The mixture was extracted with EtOAc four times, and the organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel using 0-30% EtOAc/hexanes gradient elution. Collection and concentration of the appropriate fractions afforded the title compound as a white solid. ES MS (M+1)=360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:80]1[CH2:84][CH2:83][CH2:82][CH2:81]1>>[N:80]1([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:5]2[C:4]([C:24]([F:27])([F:25])[F:26])=[CH:3][C:2]([Br:1])=[CH:15][C:14]=2[S:13]3)[CH2:84][CH2:83][CH2:82][CH2:81]1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(C(F)(F)F)c21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1c2ccc(N3CCCC3)cc2Sc2cc(Br)cc(C(F)(F)F)c21

Procedure:
To a stirred solution of 3,7-dibromo-1-trifluoromethyl-10-Boc-phenothiazine (18) (104 mg, 0.2 mmol) in xylenes (5 mL) Pd(dba)2 (5.8 mg, 0.01 mmol), BINAP (4.4 mg, 0.007 mmol), Cs2CO3 (325 mg, 1.0 mmol) and pyrrolidine (0.017 mL, 14.2 mg, 0.2 mmol) were added. The mixture was refluxed for 48 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[CH3:42][O:43][C:44](=[O:65])[C@H:45]1[O:51][C@:49](Br)(O)[C@H:48]([O:53][C:54](=[O:56])[CH3:55])[C@@H:47]([O:57][C:58](=[O:60])[CH3:59])[C@@H:46]1[O:61][C:62](=[O:64])[CH3:63]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:42][O:43][C:44]([CH:45]1[CH:46]([O:61][C:62](=[O:64])[CH3:63])[CH:47]([O:57][C:58](=[O:60])[CH3:59])[CH:48]([O:53][C:54](=[O:56])[CH3:55])[CH:49]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:51]1)=[O:65]
Reactant: COC(=O)[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1OC(OCC(C)(C)c2cc(NC(=O)Nc3ccc(-c4cn5c(n4)sc4cc(OCCN6CCOCC6)ccc45)cc3)no2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) and silver carbonate (0.5-1 equivalent) in toluene at rt is added 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester (0.8-1.5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered and the filtrate is partitioned between water and either dichloromethane or a mixture of dichloromethane and isopropanol. The separated aqueous layer is further extracted with dichloromethane or a mixture of dichloromethane and isopropanol. The combined organic layers are washed with 2N aq sodium hydroxide dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 3,4,5-triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[S:46]1(=[O:52])(=[O:51])[CH2:50][CH2:49][NH:48][CH2:47]1.CN1CCOCC1>CN(C=O)C>[O:51]=[S:46]1(=[O:52])[CH2:50][CH2:49][N:48]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:47]1
Reactant: O=S1(=O)CCNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C(=O)N1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). Thiazolidine 1,1-dioxide hydrochloride (12.17 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (8.8 mg, 43%). 1H NMR (500 MHz, DMSO-d6) δ 0.76-0.81 (m, 3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.50 (m, 1H), 3.35-3.45 (m, 2H), 3.80-3.89 (m, 2H), 4.49-4.91 (m, 4H), 5.18-5.42 (m, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd for C17H19FN4O4S, 395; found, 395.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:21])[NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)CCCCCCC(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC(=O)NCC(O)c1ccccc1
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1)=[N+]=[N-].CP(C)C.[OH-].[Na+].O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1
Reactant: [N-]=[N+]=NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: CP(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-[2-(Azidomethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 661, 92 mg, 0.19 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. Trimethylphosphine (0.97 mL, 1 M tetrahydrofuran solution, 0.97 mmol, 5 equiv) was added, the ice bath removed and the mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was treated with sodium hydroxide (1.9 mL, 1 M aqueous, 10 equiv) and stirred for an additional 1 hour. The mixture was poured into water and extracted with chloroform (4×150 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 85:15; dichloromethane:methanol containing 10% ammonium hydroxide), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO, hydrochloride salt) δ 9.27 (1H, s), 8.47 (1H, d, J=2.6 Hz), 8.33 (1H, dd, J=7.9, 1.4 Hz), 8.36-8.27 (3H, br s), 7.86-7.82 (3H, m), 7.73 (1H, d, J=1.5 Hz), 7.70-7.64 (3H, m), 7.60-7.55 (2H, m), 7.52-7.47 (3H, m), 6.54 (1H, m), 5.83 (2H, s), 4.04 (2H, q, J=5.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 447.1911 [(M+H)+; calculated for C27H23N6O: 447.1928].
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33][CH:34](P(=O)(OCC)OCC)[C:35]2=[O:37])[CH2:30][CH2:29]1.C(O)C>O1CCCC1>[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33]/[C:34](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:35]2=[O:37])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)c(F)c3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)c(F)c4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
Lithium hydroxide (0.177 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.40 g) and diethyl [(3S,8aR)-3-(2,3,4-trifluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.506 g of the title compound as a colorless solid. The property values of the compound are as follows.