Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](O)[CH:10]=[CH:11][C:12]=3O)[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1.C1(=O)OC(=O)C2=CC=CC=C12.ClC1C=CC(O)=CC=1>OS(O)(=O)=O.O=S(=O)=O.[B]>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(O)ccc(O)c21
Agent: O=C1OC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21

Procedure:
The present invention relates to a process for the production of 1,4,5,8-tetrahydroxyanthraquinone (hereinafter referred to as diquinizarine) by reacting phthalic anhydride with p-chlorophenol in oleum and in the presence of boron catalysts to give the boron complex of 1,4-dihydroxyanthraquinone, and then chlorinating this boron complex direct with chlorinating agents, in the same reaction medium, to give the boron complex of 5,8-dichloro-1,4-dihydroxyanthraquinone, and subsequently hydrolysing this chlorinated boron complex to diquinizarine.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@H:7]1[C:12](OCC)=[O:13])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.CCCCCC.C(Cl)(Cl)Cl>O1CCCC1>[OH:3][CH2:4][C@H:6]1[C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]=[CH:10][CH2:11]1
Reactant: CCOC(=O)[C@@H]1CC=CC[C@H]1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: OC[C@@H]1CC=CC[C@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 127.3 %

Procedure:
A solution of 25 g of trans-4-cyclohexene-1,2-dicarboxylic acid diethyl ester in 140 ml of tetrahydrofuran is instilled in a suspension of 10 g of lithium aluminum hydride in 140 ml of tetrahydrofuran at room temperature and the mixture is then stirred for 3 hours at reflux temperature. It is cooled to 0° C., a mixture of tetrahydrofuran/water (1+1) is instilled slowly, stirred for 30 minutes, mixed with 150 ml of chloroform, filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is distilled at 0.2 mm/Hg and at 150° C. in a bulb tube. In this way, 20 g of trans-1,6-dihydroxymethyl-3-cyclohexene is obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]([OH:20])[CH:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[CH3:24][CH:25](O)[CH3:26]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@@H:9]([O:21][CH:25]([CH3:26])[CH3:24])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(O)C(O)C(c1ccccc1)N3
Reactant: CC(C)O
Product: Cc1nc2c3c(ccn2c1C)[C@H](OC(C)C)[C@H](O)[C@@H](c1ccccc1)N3

Procedure:
1 g of the title compound of melting point 168-9° C. is obtained by reaction of 3 g of 7R, 8R, 9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine with 2-propanol according to Example 1, Method a.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CS(C)=O>[Cl:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:17])=[CH:18][CH:19]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3cc4c(-c5cnc(C6(O)CCC6)s5)c(Cl)cnc4[nH]3)cc2)CC1
Temperature: 45 °C

Procedure:
To a solution of 4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (Example 16C) (100 mg, 0.235 mmol) in N,N-dimethylformamide (1.17 mL) was added 1-methylpiperazine (78 μl, 0.704 mmol), 4-methylmorpholine (71.2 mg, 0.704 mmol), hydroxybenzotriazole (53.9 mg, 0.352 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (67.5 mg, 0.352 mmol). The solution was heated to 45° C. for 3 hours. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 m column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.67 (bs, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.10-8.05 (m, 2H), 7.51-7.44 (m, 2H), 7.17 (s, 1H), 6.68 (s, 1H), 3.76-3.48 (m, 4H), 2.69-2.58 (m, 2H), 2.47-2.25 (m, 6H), 2.20 (s, 3H), 2.05-1.91 (m, 2H); MS ESI(+) m/z 508.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)Cl.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl
Yield: 26.1 %

Procedure:
To a solution of 2.0 g (1.1×10-2 mol) of 3-chloro-4-hydroxy benzoic acid in 40 ml of dried methylene chloride containing 3.0 g (9.2×10-3 mol) of pyridine was added dropwise 3.0 g (9.2×10-3 mol) of nonanoic acid chloride, which were stirred under reflux for 7 hours. After the completion of the reaction, the solution was washed with an aqueous solution of 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the resulting product was purified through a silica gel column chromatography using methylene chloride and ethanol at 9:1 (v/v) as a developing solution and then recrystallized with 5 ml of ethanol to obtain 750 mg (yield: 25%) of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].S(Cl)(O[CH2:24][Cl:25])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([O:12][CH2:24][Cl:25])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)OCCl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Temperature: 25 °C

Procedure:
To a vigorously stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 g, 5.29 mmol), tetrabutylammonium hydrogen sulfate (0.359 g, 1.057 mmol), and Na2CO3 (2.80 g, 26.4 mmol) in DCM 20 (mL) and water (20 mL) cooled in an ice/water bath was slowly added chloromethyl chlorosulfate (1.09 mL, 10.57 mmol) over a 4 min period. After stirring in ice/water bath for 30 min the cold bath was removed and the reaction allowed to stir at room temperature. After stirring 16 h at room temperature the reaction was diluted with water and extracted with DCM. The aqueous layer was back extracted with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated to afford Preparation 5A (1.64 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:32]12[CH2:38][CH:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]2[CH:39]=O>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:39][CH:33]1[CH2:34][CH:35]2[CH2:38][CH:32]1[CH2:37][CH2:36]2
Reactant: O=CC1CC2CCC1C2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CC1CC2CCC1C2)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
In a round bottom flask was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (2.05 g, 6.18 mmol) in dichloromethane (5 mL) and cooled to 0° C. in an ice bath. To this mixture was then added slowly 1,8-diazabicyclo[5.4.0]undec-7-ene (801 μL, 5.36 mmol) and it was stirred at 0° C. for 20 min. The mixture was then treated with a solution of bicyclo[2.2.1]heptane-2-carbaldehyde (512 mg, 4.12 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was allowed to warm to 25° C. and stirred overnight. The mixture was concentrated in vacuo and then dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous ammonium chloride solution (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash chromatography (25 g column, 15% ethyl acetate/hexanes to 34% ethyl acetate/hexanes) afforded 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-2-yl-acrylic acid methyl ester (491 mg, 36%) as a clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:11]=[C:12]4[C:18](=[O:19])[N:17]([CH2:20][C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([OH:25])=[O:24])[C:16](=[S:28])[N:13]4[C:14]=3[CH:15]=2)=[CH:4][CH:3]=1.O[N:30]1[C:35](=[O:36])[C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[NH:32][NH:31]1.CCN(CC)CC>C1COCC1.CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCC.C(Cl)(Cl)Cl>[O:36]=[C:35]1[N:30]([O:24][C:23](=[O:25])[CH2:22][C:21]([CH3:26])([CH3:27])[CH2:20][N:17]2[C:16](=[S:28])[N:13]3[C:14]4[CH:15]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)[O:9][C:10]=4[CH:11]=[C:12]3[C:18]2=[O:19])[N:31]=[N:32][C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: CC(C)(CC(=O)O)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Reactant: O=C1c2ccccc2NNN1O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)On1nnc2ccccc2c1=O)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Compound 11 (105 mg, 0.25 mmol) was dissolved in dry THF (5 ml) and 3-hydroxy-dihydrobenzotriazinone (HODhbt; 49 mg, 0.3 mmol, 1.2 molequivalents) was added thereto, followed by addition of Et3N (51 mg, 0.5 mmol, 2 molequivalents) and 4-dimethylaminopyridine (DMAP; 15 mg, 0.125 mmol, 0.5 molequivalents). The reaction mixture was stirred at 25° C. for 16 hours while being monitored by TLC using a 6:4 hexane:EtOAc mixture as an eluent, until the appearance of a less polar spot, attributed to the active ester intermediate, was observed. Chloroform was thereafter added and the resulting mixture was washed with 1 M HCl, dried (Na2SO4) and the solvents were removed under reduced pressure to give a red solid. Chromatography was carried out using a 9:1 hexane:ethyl acetate mixture as eluent to give Compound 12 (38 mg, 20% yield) as a orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccccc12
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C

Procedure:
1-tert-Butoxycarbonylmethyl-1H-indole-3-carboxylic acid ethyl ester (700 mg, 2.31 mmol) was dissolved in CH2Cl2 (12 mL), TFA (2.65 mL, 34.6 mmol) was added and the solution was stirred at RT over week end. CH2Cl2 and water were added, the layers were separated and the aqueous one re-extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4, filtered and concentrated to give the desired compound. TLC, Rf (EtOAc)=0.62; MS (LC/MS): 248.1 [M+H]+, 246.0 [M−H]−; tR (HPLC conditions a): 3.03 min.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: CCCCCC[C@@H](O)C(=O)OC(C)(C)C
Product: CCCCCC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (R)-2-hydroxyoctanoate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 72-74° C; MS m/e 673 (M−H)+;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:33]=5[O:32][CH3:31])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(OC)c(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cc(OC)ccc3OC)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,5-dimethoxy-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3): tR=0.94 min; Mass spectrum (ESI+): m/z=565 [M+Na]+.
Reaction SMILES: C1([C@@H](N2CCCC2)CO)C=CC=CC=1.[C:15]1([C@H:21](O)[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[C:15]1([C@H:21]([N:30]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH3:29])[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: O[C@H](CN1CCCC1)c1ccccc1
Agent: OC[C@@H](c1ccccc1)N1CCCC1
Product: COC(=O)c1ccc(N(C)[C@H](CN2CCCC2)c2ccccc2)cc1
Yield: 52 %

Procedure:
This was prepared from the mixture of 2-(R)-phenyl-2-(pyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(pyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 52% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29](O)=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH:66]([CH2:69][OH:70])[CH2:67][OH:68]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:65][CH:66]([CH2:69][OH:70])[CH2:67][OH:68])=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a stirred mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.07 g, 0.15 mmol) and HATU (0.07 g, 0.18 mmol) in DMF (4.0 mL) was added N,N-diisopropyl-ethylamine (0.024 g, 0.032 mL, 0.18 mmol). The mixture was stirred at room temperature for 30 minutes then 2-aminopropane-1,3-diol (0.021 g, 0.23 mmol) was added. After 18 h the reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with EtOAc then the combined organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was collected by filtration, washed with dichloromethane and dried in vacuum oven to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.035 g, 0.07 mmol, 43%) as a white solid. 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.75 (d, J=7.3 Hz, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 7.44 (s, 1H), 7.24 (s, 1H), 5.68 (s, 2H), 4.42 (br. s., 1H), 4.14 (s, 3H), 4.01-4.12 (m, 4H), 3.57 (t, J=8.0 Hz, 2H), 2.51 (br. s., 2H), 0.94 (t, J=7.9 Hz, 2H), −0.04 (s, 9H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[N:11]([C:12]4[C@@H:13]5[CH2:22][C@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14]5)[CH2:10][CH2:9]2)[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:25][N:26]1[C:27](=[O:52])[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[N:11]([C:12]5[C@@H:13]6[CH2:22][C@H:16]([C:17]=5[CH:18]=4)[CH2:15][CH2:14]6)[CH2:10][CH2:9]3)[C:3]=2[CH:23]=[O:24])=[CH:31]1
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@H]2CC[C@@H]3C2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6[C@H]6CC[C@@H]7C6)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 167g (150 mg, 0.44 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (169 mg, 0.44 mmol), sodium acetate (72 mg, 0.88 mmol), K3PO4 (234 mg, 0.88 mmol), PdCl2(dppf) (36 mg, 0.044 mmol), acetonitrile (20 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under N2 for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 167h (132 mg, 53%) as a brown solid. MS-ESI: [M+H]+ 565.3
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:43])[CH:30]([NH2:42])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:42][CH:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=2)[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[OH:43])=[O:14])=[CH:4][CH:3]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 4-fluoro-1-naphthalenecarboxylic acid (163 mg), 0.86 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (214 mg, 77%).
Reaction SMILES: CS(OC(CCCCCCC)C)(=O)=O.C1C(I)=CC(I)=C(O)C=1I.C(=O)([O-])[O-].[K+].[K+].[I:31][C:32]1[CH:53]=[C:52]([I:54])[CH:51]=[C:50]([I:55])[C:33]=1[O:34][CH:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]CCCCCC)[CH3:36]>CN(C=O)C>[I:31][C:32]1[CH:53]=[C:52]([I:54])[CH:51]=[C:50]([I:55])[C:33]=1[O:34][CH:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH3:36]
Reactant: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Agent: CCCCCCCC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: Oc1c(I)cc(I)cc1I
Solvent: CN(C)C=O
Product: CCCCCCCC(C)Oc1c(I)cc(I)cc1I
Yield: 68 %

Procedure:
The 2-methanesulfonyloxynonane (22.8 g, 102 mmol), triiodophenol (48.8 g, 103 mmol) and potassium carbonate (14.2 g, 103 mmol) were reacted in DMF (206 ml) as per 2-(2,4,6-triiodophenoxy)pentadecane except at an oil bath temperature of 82° C. for 14 hrs. The reaction was processed as for 2-(2,4,6-triiodophenoxy)pentadecane to provide a light brown oil. Flash column chromatography (silica, hexanes) provided 2-(2,4,6-triiodophenoxy)nonane (40.8 g, 68.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[NH:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[C:28]([N:12]([CH2:13][CH3:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:18]([O-:20])=[O:19])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(C)=O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 3-benzyloxy-N-ethyl-2-nitroaniline (2.20 g) and triethylamine (1.23 g) in dichloromethane (21 ml) was added acetyl chloride (698 mg) under ice-cooling, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was washed with water, saturated sodium bicarbonate solution, water and brine successively, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (dichloromethane-ethyl acetate) to give N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.71 g).