Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5c(c4)OCO5)ncnc32)CC1
Temperature: 160 °C
Yield: 9.2 %

Procedure:
A mixture of Benzo[1,3]dioxol-5-ol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 11 mg, 0.074 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 25 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(Benzo[1,3]dioxol-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (3 mg, 10%) as a white solid. Mass spectrum MH+=440.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([B:16]([OH:21])[OH:17])[CH:3]=[N:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cncc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
1.91 g of 3-bromo-5-benzyloxypyridine, under argon, are added to a solution of 2 ml of triisopropyl borate in a mixture of 12 ml of toluene and 3 ml of tetrahydrofuran. The solution is cooled to −70° C. and then 5.42 ml of n-butyllithium (1.6N in hexane) are added dropwise. The reaction medium is stirred for 3 hours, and brought back to −20° C., and 7.23 ml of 2N hydrochloric acid are added dropwise. The reaction mixture is left to return to ambient temperature and poured into distilled water. The aqueous phase is extracted with ethyl acetate, and then the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure, so as to give 0.21 g of [5-(benzyloxy)pyridin-3-yl]boronic acid in the form of a white powder (adapted from Wenjie Li et al. An Improved Protocol for the Preparation of 3-Pyridyl- and Some Arylboronic Acids J. Org. Chem., (2002), 67(15), 5394-5397), the characteristics of which are the following:
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH2:12]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=1.C1CC2N(C3N(C4N2CCCC4)CCCC3)CC1.C(=O)=O.Cl>CO>[CH2:12]([C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:32])[CH2:31][CH:38]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C1=NCCCC1
Reactant: CCCCCCCCCCCCc1ccc(C(C)=O)cc1
Agent: C1CCN2C(C1)N1CCCCC1N1CCCCC21
Agent: COC(=O)[O-]
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(C(=O)CC2CCCCN2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Magnesium methyl carbonate (0.5 mole 1 M in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 4'-dodecylacetophenone, 28.9 g (0.1 mole), is added, and the mixture stirred at 120°C. for 4 hours under a stream of nitrogen, allowing the methanol that forms to escape. The reaction mixture is cooled to room temperature under an atmosphere of carbon dioxide and 10.1 g (0.12 mole) of 2,3,4,5-tetrahydropyridine trimer (α-tripiperidein) is added. The mixture is stirred at room temperature for 66 hours in an atmosphere of carbon dioxide and poured into a solution 800 ml of 2N HCl. The solid is removed by filtration, dissolved in methylene dichloride, dried over anhydrous sodium sulfate and azeotroped with methyl ether until the product precipitates. The 4'-dodecyl-2-(2-piperidyl)acetophenone, when recrystallized as the hydrochloride salt from a methylene dichloride-ethyl ether mixture, is obtained in 80% yield, (32.5 g) and has a M.P. of 126-7°C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(CCl)Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
The method described in Referential Example 502 was performed by use of 4-chloro-3-nitroaniline and chloroacetyl chloride, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>O1CCCC1>[O:13]=[C:12]1[N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:19](=[S:20])[N:9]2[CH:10]=[C:11]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1cnn(-c2ccccc2N)c1O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(=S)[nH]c3ccccc3n2c1=O
Yield: 84.8 %

Procedure:
2.47 g 1-(2-aminophenyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid, ethyl ester and 1.78 g 1,1'-thiocarbonyl-bis-[1H-imidazole] are dissolved in 50 ml tetrahydrofuran and heated for 8 hours. The residue, after distilling off the solvent, is recrystallized from dimethylformamide to yield 2.45 g of 5,6-dihydro-1-oxo-5-thioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester having a melting point of 277°-282° C.; yellow needles.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21])=[C:14]([NH:24][CH3:25])[CH:13]=1>O>[F:11][C:12]1[CH:13]=[C:14]2[C:15]([C:18](=[O:23])[C:19]([S:20]([CH3:22])=[O:21])=[CH:25][N:24]2[CH3:1])=[CH:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Solvent: O=CO
Solvent: O
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (66.0 ml) and formic acid (45.0 ml) was stirred and heated at 50°-60° under nitrogen for 2 hours and then cooled to ambient temperature. 1-(4-Fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (69.0 g), prepared in a similar manner to that described in Example 1, was added slowly below 30° and the mixture stirred for a further 2 hours. The mixture was cooled in an ice/salt bath to 0° and water (500 ml) added whilst maintaining the temperature below 30°. The mixture was filtered and the filtrate cooled in an ice/salt bath to 0°. Toluene (100 ml) and aqueous sodium hydroxide solution (specific gravity 1.5; 140 ml) were added sequentially, again maintaining the temperature below 30°. The mixture was stirred for 30 minutes at ambient temperature and the product collected by filtration, washed with water (200 ml), toluene (3×50 ml) and hexane (2×50 ml) and then dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p.228.5°-230.5° (53.7 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>CN(C)C=O.O>[Br:26][C:27]1[CH:28]=[C:29]([C:30]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
1-(2-Aminoethyl)pyrrolidine (4.34 g), diethyl cyanophosphate (5.57 ml) and triethylamine (10.4 ml) were added to a solution of 3-bromobenzoic acid (5.00 g) in N,N-dimethylformamide (DMF; 60 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residues were crystallized from hexane to give the title compound (6.31 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.3 %

Procedure:
Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylate (21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl chloride (37.39 g, 0.136 mol) and stir for 72 hours at room temperature. Dilute the reaction with diethyl ether and wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 40.4 g (80%) of the titled product. Rf=0.49 and 0.29 (5/1 hexanes/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:18][N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=2[CH:21]=[N:20]1.N1C2C=CC=C(N)C=2C=N1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][NH:9][C:10]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[N:20][N:19]2[CH3:18])=[O:11]
Reactant: O=C=NCc1ccc(N2CCCCC2)c(F)c1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+ 382.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>C(OCC)(=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1ccccn1
Solvent: CCOC(C)=O
Product: BrCCCCCOCCCc1ccccn1
Yield: 52.7 %

Procedure:
From 2-pyridinepropanol (5 g) and 1,5-dibromopentane (24.83 g), stirring the reaction mixture under nitrogen for 5 h, and using ethyl acetate for extraction. FCC eluting with cyclohexane→cyclohexane-ethyl acetate (9:1) gave the title compound as a yellow oil (5.5 g), t.l.c. (cyclohexane-ethyl acetate 9:1) Rf 0.15.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:20]([O:13][C:4]1[C:3]([CH:1]=[O:2])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C=O)c1OCc1ccccc1
Yield: 62.1 %

Procedure:
A slurry of methyl 3-formyl-2-hydroxybenzoate (640 mg, 3.56 mmol), K2CO3 (982 mg, 7.12 mmol), and benzyl bromide (0.63 mL, 5.34 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours and diluted with EtOAc (100 mL) and water (40 mL). The layers were separated and the organic phase dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via silica gel chromatography, eluting with 0-15% EtOAc in isohexane, to give the title compound as a white solid (598 mg, 62%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].O[S:9]([OH:12])(=[O:11])=[O:10]>>[S:9]([O:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][O:7][S:9](=[O:11])(=[O:10])[OH:12])([OH:12])(=[O:11])=[O:10]
Reactant: OCCNCCO
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)OCCNCCOS(=O)(=O)O
Temperature: 25 °C

Procedure:
Diethanolamine (10.84 g) was heated with concentrated H2SO4 (20.13 g) at about 10-15 mm vacuum (house vacuum) and at a temperature in the range of about 175-180° C. for 5.5 h. The resulting solution was cooled to ambient temperature and stirred over the weekend under nitrogen. The resulting light brown solution was determined by 1H NMR to contain the title compound in solution.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([NH2:19])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([NH2:19])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1
Reactant: COc1cc2c(cc1N)CN(C(=O)CCN(C)C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1N)CN(CCCN(C)C)CC2
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A solution of 2-[3-(dimethylamino)propanoyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (335 mg, 1.21 mmol) in tetrahydrofuran (10 mL) was treated with lithium aluminum hydride (10 mL, 1 M in diethyl ether, 10 mmol, Aldrich). The mixture was refluxed for 16 h, cooled, quenched carefully via sequential addition of water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL), and then water (1.2 mL) again. The mixture was stirred vigorously for 1 h and then filtered through a pad of celite. The filtrate was concentrated to provide 2-[3-(dimethylamino)propyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (284 mg, 1.08 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.65 (m, J=7.2, 7.2, 7.2, 7.2 Hz, 2 H), 2.11 (s, 6 H), 2.19-2.24 (m, 2 H), 2.36-2.41 (m, 2 H), 2.54 (t, J=6.0 Hz, 2 H), 2.63 (t, J=5.4 Hz, 2 H), 3.34-3.41 (m, 2 H), 3.70 (s, 3 H), 4.44 (s, 2 H), 6.28 (s, 1 H), 6.48 (s, 1 H); ESIMS (M+H)+=264.
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH2:27][C:28]([F:31])([F:30])[F:29])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[CH2:27][N:23]1[C:22]([C:16]2[N:15]=[C:14]3[C:13]4[CH:32]=[CH:33][C:10]([O:9][C@@H:7]([CH3:8])[C:6]([NH2:43])=[O:5])=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:26][CH:25]=[N:24]1
Reactant: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester was dissolved in DCM (3 mL), TFA (0.5 mL) added and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) then to yield 486 as a white solid (57 mg, 47%). LCMS: RT=3.52 min, [M+H]+=423; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.95 (1H, s), 7.51 (1H, br s), 7.22 (1H, br s), 6.73 (1H, dd, J=8.9, 2.6 Hz), 6.50 (1H, d, J=2.6 Hz), 5.86 (1H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz), 4.51-4.38 (4H, m), 1.40 (1H, d, J=6.4 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:33][C:29]1[CH:28]=[C:27]([NH:26][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoic acid (1.0 g, 2.85 mmol) in DMF (20 mL) was added 3-aminophenol (0.31 g, 2.85 mmol), HBTU (1.1 g, 2.85 mmol), DIEA (2 mL, 11.4 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (100 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then the resulting solution was used directly for next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH3:31][NH:32][CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:32]([CH3:33])[CH3:31])=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 42.3 %

Procedure:
Using General Procedure B: Reaction of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (157 mg, 0.40 mmol) and dimethylamine (2.0 M in THF, 0.4 mL, 0.80 mmol) with NaBH(OAc)3 (0.179 g, 0.84 mmol) in CH2Cl2 (4 mL) overnight followed by purification of the crude material by radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2—CH3OH-NH4OH) provided the free base of the title compound (72 mg, 43%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([O:14][CH3:15])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]([O:14][CH3:15])[C:8]([O:13][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COC(=O)Cc1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(OC)c(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a solution of (4-hydroxy-3,5-dimethoxy-phenyl)-acetic acid methyl ester (4.1 g, 18.1 mmol) in acetone (50 mL) was added potassium carbonate (1.39 g, 10.1 mmol) benzyl chloride (3.58 g, 28.28 mmol) and potassium iodide (catalytic amount). After completion of addition the reaction mixture was heated to reflux overnight. The next day, the reaction was cooled down to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. All combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified using silica gel chromatography (gradient 100% pentane to 100% ethyl acetate) to afford the desired compound (1.5 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:24]=1
Reactant: Cc1ccccc1CC(=O)O
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2-Methylphenylacetic acid (9.60 g, 64.15 mmoles) was dissolved in 10 ml dichloromethane. To this mixture, oxalylchloride (7 ml, 80.19 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 100 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 80.19 mmoles) was added and the reaction mixture was warmed to RT and stirred for 24 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as white solid (5.5 g, 33% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.52(s,1H), 8.02(d, J=2.4Hz, 1H), 7.65(dd, J=8.8, 2.5Hz, 1H), 7.16(m, 4H), 6.97(d, J=8.9Hz, 1H), 4.47(s, 2H), 2.14(s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][CH2+:37]1SC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][C:37]1=[N:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[CH:6][C:7]=1[NH:14][CH2:15][CH3:16])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(NCC)c1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNC(=O)c1ccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c(NCC)c1

Procedure:
In a manner similar to Example 30, intermediate N-ethyl-3-ethylamino-4-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.46–7.54 (3H, m), 7.27–7.38 (4H, m), 7.19 (1H, m), 6.96–7.08 (4H, m), 6.04 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.49 (2H, m), 3.06 (2H, q), 1.25 (3H, t), 1.05 (3H, t); MS(ESI): 544 (MH+).