Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][C:18]4([C:24]5[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=5)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1.C(N(CC)CC)C.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45]>ClCCl>[CH3:42][C:43]([CH3:48])([CH3:47])[C:44]([N:21]1[CH2:20][CH2:19][C:18]([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)([CH2:17][CH2:16][N:15]2[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH2:9][CH:8]([N:7]2[C:6]4[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=4[N:4]=[C:3]2[CH3:2])[CH2:14]3)[CH2:23][CH2:22]1)=[O:45]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(O)c2)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(O)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A mixture of 3-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol hydrobromide (0.22 g, 0.42 mmol), triethylamine (0.117 mL, 0.84 mmol) and trimethylacetyl chloride (0.057 mL, 0.462 mmol) in dichloromethane (2 mL) was stirred at rt for 3 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 3-(1-(2,2-dimethyl propanoyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol as a white solid (0.070 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.05-7.15 (m, 3H), 6.77 (m, 1H), 6.73 (s, 1H), 6.59 (m, 1H), 4.51 (m, 1H), 3.74 (m, 2H), 3.24 (m, 4H), 2.47 (s, 3H), 2.36 (m, 2H), 1.97 (m, 2H), 1.86 (m, 4H), 1.75 (m, 6H), 1.58 (m, 2H), 1.15 (s, 9H). HRMS C33H44N4O2 m/z 529.3543 (M+H)Cal., 529-3542 (M+H)Obs..
Reaction SMILES: C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=3[F:30])[C:23]([O:25]C)=O)([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]2[N:31]=[C:23]([C:22]3[CH:27]=[CH:28][C:29]([F:30])=[C:20]([C@@:15]4([CH:17]([F:18])[F:19])[C@H:14]5[C@H:12]([CH2:13]5)[O:11][C:10]([NH2:9])=[N:16]4)[CH:21]=3)[O:25][C:33]=2[CH:34]=1
Reactant: COC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(NC(=O)c3ccccc3)O[C@H]3C[C@H]32)c1
Reactant: Nc1ccc(Cl)cc1O
Product: NC1=N[C@](c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Temperature: 170 °C
Yield: 10.7 %

Procedure:
A sealable vial was charged with methyl 3-((1S,5R,6S)-3-benzamido-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorobenzoate (0.100 g, 0.24 mmol), 2-amino-5-chlorophenol (0.086 g, 0.60 mmol) and polyphosphoric acid (0.50 mL). The reaction mixture was purged with nitrogen for 1 min and then heated to 170° C. for 1 h. The reaction mixture was allowed to cool to rt, neutralized with aqueous, saturated Na2CO3 solution and 1 N NaOH. The mixture was extracted three times with a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude was purified first by silica gel chromatography 0-100% EtOAc-hexane. The collected fractions were further purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 16 min. The fractions containing the desired product were combined and neutralized with solid Na2CO3. The aqueous phase was extracted with DCM and dried over Na2SO4. The filtrate was concentrated in vacuo to obtain the title compound as a beige solid (10.5 mg, 11% yield). MS m/z=408 [M+H]+. Calculated for C19H13ClF3N3O2: 407.8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH2:18].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:16]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])[CH:17]=[CH2:18]
Reactant: C=CCNc1ccccc1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 55.1 %

Procedure:
A solution of N-propylphosphonic acid anhydride cyclic trimer (50% reagent in EtOAc solution, 1.26 mL, 2.14 mmol) was added to a degassed solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (230 mg, 1.07 mmol), N-allylaniline (142 mg, 1.07 mmol), and Hunig's Base (0.560 mL, 3.21 mmol) at 0° C. The reaction mixture was stirred under argon for 2 min at 0° C. and then warmed to rt and stirred for 1 hr. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give (S)-tert-butyl 1-(allyl(phenyl)amino)-1-oxopent-4-en-2-ylcarbamate (195 mg, 0.590 mmol, 55.2% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (t, J=7.4 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 7.24 (d, J=7.5 Hz, 2H), 5.91-5.78 (m, 1H), 5.63-5.49 (m, 1H), 5.23 (d, J=8.4 Hz, 1H), 5.18-5.05 (m, 2H), 5.05-4.94 (m, 2H), 4.43-4.19 (m, 3H), 2.33-2.23 (m, 1H), 2.20-2.08 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:18][C:12]=2[Cl:11])=[S:45])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 53%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+].C[O-].[Na+].CO>ClCCl.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:18])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (2.31 g) was dissolved. The reaction solution was cooled to 0° C. and added with meta-chloroperbenzoic acid (4.43 g), followed by stirring at room temperature for 2.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in dichloromethane (40.0 ml). The reaction solution was added with trifluoroacetic anhydride (5.6 ml) and subjected to thermal reflux for 3.5 hours. After the reaction solution had been cooled to room temperature, the solvent was distilled off. The residue obtained was dissolved in methanol (80.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution and adjusted to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent had been distilled off, the residue was added with distilled water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in chloroform (50.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (7.44 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (515.6 mg) as a yellow oily substance.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C@@H:18]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])(=[O:34])=[O:33])([CH3:16])[C@@H:14]([O:45][C:46](=[O:48])[CH3:47])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.O.C(=O)(O)[O-].[K+].Cl>CO>[C:46]([O:45][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])(=[O:33])=[O:34])[CH2:17][C@:15]12[CH3:16])[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][CH2:9]3)(=[O:48])[CH3:47]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]12C
Reaction time: 19 h
Yield: 75.5 %

Procedure:
1.37 g of the diacetate obtained in Example 93 in 27.5 cm3 of methanol with 10% water is cooled down to 0° C. and 203 mg of potassium bicarbonate is added, the reaction medium is left to return to ambient temperature and agitation is carried out for 19 hours. The reaction medium is poured into 220 cm3 of water with 55 cm3 of 0.1N hydrochloric acid added to it, extracted with ethyl acetate, dried and the solvent is evaporated off. The residue is chromatographed on silica (eluant: ethyl acetate-cyclohexane 35-65) then the residue is crystallized from a methylene chloride/isopropyl ether mixture. 973 mg of expected product is obtained. M.p.=130° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:34]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1)[CH3:33]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCC(N)=NO
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (0.373 mmol) of the compounds from Example 44A and 66 mg (0.746 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 81 mg (93% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=[C:17]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 111. NMR (CDCl3): 2.50-2.54 (4H, m, CH2), 2.74 (6H, s, Me), 3.21-3.24 (4H, m, CH2), 3.75 (2H, s, CH2), 3.78-3.82 (4H, m, CH2), 3.95-3.98 (4H, m, CH2), 4.58 (2H, br s, NH2), 6.50 (1H, d, J 8.6, Ar), 7.17 (1H, s, Ar), 8.38 (1H, dd, J 8.6 and 1.8, Ar) and 9.12 (1H, d, J 1.8, Ar). MS: (ESI+): MH+=519.34.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[CH:26]3)=[CH:23][CH:24]=2)[C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.CO.[OH-].[Na+]>C(Cl)Cl>[F:34][C:2]1([F:1])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:27]=[CH:26]3)=[CH:23][CH:24]=2)[C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a flask containing impure ethyl 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoate (35.0 mg, 0.073 mmol) was added tetrahydrofuran (0.180 mL), methanol (0.180 mL), and 1 N sodium hydroxide (0.180 mL, 0.180 mmol) was then added. After 2 h, another 5 equiv. of aqueous sodium hydroxide was added. The suspension was stirred at room temperature for 18 hours. Another 5 equiv. of aqueous sodium hydroxide was added and the reaction was heated to 50° C. After 2 h, the reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg). MS (M+1): 453.2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][O:30][CH3:31])=[C:10]([CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][O:30][CH3:31])=[C:10]([CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)O)c(COC)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
tert-Butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (50 mg) was dissolved in 80% trifluoroacetic acid-DCM (2 ml) and stirred at room temperature for 30 minutes. Solvent was evaporated and the residue was purified by flash column chromatography on silica gel (CHCl3-MeOH 95:5) to give {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetic acid (25 mg) as colorless solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:10][OH:11])[CH:9]=1.Cl[CH2:16]Cl>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.S(OC)(OC)(=O)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:10][O:11][CH3:16])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COCc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 72 %

Procedure:
Sodium hydroxide (1.88 g, 44.0 mmol) in water (15 mL) was added to a solution of (5-chloro-2-nitro-phenyl)-methanol (1.1 g, 5.88 mmol) in dichloromethane (15 mL) and stirred for 10 min. Dimethyl sulfate (1.12 mL, 11.8 nmol) and tetrabutylammonium hydrogen sulfate (100 mg) were added and the mixture stirred vigorously for 8 h at room temperature. The reaction mixture was diluted with dichloromethane and the organic layer separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in petroleum ether as eluent afforded 4-chloro-2-methoxymethyl-1-nitro-benzene (850 mg, 72%) as a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]([CH3:30])([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])#[N:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:3]([C:1]#[N:2])([CH3:30])[C:4]([N:6]([CH:16]2[CH2:18][CH2:17]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:25][CH:24]=1
Reactant: CC(C#N)(Cc1ccc(CCCO)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: Oc1c(F)ccc(F)c1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C#N)(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 80 °C

Procedure:
2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl)phenyl]-2-methylpropanamide from the previous step (1 eq.) and 2-chloro-3,6-difluorphenol (4 eq.) were taken up in freshly deoxygenated toluene (0.05 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (4 eq.) and finally tributylphosphine (4 eq.). The resulting yellow solution was heated at 80° C. for 3 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C(C(CCCCCC)C[OH:5])C.[CH2:12]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][OH:17])[CH2:13][CH3:14].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(=O)(O)O>>[CH2:12]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]([OH:5])=[O:17])[CH2:13][CH3:14]
Reactant: CCCCCCC(CC)CO
Reactant: CCCCCCCCC(CO)CCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCCCCCC(CCC)C(=O)O

Procedure:
Instead of (-)-2-ethyl-1-octanol in Example 8, 5.07 g (25.3 mmol) of (-)-2-propyl-1-decanol was used and then oxidized with potassium permanganate under the same acidic state of sulfuric acid as in Example 6 to obtain 2-propyl decanoic acid. 2.19 g (10.2 mmol) of this compound was reacted with 1.75 g (14.7 mmol) of thionyl chloride under the same conditions as in Example 8 to obtain 2.39 g of a light brown liquid of (+)-2-propyldecanoic acid chloride having a specific rotation [α]25 of +1.63.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)\[CH3:11].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)\[CH2:11][Br:19]
Reactant: C/C(=C\c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(/C(=C/c2ccc(Cl)cc2Cl)CBr)cc1
Yield: 69.5 %

Procedure:
104 g of E-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-prop-1-ene were refluxed with 62.3 g of N-bromosuccinimide and 5 g of 2,2'-azoisobutyrodinitrile in 1 liter of carbon tetrachloride, the precipitated succinimide was filtered off and the filtrate was evaporated down under reduced pressure. Treatment of the residue with methanol gives 91.5 g (69.4%) of Z-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 128° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH:18][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(C)C(N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 77 %

Procedure:
D,L-isoleucyl-L-proline benzyl ester hydrochloride (1.2 g) was dissolved in dichloromethane (10 ml), cooled down to 0° C., and DIEA (860 mg) and benzoyl chloride (477 mg) were added dropwisely. The resulting mixture was allowed to warm up naturally to room temperature to react for 2 h, concentrated under reduced pressure to remove the solvent, and purified on a column to give a pale yellow oil (1.1 g, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 3-methoxypropan-1-ol (15.9 mL, 166 mmol) in CH2Cl2 (75 mL) and pyridine (50 mL) was added DMAP (1.0 g, 8.32 mmol), followed by p-toluenesulfonyl chloride (31.7 g, 166 mmol). This mixture was allowed to stir at ambient temperature for 72 hours, then was quenched with 5% aqueous HCl (30 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, eluted with 75% hexanes in EtOAc) to give the title compound (31 g, 127 mmol, 76% yield). MS (DCI/NH3) m/z 262 (M+NH4).