Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[I-].[CH2:33]([Zn+])[C:34]([CH3:37])([CH3:36])[CH3:35].[Li+].[OH-].Cl>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[CH2:33]([C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: CC(C)(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (200 mg, 0.443 mmol) was dissolved in THF (7.0 mL) and neopentylzinc(II) iodide (2.66 mL of a 0.5 M solution in THF) and bis(tri-t-butylphosphine)palladium(0) (0.011 g, 0.022 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then warmed to 50° C. After stirring for 24 h, neopentylzinc(II) iodide (5.0 mL of a 0.5 M solution in THF) was added and the reaction mixture was heated to 90° C. The reaction vessel was cooled to room temperature before 1.0 M LiOH (5 mL) and dioxane (5.0 mL) were added. After stirring for 24 h, the reaction was acidified with 1.0 M HCl to pH 3 and extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC. The purified fractions were neutralized with sodium bicarbonate and then acidified to pH 5 with 1.0 M citric acid. The aqueous mixture was extracted with EtOAc and the organic layer was washed two times with water. The EtOAc layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (12.3 mg). LCMS m/z=460.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.96 (s, 9H), 2.08-2.19 (m, 1H), 2.61 (dd, J=17.0, 10.9 Hz, 1H), 2.73-2.90 (m, 6H), 3.54-3.63 (m, 1H), 5.09 (s, 2H), 6.85 (dd, J=8.8, 2.5 Hz, 1H), 7.0 (d, J=2.5 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.74 (d, J=1.1 Hz, 1H), 8.29 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH3:35]>CS(C)=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][O:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH:30]([CH3:35])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: CC1CNCCN1C
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (390 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (392 mg, 84%) as a yellow solid.
Reaction SMILES: [K].Cl[CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:4]([C:3]1[N:17]2[C:16]([CH3:18])=[CH:15][CH:14]=[CH:13][C:12]2=[N:11][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Cc1cccc(N)n1
Agent: [K]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cccc(C)n12
Yield: 57.1 %

Procedure:
In 10 ml of ether was suspended 560 mg (5.0 mM) of potassium tert-butoxide and while the suspension was vigorously stirred, a solution of ethyl formate:370 mg (5.00 mM) and ethyl chloroformate: 613 mg (5.00 mM) in 10 ml of ether was added dropwise over 3 minutes at room temperature. This mixture was stirred at room temperature for 30 minutes and the precipitate that formed was recovered by filtration and rinsed with a small amount of ether. This precipitate was dried in vacuo to give 700 mg (yield 73.8%) of ethyl 2-chloro-2-formylacetate potassium salt as light-yellow solid. Then, 700 mg (3.69 mM) of ethyl 2-chloro-2-formylacetate potassium salt and 399 mg (3.69 mM) of 6-amino-2-methylpyridine were mixed with 20 ml of ethanol and after addition of 0.53 ml (9.23 mM) of acetic acid, the whole mixture was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with 20 ml of ethyl acetate and 20 ml of purified water. Then, saturated aqueous NaHCO3 solution was added until the water layer became pH 8. This mixture was extracted with 40 ml of ethyl acetate and the organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 430 mg (yield 57.1%) of the title compound as light-yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].COC1C=CC(CNC2CCC2)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: COc1ccc(C=O)cc1
Agent: COc1ccc(CNC2CCC2)cc1
Solvent: CO
Product: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1

Procedure:
253A was prepared from 4-methoxybenzaldehyde and tert-butyl 3-aminobenzoate following the procedure as described in 4A. HPLC: Rt=3.82 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=314.0 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2O)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:6][CH2:5]1.Cl.Cl.N1(C[C@H](C2(O)CCCCC2)C2C=CC=C([O:46]C(F)(F)F)C=2)CCNCC1>>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]([C:23]2([OH:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=2)[CH2:8][CH2:9]1
Reactant: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2CCCC[C@H]2O)CC1
Reactant: OC1([C@@H](CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Agent: Cl
Product: CN1CCN(C[C@@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-{(1R)-2-(4-methylpiperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from, 1-{(1R)-2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 244). HRMS: calcd for C20H29F3N2O2+H, 387.22594. found (ESI, [M+H]+), 387.2269.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH:9]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([NH:15][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[S:14][C:10]=2[CH:9]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Cc3ccccn3)cc2s1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(Cc3ccccn3)cc2s1

Procedure:
A solution of 6-[(2-pyridyl)methyl]-2-aminobenzothiazole (1.3 g) and ethyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) was stirred at 60° C. for 4 hours. Evaporation of the solvent gave a residue which was crystallized from tetrahydrofuran. The crystal was collected by filtration to give 6-[(2-pyridyl)methyl]-2-(3-ethylureido)benzothiazole (0.68 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15]([CH3:16])=[O:26])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: CSc1nnc2n1C=Cc1cc(C)ccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1ccc2c(c1)C=Cn1c(nnc1S(C)=O)C2

Procedure:
By a procedure similar to that described in Example 17, 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 8-methyl-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from methanol), m.p. 158°-159° C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2CCCN(Cc3ccccc3)C2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc(C2CCCNC2)c1

Procedure:
(-)-N-benzyl-3-(3-methoxyphenyl)piperidine hydrochloride (3.8 g, 0.0120 mol) was dissolved in ethanol (80 ml), 10% Pd/C was added and the mixture was hydrogenated at room temperature and atmospheric pressure (28 h). The catalyst was removed (Celite) by filtration, the solvent was evaporated off and the crystalline residue was recrystallized from methanol-ether giving the desired (+)-3-(3-methoxyphenyl)-piperidine hydrochloride (2.54 g, 30% total yield of the maximal theoretical) m.p. 175.5°-177° C.; [α]22D+10.1° (C 2.1, CH3OH).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:12][N:5]2[C:6](=O)[CH2:7][NH:8][C:9](=O)[C@@H:4]2[CH2:3]1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[F:13][C:2]1([F:1])[CH2:12][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3]1
Reactant: O=C1NCC(=O)N2CC(F)(F)C[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC1(F)CC2CNCCN2C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A pressure bottle was charged with (S)-7,7-difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (350 mg, 1841 μmol) and THF under nitrogen, and the solution was cooled to 0° C. under nitrogen. Lithium aluminum hydride (3681 μl, 3681 μmol) was added, the mixture was allowed to warm to RT, followed by heating at reflux for 3 h. 2 mL of water was carefully added, followed by 2 mL of 6N NaOH. After stirring for 10 min, the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated. GC/MS: [M+H]=163.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]([CH3:10])([CH3:8])[CH3:9])\[CH3:24])[CH3:19]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1C(C)(C)C
Temperature: 23 °C
Yield: 77.8 %

Procedure:
Potassium t-butoxide (11.3 g, 0.10 mol) was added to a stirred solution of 2-t-butyl-phenol (7.60 g, 0.05 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.05 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (10.2 g, 77%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH3:31]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:30][CH3:31])[CH2:22][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Reactant: CCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and iodoethane.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH3:21])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:11]=2[CH3:21])=[CH:15][CH:16]=1
Reactant: NC(=O)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Product: Cc1oc(-c2ccccc2)nc1-c1ccc(Br)cc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
a mixture of benzamide (4.919 ml, 54.46 mmol) and 2,4′-dibromopropiophenone (10.60 g, 36.31 mmol) was heated in a 135° C. oil bath. The mixture became homogenous at >100° C. The reaction was stirred at 135° C. for 2 hours, after which time a precipitate had developed, and removed from the hot oil bath. Approximately 20 mL of acetonitrile was added to the mixture, which was left to equilibrate to room temperature. The precipitate was collected by filtration, rinsing with acetonitrile to afford a colorless solid. ESI+ m/z=314.0; 316.0 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: C
Product: O=[N+]([O-])c1cc2oc(-c3ccccc3)nc2cc1Cl

Procedure:
To a flask equipped with a vigreux column was added 2-amino-4-chloro-5-nitro-phenol, benzaldehyde, Darco KB and xylenes. The mixture was then refluxed overnight and the mixture was cooled, filtered and the solvent removed under vacuum. The resultant solid was recrystallized from Et2O to yield 5-chloro-6-nitro-2-phenyl-benzooxazole which was subjected to the procedure from Example 349B substituting 5-chloro-6-nitro-2-phenyl-benzooxazole for the product from Example 349A to provide the title product.
Reaction SMILES: [CH:1]1([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[C:10]([CH3:16])([CH3:15])[C:9]2=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[CH:1]1([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([CH3:15])([CH3:16])[C:9]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)C(=O)N(C2CCCCCC2)CC1CO
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(C2CCCCCC2)CC1COc1ccccc1
Temperature: 80 °C

Procedure:
A solution of Example 3A (50 mg, 0.2 mmoles), phenol (23.5 mg, 0.25 mmoles), and triphenyl phosphine (85.8 mg, 0.33 mmoles) was stirred in anhydrous Toluene (1.25 mL). To the reaction, di-tert-butyl azodicarboxylate (76.9 mg, 0.33 mmoles) was added and heated to 80° C. for one hour. The reaction mixture was partitioned between toluene and water. The organic phase was separated and solvent evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.32 (m, 2H), 6.95-6.99 (m, 1H), 6.88-6.91 (m, 2H), 4.06-4.19 (m, 1H), 4.07 (dd, J=9.15, 5.65 Hz, 1H), 3.92 (t, J=8.77 Hz, 1H), 3.51 (dd, J=9.92, 7.63 Hz, 1H), 3.13 (dd, J=9.76, 7.78 Hz, 1H), 2.45 (qd, J=7.86, 5.72 Hz, 1H), 1.43-1.82 (m, 12H), 1.25 (s, 3H), 1.05 (s, 3H). MS (APCI+) m/z 316.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9]O.[Br:11]P(Br)Br>C1(C)C=CC=CC=1>[Br:11][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(CBr)c1Cl
Yield: 233.8 %

Procedure:
To a solution of (2,3-dichlorophenyl)methanol (75 g, 0.431 mol), in toluene (800 mL), tribromophosphine (40.7 g, 0.151 mol) was added dropwise at room temperature with stirring. Then the reaction mixture was stirred at room temperature for 2 h and concentrated. The resulting residue was neutralized with aq. NaHCO3 and extracted with DCM (300 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (84.7 g, 83%), as a deep red solid.
Reaction SMILES: [F:1][C:2]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][N:35](C(=O)C(F)(F)F)[CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1F)=[O:5].C1C[O:54][CH2:53]C1.[Li+].[OH-]>O>[F:1][C:2]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][NH:35][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1[O:54][CH3:53])=[O:5]
Reactant: C1CCOC1
Reactant: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)ccc1F)c1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 50 °C
Yield: 82 %

Procedure:
To a solution of 2,6-difluoro-N-{2-fluoro-5-[3-(2-{[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide (55 mg, 0.08 mmol) in 10:1 THF:H2O (10 mL) was added 1M LiOH (0.48 mL, 0.48 mmol) and the reaction mixture was heated at 50° C. overnight. The reaction was washed with brine (10 mL) and the organic layer removed, adsorbed to silica gel and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (39 mg, 82%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.72 (t, 2H, J=5.86 Hz), 3.04 (t, 2H, J=5.86 Hz), 3.86 (s, 2H), 6.55 (d, 1H, J=5.30 Hz), 6.88-6.97 (m, 4H), 7.11-7.16 (m, 1H), 7.23-7.39 (m, 5H), 8.09 (t, 1H, J=5.31 Hz), 8.28-8.29 (d, 1H, J=8.78 Hz), 8.45 (d, 1H, J=6.95 Hz), 8.61-8.63 (m, 1H); ESIMS (M+H)+=592.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)CCCc1ccc(C(=O)C(F)(F)F)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(C(=O)C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
Methyl 4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoate (250 mg, 0.89 mmol) was dissolved in THF-H2O (15 MI, 2:1 v/v) and cooled to 0° C. LiOH.H2O (35 mg, 0.89 mmol) was added and the reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h. Solvent was removed under reduced pressure and the aqueous layer was washed with EtOAc. The Ph of the aqueous layer was adjusted to 2-3 using 1.5N HCl. The product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get 4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoic acid (220 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 8.00-7.98 (m, 1H), 7.21-7.19 (d, J=3.9 Hz, 1H), 2.98-2.93 (t, J=7.7 Hz, 2H), 2.31-2.26 (m, 2H), 1.93-1.83 (m, 2H). MS (ESI) m/z: Calculated for C10H9F3O3S: 266.02. found: 264.8 (M−H)−
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[N:15]=[CH:14][N:13]=2)[C:10]=1[NH2:11])=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:11][C:10]1[N:9]([C:12]2[CH:17]=[C:16]([N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH3:19])[N:15]=[CH:14][N:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1cc(-n2ncc(C(=O)O)c2N)ncn1
Temperature: 85 °C

Procedure:
A mixture of 5-amino-1-[6-(tert-butoxycarbonyl-methyl-amino)-pyrimidin-4-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.5 g, 15.2 mmol), lithium hydroxide (1.82 g, 75.8 mmol) dissolved in a mixture of 1,4-Dioxane (20 mL) and water (5 mL) is heated to 85° C. for 8 hours. The reaction mixture is then neutralized with 2 M HCl aqueous solution until pH˜4-5 causing a white precipitate to form. After filtration, the undissolved solid is washed with small amount of water, air-dried to give 5-amino-1-[6-(tert-butoxycarbonyl-methyl-amino)-pyrimidin-4-yl]-1H-pyrazole-4-carboxylic acid as white powder: 1H NMR 400 MHz (d6-DMSO) δ 8.41 (s, 1H), 8.00-7.40 (m, 4H), 6.86-6.58 (m, 1H), 2.86 (s, 3H); MS m/z 235.10 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15]C)=[O:14])[CH:7]=[N:8]2.[OH-].[Li+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[N:8]2
Reactant: COC(=O)c1cnc2cccc(OC)c2c1
Agent: [Li+]
Agent: [OH-]
Product: COc1cccc2ncc(C(=O)O)cc12

Procedure:
Methyl 5-methoxyquinoline-3-carboxylate (Organic and Biomolecular Chemistry, 7(12), 2612-2618; 2009) was saponified using aqueous lithium hydroxide. +ESI (M+H) 203.9; 1H NMR (400 MHz, DMSO-d6, δ): 9.30 (d, 1H), 9.03 (d, 1H), 7.84-7.80 (m, 1H), 7.66 (d, 1H), 7.15 (d, 1H), 4.04 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:15]=[N+]=[N-])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])C[C@H]2C[C@H]21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CN)C[C@H]2C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3S,5R)-3-azidomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (195 mg, 0.82 mmol) was suspended in THF (10 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (20 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT overnight. The catalyst was removed through a 0.45 microns filter, and the filtrate was concentrated in vacuo to give the title compound. MS (LC-MS): 213.0 [M+H]+; tR (HPLC conditions k): 2.51 min. The material thus obtained was used in the next step without further purification.