Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][C:16]([F:20])([F:19])[CH2:17]O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[N:14]2[CH2:15][C:16]([F:20])([F:19])[CH2:17]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(F)(F)CO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(F)(F)CN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of 3-{2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl}-2,2-difluoropropan-1-ol (Reference example 154, 48.9 mg, 0.110 mmol) in pyridine (1.5 mL) was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs. The starting material wasn't consumed completely. To the mixture was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. and the mixture was stirred at room temperature for 14 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (1.5 mL) and to the solution was added potassium carbonate (30.4 mg, 0.220 mmol) at room temperature. The mixture was stirred at 40° C. for 1 hr. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (24.0 mg, 0.0564 mmol, 51%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12]>C1(C)C=CC=CC=1>[CH3:14][N:13]([CH3:15])[C:11](=[N:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)[CH3:12]
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1ccc(Cl)nn1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(Cl)nn1)N(C)C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
3-Amino-6-chloropyridazine (1.29 g, 10 mmol) was suspended in dry toluene (20 ml) and dimethylacetamide dimethyl acetal (1.46 ml, 10 mmol) was added. The mixture was stirred and heated at reflux for 3 hours and then left to stand at ambient temperature for 18 hours. Insolubles were removed from the reaction mixture by filtration and the filter washed with ethyl acetate. The filtrate was then evaporated and the residue triturated with isohexane, the solid product collected by filtration and washed with isohexane to give the title compound (1.7 g, 85%) as a yellow solid. NMR: (CDCl3) 2.13 (s, 3H), 3.1 (s, 6H), 6.92 (d, 1H), 7.25 (d, 1H); m/z: 199 [MH]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[NH:14]C(OC(C)(C)C)=O)=O)[CH2:3][CH2:2]1.[CH2:22](Cl)Cl>FC(F)(F)C(O)=O>[CH:3]1([C:1]2[NH:14][C:7]3[C:6]([CH:4]=2)=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=3)[CH2:2][CH2:22]1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C2CC2)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(C3CC3)cc2c1
Yield: 49 %

Procedure:
[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl] cyclopropyl ketone (13 g, 43 mmol) in 250 mL of CH2Cl2 and 25 mL of trifluoroacetic acid was stirred for 4 hours, washed with water, NaHCO3 solution, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with a gradient, toluene→20% EtOAc/hexane) to give 4.15 g (49% yield) of 2-cyclopropyl-5-methoxy-1H-indole as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN1CCC(CN)CC1
Product: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 85.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (0.880 g, 2.83 mmol) was reacted with (1-methylpiperidin-4-yl)methanamine (435 mg, 3.39 mmol) to afford the desired product (970 mg, 85%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 10.87 (s, 1H), 9.22 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.73 (dd, J=8.9, 2.0 Hz, 1H), 3.69 (dd, J=6.4, 5.2 Hz, 2H), 2.93 (d, J=11.4 Hz, 2H), 2.79-2.60 (m, 1H), 2.31 (s, J=9.0 Hz, 3H), 2.01 (t, J=11.7 Hz, 2H), 1.89 (d, J=12.7 Hz, 2H), 1.76-1.60 (m, 1H), 1.53-1.30 (m, 2H), 1.30-1.17 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][S-:16].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:16][CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)C1(CCCCBr)CCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CCCCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
To a solution of 1-(4-bromobutyl)cyclopentane carboxylic acid methyl ester (38 mmol, 10 g) in DMF (100 mL) was added sodium thiomethoxide (72.6 mmol, 5.09 g). After addition of sodium thiomethoxide, the reaction was exothermic and the mixture became a light brown cloudy solution. The mixture was stirred for 15 h at room temperature and was poured into water (200 mL). The organic compound was extracted with ether (2×150 mL). The combined extracts were washed with brine (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 4.43 g (51%) of a colorless oil. LR MS (C12H22O2S): 230 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.Cl[S:13]([OH:16])(=[O:15])=[O:14].CO>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:6][C:7]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: CC(C)(C)c1cccc(Br)c1
Reactant: O=S(=O)(O)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a cooled (0° C.) solution of commercially available 1-bromo-3-tert-butylbenzene (42.6 g; 199 mmol) in anhydrous dichloromethane (800 mL) was added chlorosulfonic acid (15.9 mL; 239.0 mmol) dropwise. After addition was complete, the reaction was stirred at 0° C. for an additional 30 minutes, allowed to gradually warm to room temperature and further stirred overnight. The reaction mixture was concentrated under reduced pressure to about 500 mL and washed with aqueous hydrochloric acid (20 mL; 20N). The organic layer was separated and dried over magnesium sulfate which resulted in formation of a white precipitate. Methanol (200 mL) was added to dissolve the precipitate. The organic solution was filtered and concentrated under reduced pressure to yield the title product as a white solid (53.0 g).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]([O:21]C)=[O:20])=[CH:12][C:13]([N:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1>C1COCC1.CO.Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:19]([OH:21])=[O:20])=[CH:12][C:13]([N:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(N(C)C)ccc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
2M Lithium hydroxide (8.5 mL, 17.0 mmol) was added to a solution of methyl 4′-bromo-4-(dimethylamino)biphenyl-2-carboxylate (1.9 g, 5.69 mmol) in THF (20 mL) and methanol (20 mL) and stirred at r.t. for 18 hrs. The reaction was then diluted with 1M HCl and extracted with EtOAc. The organic layer was washed with water then brine, dried over MgSO4, filtered and then evaporated to give 4′-bromo-4-(dimethylamino)biphenyl-2-carboxylic acid (1.34 g, 4.19 mmol, 74% yield) as a white solid. LCMS: rt=1.54 min. [M+H]+=319 and 321; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent. A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][C:7]1=[C:6]([CH2:15][CH2:16][CH3:17])[C:5](=[O:18])[CH2:4][CH2:3]2.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]3([CH3:14])[O:27][CH2:13]3)[CH2:8][C:7]1=[C:6]([CH2:15][CH2:16][CH3:17])[C:5](=[O:18])[CH2:4][CH2:3]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)[C@@H]1CCC2(C)CCC(=O)C(CCC)=C2C1
Solvent: ClCCl
Product: CCCC1=C2C[C@H](C3(C)CO3)CCC2(C)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1.68 g (6.83 mmol) of compound obtained from step A, 1.24 g (7.17 mmol) of m-chloroperbenzoic acid was dissolved in 100 mL of methylene chloride and stirred at room temperature for 4 hours. After 4 filtration, the filtrate was washed with 10 mL of 1 N NaOH solution, brine, dried and evaporated to give title product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O[CH:17]([O:21][CH2:22]C)[O:18][CH2:19]C)C.CO[Na]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:17]([O:18][CH3:19])[O:21][CH3:22])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC(OCC)OCC
Agent: CO[Na]
Solvent: CO
Product: COC(OC)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a stirred solution of 4-chloro-2-(trifluoromethyl)benzaldehyde (17; 4.20 g, 20.0 mmol) in methanol (25 mL) was added triethoxymethane (3.60 g, 24.0 mmol) at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 12 h. A solution of MeONa in methanol was added to adjust the pH=10. The solvent was removed under reduced pressure and the resulting residue was diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 4-chloro-1-(dimethoxymethyl)-2-(trifluoromethyl)benzene 18 (3.20 g, 12.6 mmol, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH2:16][CH3:17]
Reactant: CCCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 86 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and propyl chloroformate (2.70 mL) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 5.26 g (86% yield) of the title compound as a solid. LC-MS (m/z) 287 (MH+); tR=3.18, (UV, ELSD) 99%, 95%. 1H NMR (500 MHz, CDCl3): 0.93 (t, 3H), 1.62 (m, 2H), 2.15 (s, 6H), 4.00 (t, 2H), 7.28 (s, 2H), 8.74 (b, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[N:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Amino-pyridine-2-carboxylic acid methyl ester (6-1, Kelly, T. R.; Lang, F. J.Org.Chem. 1996, 61, 4623-4633) 2.37 g (15.6 mmol) was dissolved in 16 mL anhydrous THF and the resulting solution was cooled to 0° C. LAH (15.6 mL of a 1M solution) was added slowly. An additional 8 mL of THF was added during the addition of LAH to keep the mixture from becoming too viscous. After 3 h the reaction was quenched by the sequential addition of 0.59 mL water, 0.59 mL 15% NaOH (aq), and 1.77 mL water. After stirring for 1 h the mixture was filtered through a plug of celite, washing with THF. The filtrate was concentrated to afford 1.6 g of a yellow oil. Purification by flash column chromatography (eluting with a gradient of CH2Cl2 to 90:10 CH2Cl2/MeOH) afforded the titled compound as a white solid. 1H NMR(CDCl3): δ7.42 (t, 1H, J=7.6 Hz), 6.60 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.5 Hz), 4.59 (s, 2H), 4.52 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH:30][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1cc(Cl)ccn1
Reaction time: 8 h

Procedure:
The crude 4-chloro picolinoyl chloride and triethylamine (5.55 g, 0.055 mole) were added dropwise simulaneously to the above stirred filtrate of N-(3-amino-2-pyridinyl)glycine ethyl ester at room temperature and allowed to stir overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].O>O1CCOCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[CH:13]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Yield: 77.4 %

Procedure:
870 mg (2.78 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5 mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-one are refluxed in 15 ml of dioxane for 8 hours. After water is added, the dioxane is distilled off in a vacuum, made alkaline with about 12% ammonia solution and shaken out several times with ethyl acetate. The collected ethyl acetate phase is washed, dried, filtered and concentrated by evaporation. As a residue, 700 mg (77% of theory) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C@H:14]([CH3:35])[C@H:15]([OH:34])[C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].O[Li].O.Cl>C1COCC1.O>[OH:34][C@H:15]([C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28])[C@@H:14]([CH3:35])[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To an above solution 48 (8.0 mg) in THF-H2O (0.3 ml, 0.1 ml each) was added LiOH.H2O (1.3 mg) and the solution was warmed to 60° C. After stirring 6 h, 1N HCl (1 ml) was added and reaction mixture was extracted with CH2Cl2 (10 ml×2). After drying over MgSO4 and evaporation under vacuum, the crude was chromatographed on SiO2 (EtOAc/hexane 1:3) to yield 6.3 mg (81%) of the 49 as a colorless oil: IR (CHCl3) 3412, 2964, 2921, 2850, 2658, 1710, 1459, 1404, 1268, 971, 903 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.64 (ddd, J=16.7, 10.6, 10.0 Hz, 1H), 6.20 (apparent t, J=10.9 Hz, 1H), 5.54–5.46 (m, 1H), 5.42–5.36 (m, 2H), 5.32–5.18 (m, 4H), 3.88–3.84 (m, 1H), 3.48 (d, J=9.2 Hz, 1H), 3.23 (apparent t, J=5.7 Hz, 1H), 2.86–2.76 (m, 1H), 2.69–2.60 (m, 2H), 2.34 (t, J=7.4 Hz, 2H), 2.21–2.04 (m, 5H), 1.70–1.62 (m, 5H), 1.28 (br, 13H), 1.00 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 180.6, 134.4, 133.8, 132.1, 132.0, 132.0, 131.3, 128.8, 119.1, 80.7, 79.2, 76.2, 37.6, 35.5, 34.6, 29.8, 29.7, 29.5, 29.2, 29.1, 29.0, 27.6, 24.8, 24.2, 22.8, 18.1, 16.7, 15.4, 14.2, 4.5; LRMS (API-ES) 515.3 (M+Na)+, 493 (M+H)+, 475 (M+H-H2O)+, 457 (M+H-2H2O)+, 242; [α]20D +33.0 (c 0.23, CHCl3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>CO>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A reaction container was charged with 1,5-dibromopentane (43 g, 186.6 mmol), sodium carbonate (30 g, 280 mmol) and 100 ml of methanol which were weighed and the mixture was stirred at ambient temperature. Then, p-toluidine (10 g, 93.3 mmol) was dissolved in methanol (50 ml) and the solution was added dropwise to the reaction solution. The reaction solution was heated to 55° C. and stirred for 5 hours. The reaction solution was filtered and the resulting filtrate was concentrated under a reduced pressure. The resulting oily mixture was dissolved in ethyl acetate, which was washed with aqueous saturated sodium bicarbonate by using a separating funnel and extracted with 3% hydrochloric acid. Sodium bicarbonate was added to the water phase with stirring the water phase to neutralize it and then the water phase was extracted with ethyl acetate three times. The resulting ethyl acetate solutions were combined and the combined solution was dried using magnesium sulfate and filtered and the filtrate was concentrated under a reduced pressure and distilled under a reduced pressure to obtain 1-(4-methylphenyl)piperidine (8.2 g, yield: 50.3%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C12BC(CCC1)CCC2.C1C[O:30]CC1>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:15][OH:30])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: C=C1c2ccccc2C=Cc2cc(Br)ccc21
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-5-methylene-dibenzo[a,d]cycloheptene (5.7 g) in dry THF (20 ml), under an inert atmosphere, was added 9-borabicyclo[3,3,1]nonane (4.4 ml of a 0.5 molar solution in THF) at ambient temperature, and the reaction mixture was then refluxed for 3 h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (100 ml) and 30% hydrogen peroxide (20 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 h period then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×100 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent to give the title compound (6.0 g) as a colourless oil. δ (360 MHz, CDCl3) 3.81 (2H, d, J=7.9 Hz, CH--CH2OH), 4.17 (1H, t, J=7.9 Hz, CH--CH2OH), 6.75 (1H, d, J=12 Hz, CHA =CHB), 6.89 (1H, d, J=12 Hz, CHA =CHB), 7.15-7.48 (7H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:35]([CH2:36][NH2:37])=[CH:34][C:33]([CH:38]3[CH2:40][CH2:39]3)=[N:32]2)[CH:28]=[CH:29][CH:30]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:35]([CH2:36][NH:37][C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=3)=[O:23])=[CH:34][C:33]([CH:38]3[CH2:39][CH2:40]3)=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)CCc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: NCc1cc(C2CC2)nn1-c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CCc1ccc(NC(=O)NCc2cc(C3CC3)nn2-c2cccc(Cl)c2)cc1F
Temperature: 150 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(2-(methylsulfonyl)ethyl)phenylcarbamate (90 mg, 0.267 mmol) and (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanamine (70 mg, 0.286 mmol) in THF (4 mL) was added N-ethyldiisopropylamine (0.087 mL, 0.507 mmol) and stirred for 1 h in a microwave (150° C., 7 bar). The reaction mixture was concentrated in vacuo and purified by CC (eluent: ethyl acetate/cyclohexane (2:1)) to give 1-[[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methylsulfonyl-ethyl)-phenyl]-urea (30 mg, 23%).
Reaction SMILES: [Si]([O:8][C:9]([CH3:38])([CH3:37])[CH2:10][C:11]1[S:12][C:13]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[N:33][C:32]=23)=[O:27])=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[N:15]=1)(C(C)(C)C)(C)C>FC(F)(F)C(O)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:14]2[N:15]=[C:11]([CH2:10][C:9]([OH:8])([CH3:38])[CH3:37])[S:12][C:13]=2[NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[N:33][C:32]=23)=[O:27])[CH:21]=1
Reactant: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1NC(=O)c1cnn2cccnc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O)sc1NC(=O)c1cnn2cccnc12
Yield: 70.5 %

Procedure:
A solution of N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 35.0 μmol) in trifluoroacetic acid (3 mL) was stirred for 7 days at room temperature. The reaction was evaporated under vacuum and the crude product purified by reverse phase HPLC then lyophilized to afford 11.3 mg (71%) of N-(4-(5-chloro-2-methoxyphenyl)-2-(2-hydroxy-2-methylpropyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (ESI) m+H=458.0; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, br, 1H); 9.38 (dd, 1H); 8.74 (dd, 1H); 8.73 (s, 1H); 7.51 (dd, 1H); 7.46 (d, 1H); 7.35 (s, 1H); 7.32-7.31 (m, 1H); 4.76 (s, 1H); 3.79 (s, 3H); 3.01 (s, 2H); 1.19 (s, 6H).