Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].S(=O)(=O)(O)O>>[OH:24][CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:4]1[C:5](=[O:15])[C:6]2[N:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(O)CCCCCl
Agent: O=S(=O)(O)O
Product: CC(=O)Cn1cnc2c1c(=O)n(CCCCC(C)O)c(=O)n2C

Procedure:
This compound was prepared starting from 3-methyl-7-(2-oxopropyl)-xanthine by alkylation with 1-chlorohexan-5-ol as described in Example 1; however, without the sulfuric acid treatment.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]([N+:22]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:22][C:9]1[C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(NCc2ccc(OC)cc2)cc1F
Yield: 65.9 %

Procedure:
To a solution of methyl 2-fluoro-4-(4-methoxybenzylamino)-5-nitrobenzoate (50.0 g, 149.57 mmol) in methanol (1500 ml) was added palladium on carbon (15 g). The mixture was allowed to react for 2 hours at room temperature under an atmosphere of H2 (g). The solids were filtered out and the filtrate was concentrated in vacuo to afford methyl 5-amino-2-fluoro-4-(4-methoxybenzylamino)benzoate as a gray solid (30.0 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)[N:10]3[CH:32]=[CH:33][N:34]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[B-](F)(F)(F)[F:36].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C>CC#N>[F:36][C:32]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:34][CH:33]=1
Reactant: F[B-](F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1cc(-c2cc3ncc(F)n3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (Example 96; 0.200 g, 0.407 mmol), Selectfluor (0.288 g, 0.814 mmol) and acetic acid (0.233 mL, 4.07 mmol) were suspended in MeCN (20 mL) and heated to 80° C. overnight. The reaction mixture was cooled to ambient temperature and the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The combined organic extracts were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/dichloromethane to provide 2-(3-(4-(3-fluoro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (0.043 g, 0.084 mmol, 21% yield). MS (apci) m/z=510.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=3)[N:4]([CH3:15])[N:3]=2)=[CH:31][CH:32]=1
Reactant: Cn1nc(Cl)c2cnc(NCCO)nc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCO)nc21
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a solution of 2-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (244 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhydrous potassium carbonate (443 mg, 3.21 mmol, 3 eq), followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The system was then heated under reflux for 24 hours and cooled to room temperature. The layers were separated. The organic solution was treated with ethyl acetate (50 mL) and water (10 mL). The resulting organic layer was then separated, washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography (100% ethyl acetate) to give 130 mg (42% yield) of pure 2-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol; 1H-NMR (DMSO): δ 3.44 (m, 2H), 3.59 (m, 2H), 3.79 (s, 3H), 4.70 (br s, 1H), 5.32 (br s, 2H), 6.65 (d, 2H, J=8.5 Hz), 7.23 (br s, 1 H) 7.64 (d, 2H, J=8.5 Hz), 9.05 (br, 1H); LC/MS (m/e)=285.4 (MH+), Rt=1.54 min.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][N:3]=[N:2]1.[Cl:10]C(N(C)C)=C(C)C>C(Cl)Cl>[N:1]1([CH2:6][C:7]([Cl:10])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)=C(Cl)N(C)C
Reactant: O=C(O)Cn1cnnn1
Solvent: ClCCl
Product: O=C(Cl)Cn1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.58 g of 2-(tetrazol-1-yl)-acetic acid are suspended in 27 ml of absolute methylene chloride, and 1.9 ml of 1-chloro-1-dimethylaminoisobutene (CDIB) are added. After stirring for 30 minutes at room temperature, a further 0.5 ml of CDIB is added and stirring is continued for a further 90 minutes. This solution of the acid chloride [IR (methylene chloride): 3.20, 5.57 μm] is further reacted directly.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:38])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH:26]=[CH:27][C:23]([NH:22][S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([C:5]2[C:4]([O:29][CH3:30])=[CH:3][C:2]([C:34]4[CH:33]=[C:32]([F:31])[CH:37]=[C:36]([F:38])[CH:35]=4)=[C:7]([F:8])[CH:6]=2)[C:10](=[O:28])[CH:11]=[CH:12]3)(=[O:21])=[O:20])=[N:24]1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cc(F)cc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (272 mg, 0.550 mmol), (3,5-difluorophenyl)boronic acid (130 mg, 0.825 mmol), potassium carbonate (228 mg, 1.651 mmol), and Pd(Ph3P)4 (63.6 mg, 0.055 mmol). The vial was sealed with a septum cap and flushed with N2 (g), then Dioxane (2064 μl) and Water (688 μl) were added via syringe. The mixture was heated at 90° C. for 40 min. The mixture was diluted with HCl (8 mL, 1M aq) then extracted with EtOAc (2×20 mL). The organic layers were combined and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0%-3% MeOH in DCM, to provide N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide. The racemic N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC on an AS-H column (25% MeOH/75% CO2) to give (P)—N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16]I>CCO>[CH3:16][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: CI
Solvent: CCO
Product: CSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and methyliodide (0.093 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[S:14][C:15]([CH3:25])([CH3:24])[C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[S:14][C:15]([CH3:25])([CH3:24])[C@@H:16]2[C:20]([O:22][CH3:23])=[O:21]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1N2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2SC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1N2C(=O)[C@@H](N)[C@H]2SC1(C)C

Procedure:
Methyl (2S,5R,6R)-6-benzyloxycarbonylamino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylate (364 mg, 1 mmol) was hydrogenated with about 1.5 g of 10% palladium on activated carbon in 25 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 10 hrs. After removal of catalyst by filtration, deprotected methyl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylate in ethyl acetate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26].Cl>C(O)C>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a solution of N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) in ethanol (2.5 ml) was added a solution of HCl (0.25 ml, 1M in diethyl ether), and the reaction was heated to 70° C. After 5 h, the precipitate was filtered off and washed with ethanol and dried to give the title compound as a white solid (104 mg, 87%). 1H NMR (300 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.74 (m, 1H), 7.93 (d, J=6.6 Hz, 1H), 7.60-7.65 (m, 3H), 7.41 (s, 1H), 7.24-7.29 (m, 3H), 5.90 (s, 1H), 4.39 (s, 2H), 4.09 (m, 1H), 3.69 (s, 3H), 3.49 (s, 3H), 2.87 (s, 3H), 1.33 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=480 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Oc1c2c(nc3ccccc13)CCCN(Cc1ccccc1)C2
Product: CCOC(=O)N1CCCc2nc3ccccc3c(O)c2C1
Yield: 9 %

Procedure:
11-Hydroxy-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 2-benzyl-11-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 208. Yield: 9% of theory; m.p. 285° C.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:6](ON1C(=O)CCC1=O)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>O1CCOCC1>[N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C1=CCNC1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 2,5-dihydro-1H-pyrrole (30 g, 434 mmol) in dioxane (0.43 M solution) was added CbzOSu (130 g, 521 mmol). After being stirred at room temperature for 18 h, the reaction mixture was concentrated to around 300 mL, diluted with 1000 mL of EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate was obtained in 91% yield (80.0 g) as a colorless oil by flash column chromatography. 1H NMR (CDCl3, 400 MHz): δ 7.32 (5H, m), 5.80 (2H, m), 5.77 (2H, s), 4.22 (4H, m). LC/MS (uplc): MH+ 204.2, 160.1 (−44), 0.86 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.[CH3:16][C:17]1(C)[C:21](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:4]1[CH:3]=[C:2]([C:17]([CH3:21])=[CH2:16])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl 4-bromo-2-chlorobenzoate (1.0 g, 3.43 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (588 mg, 3.50 mmol) in 1,4-dioxane (40 mL) and water (10 mL) were added sodium carbonate (742 mg, 7.0 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol). The resultant reaction mixture was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated. The residue was purified by pre-HPLC to get tert-butyl 2-chloro-4-(prop-1-en-2-yl)benzoate (800 mg, 92.3%) as a yellow oil. LRMS (M+H+) m/z: calcd 253.09. found 253.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1.N1C=CN=C1.CN(C=O)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Si:27]([O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOc1ccc(CO)nc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of (5-(methoxymethoxy)pyridin-2-yl)methanol (8.12 g), imidazole (4.90 g) and DMF (50 mL) was added tert-butyldimethylchlorosilane (8.68 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.6 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[N:14]1)[CH3:4].I[CH3:27]>C1COCC1>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:27])=[N:14]1)[CH3:4]
Reactant: CCOC(=O)CCCCCCn1ccc(-c2ccccc2O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCn1ccc(-c2ccccc2OC)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
Add sodium hydride (900 mg, 18 mmol, 60% suspension in mineral oil) to a suspension of 7-[3-(2-hydroxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (4.73 g, 15 mmol) and iodomethane (1.1 mL, 18 mmol) in THF (70 mL) at 0° C. under nitrogen and warm the mixture to room temperature to stir for 12 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (150 mL), wash with water (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to provide 7-[3-(2-Methoxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (3.75 g, 76%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]([F:19])(S(F)(=O)=O)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][CH:11]([F:19])[F:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(O)c(Br)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(OC(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) and sodium carbonate (28.2 g, 0.270 mol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-10%, EtOAc/hexanes) afforded the title compound as an off-white solid (22 g, 70%). M+H]=238.09/240.09.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].C([O:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)(=O)CC>>[OH:11][C:12]1[C:21]([C:12](=[O:11])[CH2:13][CH3:14])=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: CCC(=O)Oc1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)c1cc2c(cc1O)CCCC2
Yield: 48.3 %

Procedure:
To a mixture of aluminium chloride (120 g) and sodium chloride (52.6 g) at 160° was added, over 10 minutes, the product of step (a) (60 g). The mixture was then heated at 180° for 30 minutes, cooled and poured onto ice. The precipitate was extracted into ether and the extract was filtered and evaporated. The residue was twice crystallised from petroleum ether (40°-60°) to give 5,6,7,8-tetrahydro-2-hydroxy-3-propionylnaphthalene, (14.5 g) as a pale brown solid, m.p 57°-58°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH2:37])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:22][CH2:21]2)[CH2:12]1)=[O:10])[CH3:3].[CH3:39][O:40][CH2:41][CH2:42][C:43](O)=[O:44].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH:37][C:43](=[O:44])[CH2:42][CH2:41][O:40][CH3:39])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:24][CH2:25]2)[CH2:12]1)=[O:10])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)NC(=O)CCOC
Temperature: 0 °C

Procedure:
To a mixture of N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (1 g), 3-methoxypropionic acid (0.17 ml) and 1-hydroxybenztriazole (0.24 g) in N,N-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 ml) under stirring at 0° C. After stirring at ambient temperature for overnight, the mixture was poured into water and extracted with ethyl acetate. The extract washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(3-methoxypropionyl)amino-β-alanine ethyl ester (0.59 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C(C)=[N:48][O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:45]([CH3:44])=[N:46][O:47][N:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nonc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light-yellow gum. MS(m/e): 379.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[N:5][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1cnnc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cnnc1C(=NO)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (4-methyl-4H-1,2,4-triazol-3-yl)(phenyl)methanone (2.4 g, 12.82 mmol, 1 eq.) in 100 ml of pyridine was added hydroxylamine hydrochloride (3.56 g, 51.28 mmol, 4.0 eq.). The temperature was raised to 50° C. and the reaction stirred overnight. The solvent was then evaporated and the residue dissolved in DCM and washed with H2O. The organic layer was washed with 0.1N HCl and dried over MgSO4. The solvent was evaporated to give N-hydroxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (2.51 g, 89% yield) as a white solid.