Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@:6]2([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7]([CH2:9][C@H:3]1[CH2:4][CH2:5]2)=[O:8].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:29]2[CH:28]=[C:27]([CH3:30])[N:26]=[C:25]([NH2:31])[C:24]=2[N:23]=[C:22]1[CH2:32][O:33][CH2:34][CH3:35]>>[NH2:31][C:25]1[C:24]2[N:23]=[C:22]([CH2:32][O:33][CH2:34][CH3:35])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:11]([CH2:10][C@:6]34[C:2]([CH3:15])([CH3:1])[C@H:3]([CH2:4][CH2:5]3)[CH2:9][C:7]4=[O:8])(=[O:13])=[O:12])[C:29]=2[CH:28]=[C:27]([CH3:30])[N:26]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)Cl)C(=O)C2
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNS(=O)(=O)C[C@]12CC[C@H](CC1=O)C2(C)C

Procedure:
Using the method of Examples 32-46, D-(+)-10-camphorsulfonyl chloride was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 565.2720.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([O:22]C)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>Br>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([OH:22])[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(O)c3O2)cc1
Yield: 68.6 %

Procedure:
Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (22.1 g, 0.06 mol) with hydrogen bromide (400 mL, 30 wt. % in acetic acid) generally according to the procedure described for Intermediate 46 gave 14.6 g of (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 12.68 mmol) with trifluoromethanesulfonic anhydride (2.34 mL, 13.9 mmol) and diisopropylethylamine (2.43 mL, 13.9 mmol) generally according to the procedure described for Intermediate 7 provided 6.27 g (99%) of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a light yellow solid. mp 55-57° C.; Anal. calcd. for C17H14ClF3O7S2: C, 41.94; H, 2.90. Found: C, 42.10; H, 2.76.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:13][C@H:11]([C:9]2[N:8]([CH3:14])[C:7]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=2)[CH3:12])[N:19]=[CH:18][N:17]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A mixture of (S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamine (1 g, 3.9 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.64 g, 4.1 mmol) and DIPEA (2.1 mL, 4.1 mmol) in IPA (7.8 mL) was heated for 16 h at 90° C. After cooling to RT, the reaction mixture was filtered and the solid washed with MeOH and DCM to afford 421 as a cream solid (1.05 g, 72%). LCMS (Method K): RT 3.27 min [M+H]+ 372 (for 79Br) 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.79 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=4.0 Hz), 7.32 (2H, bs), 7.11 (1H, dd, J=8.0, 8.0 Hz), 5.70 (1H, dq, J=7.5, 7.0 Hz), 4.01 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.[CH:10](O)=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=[O:11])[CH:3]=1
Reactant: NCc1cc(Br)ccn1
Reactant: O=CO
Product: O=CNCc1cc(Br)ccn1
Temperature: 25 °C

Procedure:
20.00 g of C-(4-bromopyridin-2-yl)methylamine are taken up in 60 ml of formic acid and the solution is heated to reflux over 3 hours. The reaction solution is cooled to room temperature and concentrated by evaporation, and the residue is taken up in saturated aqueous sodium hydrogencarbonate solution (300 ml) and the aqueous solution extracted with dichloromethane (3×300 ml). The combined organic phases are washed with water (300 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Dissolve 4bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (153 mg, 6.4 mmol) in portions. After the vigorous gas evolution stops, add 2-bromo-propane (0.60 mL, 6.4 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (300 mL) and extract with ethyl acetate (2×150 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with 5% ethyl acetate in hexanes to yield 1.1 g of 1-bromo-4-isopropylsulfanyl-benzene (92%).
Reaction SMILES: C(O[C:4](=[O:8])[CH:5]([F:7])[F:6])C.[NH2:9][C@H:10]([CH2:20][F:21])[C@@H:11]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[OH:12]>>[F:7][CH:5]([F:6])[C:4]([NH:9][C@H:10]([CH2:20][F:21])[C@H:11]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)=[O:8]
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: CCOC(=O)C(F)F
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(F)F

Procedure:
Using the same procedure as Step 1 of Example 4 and reacting ethyldifluoroacetate with commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol the title compound is obtained (18.3 g): m/z 373 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17](B(O)O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH:13]=[CH:14]3)[CH:5]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccnc(Cl)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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc3[nH]ccc3c2)c1
Reaction time: 12 h
Yield: 24.5 %

Procedure:
2-Chloroisonicotinic acid methyl ester (1.22 g, 7.11 mmol), 1H-indole-5-boronic acid (1.15 g, 7.13 mmol), 2M-aqueous sodium carbonate solution (10 mL, 20 mmol) and tetrakis(triphenylphosphine)palladium (0.41 g, 0.35 mmol) were dissolved in toluene (140 mL), and stirred for 12 h under reflux. After completion of the reaction, ethyl acetate (200 mL) was added, and washed with aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to give the title compound (440 mg, 1.74 mmol, 25% Yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(C)N=C=O
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CC(C)NC(=O)NCCSCc1ccc(CN(C)C)o1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and isopropylisocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. Solvents were removed and the residue recrystallised from methanol:ether to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl-N'-(1-methylethyl)urea as crystals m.p. 65°-67° (2.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14]Cl)[N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2)n(CCCl)n1
Solvent: CC#N
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)n(CCN2CCOCC2)n1

Procedure:
A solution of 5-(4-bromophenyl)-1-(2-chloroethyl)-3-(trifluoromethyl)-1H-pyrazole (200 mg, 0.56 mmol) and morpholine (0.245 mL, 5 equiv) in acetonitrile (2 mL) was stirred overnight at 90° C. Evaporation of solvent gave of 4-(2-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)morpholine. MS (ES): 404 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[NH:11][CH2:12][C:13]([N:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]([C:26]([O:28]C)=[O:27])[CH2:17][CH:16]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:14])[CH:6]=[CH:7][CH:8]=1.O.CO>[OH-].[K+]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[NH:11][CH2:12][C:13]([N:15]2[CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:18]([C:26]([OH:28])=[O:27])[CH2:17][CH:16]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(SC)c2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)O)C2c2ccccc2)c1
Yield: 71.9 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.5 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(3-(methylthio)phenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate in a mixture of 2.8 cm3 of a normal aqueous potassium hydroxide solution, 15 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.05 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(3-(methylthio)phenyl)ureido]-acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 130° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C[N:23](C=O)C>>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[CH3:11])[N:23]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(Nc1nc(Br)cnc1N)c1ccc2ncccc2c1
Reactant: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)n1nnc2ncc(Br)nc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of the 5-bromo-N*3*-(1-quinolin-6-yl-ethyl)-pyrazine-2,3-diamine in anhydrous DMF (25 mL) was added isoamyl nitrile (0.98 mL, 1.2 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min, then the ice bath was removed and allowed to stir at ambient temperature for 5 min. The reaction was then heated at 70° C. for 1 hour, cooled and quenched with sat. aqueous solution of Na2SO3 (10 mL). Water (50 mL) and EtOAc (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organics were washed with NaHCO3 (50 mL) and water (3×50 mL), dried over Na2SO4, filtered and concentrated to give 6-[1-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-ethyl]-quinoline (1.56 g, 72% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:21](/[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)\[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCC/C(=N\Nc1ccc(Br)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
A mixture of 1.91 g (8.55.10−3 mol) of 4-bromophenylhydrazine hydrochloride and 0.73 g (8.9.10−3 mol) of sodium acetate in 17 ml of water is prepared and 2.05 ml (35.8.10−3 mol) of acetic acid are added. This mixture is subsequently heated to 70° C., with stirring, and a suspension of 2.0 g (8.54.10−3 mol) of ethyl ε-oxobenzenehexanoate in 27 ml of water is then added slowly. The reaction mixture is stirred at 70-80° C. for 45 min and then at room temperature for 12 hours, after which it is extracted with 2 times 50 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3.38 g of the expected compound, which is used directly in the next step.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N-:22]=[C:23]=[O:24].[K+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:23]([NH2:22])=[O:24])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.36 mmol) and potassium isocyanate (32 mg, 0.40 mmol) were stirred in a 1:1 mixture of water and acetic acid (3 mL) at ambient temperature for 2 h. Then a satured solution of sodium bicarbonate was added, the aqueous phase was extracted with ethyl acetate, the organic phase washed with brine and dried over sodium sulfate. Over night the desired product precipitated and subsequently the crystals were collected and dried under vacuum. [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea was obtained as a white solid (44 mg; 38%); MS: m/e=319.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCCc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCc2c(F)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A round bottom flask was charged with 0.15 g of 4-(2-fluorophenyl)butanoic acid, which was dissolved in 20 mL DCM and cooled to 0° C. Oxalyl chloride (0.15 mL) was added, followed by 1 drop of DMF. A drying tube was attached, and the solution was stirred at 0° C. for two hours. Aluminum chloride (0.121 g) was added and the solution was allowed to slowly warm to RT overnight. The mixture was poured onto ice water, and extracted three times with DCM. The combined organic layers were washed with 0.5 M NaOH and brine. The organic phase was dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hexanes), to give 0.07 g (53%) of 5-fluoro-3,4-dihydronaphthalen-1(2H)-one (32).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]1([O:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)n1cc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(NC(=O)Oc2ccccc2)cn1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution containing 1-tert-butyl-1H-pyrazol-4-amine (0.995 g, 7.16 mmmol) in THF (20 mL), phenylchloroformate (1.00 mL, 8.02 mmol) and K2CO3 (1.32 g, 9.52 mmol) were added at room temperature. After stirring overnight, the mixture was filtered and the solid washed with THF. The filtrate was concentrated to dryness and the residue was dissolved in DCM and the organic solution was washed with brine and dried over MgSO4 to yield phenyl 1-tert-butyl-1H-pyrazol-4-ylcarbamate as a solid (1.65 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.30 (6H, m), 1.60 (9H, s).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (47 mg, 0.108 mmol) and 1,2-dichloroethane (4 ml). To the stirred solution was added methanesulfonyl chloride (10 μm, 0.12 mmol), triethylamine (30 μl, 0.22 mmol) and 4-dimethylaminopyridine (catalytic amount). The solution was stirred for 17 hr then partitioned between aqueous sodium hydroxide (5 ml, 0.2M) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic layers were washed with brine (8 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 1:3, v/v) to give the title compound (39 mg, 70%) which solidified on standing. δH(CDCl3) 0.17 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.00 (9H, s), 1.53 (2H, m), 1.71 (4H, m), 1.94 (2H, m), 2.85 (1H, m), 2.99 (3H, s), 3.78 (1H, m), 4.83 (1H, d), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of compound 5-bromopyridin-2(1H)-one (348 mg, 2.0 mmol) and K2CO3 (830 mg, 6.0 mmol) in DMF (15 mL) was added ethyl bromoacetate dropwise. The mixture was stirred at room temperature for 2 h, filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep TLC (1:1 PE/EtOAc) to afford ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (300 mg, 57.7%). 1H NMR CDCl3: δ 7.41-7.26 (m, 2H), 6.53-6.5 (d, 1H), 4.59 (s, 2H), 4.28-4.21 (q, 2H), 1.32-1.23 (q, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH:3]=[CH2:4].[CH2:13]([O:16][C:17]1([CH3:46])[CH2:22][CH2:21][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32]I)[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:19][CH2:18]1)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:16][C:17]1([CH3:46])[CH2:18][CH2:19][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32][O:12][CH2:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[CH:6]=4)[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:21][CH2:22]1)[CH:14]=[CH2:15]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1cccc(COCc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a mixture of (3-(but-3-en-1-yl)phenyl)methanol (40.2 mg, 0.248 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (145 mg, 0.248 mmol) and NaH (9.92 mg, 0.248 mmol). The mixture was stirred at 0° C. for 3 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((3-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol, 32.6% yield) as an oil. LCMS (M+1)=619.5.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([Cl:10])=[C:8](Cl)[S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1scc(Cl)c1NC(C)=O

Procedure:
was obtained by catalytically hydrogenating a mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate in 300 ml of methanol, 9.5 g of triethylamine and with 10 g of palladium on carbon and room temperature and 760 mmHg column (standard pressure conditions). After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solvent was distilled off on a Rotavapor and the product was crystallized under water.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[CH:8]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a yellow oil (yield: 97.7%).