Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:12][C@H:10]1[CH2:11][C@H:8]([NH2:7])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of (trans-3-benzyloxycyclobutyl)carbamic acid tert-butyl ester (0.99 g, 3.56 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture stirred at RT for 3 h. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and loaded onto an SCX-2 (20 g) cartridge. The cartridge was washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow oil (0.6 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.36-7.31 (5H, m), 4.40 (2H, s), 4.29-4.20 (1H, m), 3.75-3.65 (1H, m), 2.39-2.26 (2H, m), 2.02-1.90 (2H, m), 1.49 (2H, s, br).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]([CH3:25])([CH3:24])[O:15][C:14]2=[O:26])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[CH3:24][C:16]1([CH3:25])[O:15][C:14](=[O:26])[N:13]([C@H:10]2[CH2:11][CH2:12][C:7]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:8][CH2:9]2)[C@H:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(OS(=O)(=O)C(F)(F)F)CC2)[C@H]1c1ccccc1
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: CC1(C)OC(=O)N([C@@H]2CC=C(c3cccnc3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
A microwave tube was charged with (S)-4-((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (0.205 g, 0.489 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.120 g, 0.587 mmol), tetrakis(triphenylphosphine)palladium(0) (0.085 g, 0.073 mmol) and sodium carbonate (0.155 g, 1.466 mmol). Dioxane (1.70 mL) and water (0.25 mL) were added and the vial was charged with argon. The reaction mixture was heated to 100° C. with microwave for 1 h. The reaction mixture was purified via column chromatography on silica gel (RediSep 12 g column, gradient elution with 0% to 50% (90:10 CH2Cl2—MeOH—CH2Cl2) to afford (S)-5,5-dimethyl-4-phenyl-3-((S)-4-(pyridin-3-yl)cyclohex-3-en-1-yl)oxazolidin-2-one (0.128 g, 0.367 mmol, 75% yield) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]1[S:28][CH:29]=[C:30]([C:32]([OH:34])=O)[N:31]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:40][NH:41][O:42][CH3:43].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C)C=O>[CH2:35]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([N:41]([O:42][CH3:43])[CH3:40])=[O:34])[N:31]=3)[CH:17]=2)[N:12]=1)[CH:36]([CH3:37])[CH3:38]
Reactant: CNOC
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nc(C(=O)O)cs4)cc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)-6-quinolinyl]-1,3-thiazole-4-carboxylic acid (0.27 g, 0.5 mmol), N,O-dimethylhydroxylamine hydrochloride (0.06 g, 0.6 mmol), ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.6 mmol), 1-hydroxy-1H-benzotriazole (0.09 g, 0.6 mmol), triethylamine (0.08 ml, 0.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.24 g, yield 85%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][OH:12])[CH:5]=[C:6]([CH2:8][F:9])[CH:7]=1.Cl>C(Cl)Cl>[NH2:13][C@@H:10]([C:4]1[CH:5]=[C:6]([CH2:8][F:9])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(CF)c1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](CO)c1cc(F)cc(CF)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of (S)-tert-butyl (1-(3-fluoro-5-(fluoromethyl)phenyl)-2-hydroxyethyl)carbamate (220 mg, 0.766 mmol) in DCM (2.5 mL), HCl (4M in dioxane) (1.9 mL 7.66 mmol) was added at room temperature, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated to dryness. The residue was recrystallized from DCM and heptane. The solid was filtered and air dry to yield (S)-2-amino-2-(3-fluoro-5-(fluoromethyl)phenyl)ethanol (145 mg, 0.908 mmol, 100% yield) HCl salt as white solid. LCMS (m/z): 188.2 (MH+), 0.32 min.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:10](ON1C(=O)CCC1=O)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].O.[OH-].[Na+]>CC#N.CC(N(C)C)=O.O.CC(N(C)C)=O.[Cl-].[Na+].O>[OH:9][CH2:8][C:2]1([CH3:1])[NH:3][CH2:4][CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC1(CO)CNCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To crude (2-methylpiperazin-2-yl)methanol (10 C) (0.042 mol) dissolved in CH3CN/DMA/H2O (20 mL, 20 mL, 20 mL) cooled to 0° C. was added CBZ-OSu (9.5 g, 0.038 mol) in DMA (15 mL). The reaction was stirred at 0° C. for 30 min then warmed to RT. To the mixture was added H2O (500 mL), sat'd brine (50 mL) and 1M NaOH (50 mL), then the residue was extracted four times with EtOAc (100 mL). The combined EtOAc layers were washed twice with brine then dried over MgSO4 and the solvent removed in vacuo to give racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (9.7 g). HPLC RT: 1.302 min (4 min Chromolith column TFA).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:32]=[N-:33]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(2-methylpropanoyloxy)butanoate (36c) (0.23 g, 0.49 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 64 mg (0.98 mmol) of sodium azide (NaN3). After work-up, the crude material (36d) was obtained and used in the next step without further purification. MS (ESI) m/z 504.01 (M+Na)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:18][CH:17]=1)[C:5]2=[O:36].C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]([CH3:33])([CH3:34])[CH3:35])(=[O:30])=[O:31])=[CH:20][CH:21]=1)[C:5]2=[O:36]
Reactant: CCCc1nc2ccc(I)cc2c(=O)n1Cc1ccc(-c2ccccc2NS(=O)(=O)C(C)(C)C)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(-c3ccccn3)cc2c(=O)n1Cc1ccc(-c2ccccc2NS(=O)(=O)C(C)(C)C)cc1

Procedure:
A solution of 0.5 g (0.8 mmol) of 6-iodo-2-propyl-3-[(2'-(t-butylsulphonamido)biphen-4-yl)methyl]-quinazolin-4(3H)-one in 3 mL of dry DMF under nitrogen was treated with 0.24 g (1.1 mmol) of 2-trimethylstannylpyridine and 10 mg (0.01 mmol) bis(triphenylphophine)palladium dichloride. The solution was heated at 80°-90° C. for 2 hours to give a black solution. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 40% EtOAc/hexanes to give the title compound. 1H-NMR (CDCl3, 200 MHz): δ0.98 (s, 9H), 1.06 (t, 3H,), 1.78 (m, 2H), 2.76 (t, 2H,), 5.49 (bs, 2H), 7.29 (m, 7H), 8.50 (m, 8H), 7.75-7.91 (m, 2H), .8.15 (dd,1H), 8.57 (dd, 1H), 8.71 (dm, 1H), 8.82 (d, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:25]([F:28])([F:27])[F:26])[C:19]=2[F:23])[CH:14]=1.C1(C)C=CC=CC=1.O>CN(C)C=O.[Cu](I)I.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>[F:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[O:24][C:25]([F:28])([F:27])[F:26]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1c(OC(F)(F)F)ccc2cc(Br)ccc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(C#Cc2ccc3c(F)c(OC(F)(F)F)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
10 g of 4-propyl-1-ethynylbenzene and 19.5 g of 2-bromo-5-fluoro-6-trifluoromethoxynaphthalene were dissolved in 50 ml of N,N-dimethylformamide (DMF). To the solution were then added 50 mg of copper iodide (I) and 100 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at room temperature for 5 hours. To the reaction solution was then added toluene. Insoluble matters water removed by filtration. The residue was then washed with water and saturated brine. The solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate 9/1), and then recrystallized from ethanol to obtain 8.6 g of 1-fluoro-2-trifluoromethoxy-6-[(4-propylphenyl)ethynyl]naphthalene.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([I:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:31][OH:32].C[O-].[Na+].O>C1COCC1>[I:30][C:8]1[C:7]2[C:2]([O:32][CH3:31])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: CO
Reactant: Clc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.7 g) in THF (20 mL) was added sodium methoxide methanol solution (1.5 M, 2.7 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.6 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][C@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C[C@H]1COC(=O)N1
Product: COC(=O)c1ccc(CN2C(=O)OC[C@@H]2C)cc1
Yield: 80.9 %

Procedure:
Using methyl 4-bromomethylbenzoate (500 mg) and (S)-4-methyloxazolidin-2-one (243 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (440 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:42])=[CH:20][N:19]=1>>[Cl:42][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 308c. Product isolated as a white foam (81 mg, 40%). LCMS (m/e) 579; 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.37 (d, 1H, J=10.9 Hz), 7.23 (s, 1H), 7.06 (d, 1H, J=8.1 Hz), 6.93-6.83 (m, 2H), 6.22-6.13 (m, 1H), 4.00 (s, 3H), 3.50 (t, 2H, J=5.5 Hz), 3.37 (s, 3H), 2.92 (d, 3H, J=4.8 Hz), 2.88-2.80 (m, 2H), 2.79-2.71 (m, 2H), 2.71-2.63 (m, 4H), 2.63-2.54 (m, 2H); 19F-NMR (CDCl3, 400 MHz) δ −113.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[S:8]1(=[O:25])=[O:24]
Reactant: NC1CCCC1
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: O=S1(=O)N(CCOCCNC2CCCC2)c2ccccc2N1c1c(F)cccc1F

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with cyclopentylamine (2.4 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)cyclopentanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white soldi (0.94 g, 87%). HRMS: calcd for C21H25F2N3O3S+H+, 438.16574; found (ESI, [M+H]+Obs'd), 438.1652.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=[CH:21][CH:20]=1.CCO.C(C#N)C=C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:20]([CH3:21])[CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Agent: C=CCC#N
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CC#N)N1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.00 g, 7.04 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.768 mL, 1.69 mmol, 0.24 mole %) in abs. EtOH (32 mL) was added allyl cyanide (1.42 mL, 17.6 mmol, 2.5 eq) all at one time at room temperature and the mixture was heated at 80° C. for 2.5 hr. Additional benzyltrimethyl-ammonium hydroxide (0.77 mL) was added and the heating continued another 24 hr. The reaction was cooled to room temperature and poured into H2O (100 mL). The reaction mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (97/2/1) to give the title compound as a white solid (0.299 g, 16% ). Anal. Calc'd for: C15H15BrN2O3: C, 51.3; H, 4.3; N, 7.98. Found: C, 51.55; H, 4.47; N 7.99. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 350/352 [M+]; one Br pattern observed. m.p.: 112-113° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24](OCC)=[O:25])[C:12]2=[O:29])=[CH:2]1.[C@@H:30]1([OH:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:35][C@@H:31]3[CH2:32][CH2:33][CH2:34][C@@H:30]3[OH:36])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: O[C@@H]1CCC[C@@H]1O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(O[C@@H]1CCC[C@@H]1O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, (1R,2S)-1,2-cyclopentanediol (0.26 g, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 130° C. for 2 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.025 g, y. 20%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:19]3[CH2:20][CH2:21][CH2:22][O:17][C:18]3=[O:23])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCCO1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: O=C1OCCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light brown solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1,3-oxazinan-2-one.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].II.[Cl:13][Si:14](Cl)([CH3:16])[CH3:15]>O1CCCC1.C(OCC)C>[Cl:13][Si:14]([CH3:16])([CH3:15])[C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: ClC=Cc1ccccc1
Reactant: C[Si](C)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1ccc([Si](C)(C)Cl)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Two milliliters of chlorostyrene was added to 0.97 gram of magnesium turnings in 20 milliliters (ml) of dry tetrahydrofuran under argon. A crystal, about 5 milligrams of iodine, was then added, and the reaction mixture was heated at 65° C. with an air gun until the reaction started (approximately 15 minutes). Thereafter, an additional 2.33 milliliters of chlorostyrene was added slowly to the reaction mixture with a syringe over a period of 15 minutes. The reaction mixture was then refluxed for about 5 minutes at 67° C., and then allowed to cool to room temperature. Dichlorodimethylsilane (9.7 milliliters) was then carefully added with a syringe, (the reaction was exothermic) followed by stirring at 60° C. in an oil bath for 30 minutes. The reaction mixture was then cooled to room temperature, diluted with anhydrous diethylether (approximately 75 ml), and filtered to remove the insoluble magnesium salts. Subsequently, the solvent tetrahydrofuran was removed under reduced pressure and the resulting oil was distilled to yield 3.9 grams (55 percent) of the above product, which was characterized by NMR.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CO)cc1OC1CCCC1
Yield: 97.9 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (38 grams, 0.17 mol) in 40 milliliters of ethanol and sodium borohydride (1.63 grams,0.043 mol) was stirred for 2 hours at room temperature until complete by TLC. The reaction was diluted with water and extracted with ethyl acetate. Evaporation of the ethyl acetate afforded 3-cyclopentyloxy-4-methoxybenzyl alcohol (37 grams, 98%) suitable for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-chlorophenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([CH2:32][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:8]=3)[CH2:3][CH2:2]2)=[CH:31][C:26]=1[C:25]([OH:36])=[O:24]
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccsc1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4ccsc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.38 mmol) of 3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 0.13 g (0.48 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column, and 0.002 g (94% of purity) of the expected acid were isolated.