Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][N:5]1[CH:8]([S:9][CH2:10][CH:11]=[CH2:12])[CH:7]([CH2:13][CH3:14])[C:6]1=[O:15].[OH-].[K+].Cl.C(=O)(O)[O-].[Na+].C(=O)(O)[O-]>C(O)C.O.ClCCl>[CH2:10]([S:9][CH:8]1[N:5]([CH2:4][C:3]([OH:16])=[O:2])[C:6](=[O:15])[CH:7]1[CH2:13][CH3:14])[CH:11]=[CH2:12]
Reactant: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: C=CCSC1C(CC)C(=O)N1CC(=O)O

Procedure:
To a solution of 3 g of Methyl-(4-allylthio-3-ethylazetidin-2-on-1-yl)acetate in 10 ml of absolute ethanol was added, at room temperature and dropwise over 5 minutes, a solution of 0.90 g of potassium hydroxide in a mixture of 12 ml of ethanol and 1 ml of water. The resulting solution was then poured into 10 ml of dichloromethane, 13 ml of 2M hydrochloric acid and 20 ml of water were added, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane, and then the combined dichloromethane extracts were re-extracted with aqueous sodium bicarbonate (2.7 mol equivalents in 27 ml) and then discarded. The aqueous bicarbonate layer was then layered with dichloromethane and acidified to pH 1.5 with hydrochloric acid. The aqueous layer was then further extracted with dichloromethane. The combined organic layer was dried over magnesium sulphate and evaporated in vacuo to give the title compound as a colorless crystalline solid. (Yield 2.56 g)
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45]>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[O:15][C:13]3=[N:14][C:9]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[C:10]([C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH:11]=[C:12]3[C:17]=2[C:18](=[O:21])[NH:19][CH3:20])=[CH:27][CH:26]=1
Reactant: NCC(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Sodium 2-methylbutan-2-olate (229 mg, 2.08 mmol), tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (200 mg, 0.416 mmol), 2,2,2-trifluoroethanamine (206 mg, 2.08 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (33 mg, 0.042 mmol) was combined, degassed, and taken up in dioxane (8.3 ml) at rt and then was heated to 80° C. LCMS at 30 min showed major peak with M+H matching that of the expected product. The mixture was diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was concentrated and triturated with DCM to give the expected product tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoate (130 mg, 0.239 mmol, 58% yield) consistent by LCMS. LC-MS retention time: 2.13 min; m/z (MH+): 544. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (5 g, 33.3 mmol), ethyl 2-bromoacetate (1.1 eq.), and cesium carbonate (2 eq.) in acetonitrile (200 mL) was stirred at room temperature overnight. The acetonitrile was removed in vacuo, and the crude oil was dissolved in ethyl acetate (50 mL) and washed with 1M HCl (2×50 mL), water (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain ethyl 2-(4-acetyl-2-methylphenoxy)acetate (683).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:49]=[CH:48][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[CH:22]4)[CH:15]=2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:22]4)[CH:15]=2)=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.175 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH=10:1 to give 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (75 mg, 0.146 mmol) as a yellow solid. LCMS [M+H]+=515. 1H NMR (500 MHz, CDCl3) δ ppm: 8.42 (d, J=8.51 Hz, 1H), 7.93 (d, J=1.26 Hz, 1H), 7.81 (d, J=1.58 Hz, 1H), 7.17-7.37 (m, 6H), 7.09 (t, J=8.51 Hz, 2H), 6.49 (s, 1H), 6.33 (s, 1H), 4.17 (s, 2H), 2.22-2.39 (m, 4H), 1.38-1.65 (m, 4H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)cn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 87B (0.193 g, 0.297 mmol) in a mixture of THF (2 mL), methanol (2 mL), and aqueous HCl (2 mL, 1 N) was stirred at 60° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.O[CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH:15]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5]2
Reactant: Cc1c(O)ccc2cc(Br)ccc12
Reactant: CCOC(=O)C(O)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)Oc1ccc2cc(Br)ccc2c1C
Yield: 43.7 %

Procedure:
Following the procedure described in Step 2 of Example 4, 6-bromo-1-methyl-2-naphthol (2.44 g 10.3 mmol) was coupled to ethyl 2-hydroxy-3-phenylpropanoate (3.0 g, 15 mmol) in presence of triphenylphosphine (4.17 g, 15.9 mmol) and diisopropyl azodicarboxylate (3.0 mL, 15 mmol) in benzene (65 mL). Purification by flash chromatography using 100% hexane and 1-4% ethyl acetate in hexane as eluants afforded ethyl 2-[(6-bromo-1-methyl-2-naphthyl)oxy]-3-phenylpropanoate as a transparent yellow gum (1.86 g). 1HNMR (400 MHz, DMSO-d6): δ8.1 (s, 1H), 7.9 (d, 1H, J=7.0 Hz), 7.7 (d, 1H, J=7.0 Hz), 7.6 (d, 1H, J=6.3 Hz), 7.3-7.4 (m, 4 H), 7.2-7.3 (m, 2H), 5.25 (t, 1H, J=6.3 Hz), 4.1 (q, 2H, J=7.0 Hz), 3.25-3.35 (m, 2H), 2.45 (s, 3H), and 1.1 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(C)=O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (350 mg, 1.0 mmol, 1.0 eq) in acetone (5 mL) was added Cs2CO3 (492.5 mg, 1.5 mmol, 1.5 eq). The resulting mixture was stirred for 30 min at room temperature then ethyl bromoacetate (202 mg, 1.21 mmol, 1.2 eq) was added. The resulting mixture was stirred 1 h then water added and the mixture extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (385 mg, 88%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)thiazol-2(5H)-one dihydrochloride (1.50 g) in DMF (23.3 mL) were added 4-bromo-2-(trifluoromethyl)benzaldehyde (1.99 g) and triethylamine (2.93 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (3.34 g) was added. The reaction mixture was stirred at room temperature for 1 hr and poured into water, and the mixture was extracted with ethyl acetate. The extract was 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 (ethyl acetate/hexane) to give the title compound (1.71 g).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=3)[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][Mg]Cl>O1CCCC1>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([OH:16])[CH3:19])[CH:13]=3)[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c2cc(C=O)ccc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCc1nn(C2CCCC2)c2cc(C(C)O)ccc12
Temperature: 25 °C

Procedure:
A solution of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxaldehyde (1.00 g, 4.13 mmol) in 40 mL of tetrahydrofuran under argon was cooled to −78° C. and with stirring treated with 3 mL of 3 M methylmagnesium chloride in tetrahydrofuran. The reaction was stirred at −78° C. for 1 hour, slowly warmed to room temperature overnight and then quenched by addition of 100 mL of saturated aqueous NH4Cl. The mixture was extracted with 3×50 mL of ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated to give 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol as a yellow solid. The crude residue was not purified but used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=O)[N:4]2[N:3]=1.[CH3:18][N:19]([CH3:26])[C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23].N1CCCCC1>>[CH3:18][N:19]([CH3:26])[C:20](=[O:25])[C:21]([C:22](=[O:23])[CH3:24])=[CH:10][C:9]1[N:4]2[C:5]([S:6][C:2]([CH3:1])=[N:3]2)=[N:7][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Reactant: CC(=O)CC(=O)N(C)C
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1c(-c2ccccc2)nc2sc(C)nn12)C(=O)N(C)C

Procedure:
0.03 mole of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazol-5-carbaldehyde, 0.1 mole (13.0 g) of acetoacetic acid dimethylamide and 0.6 ml of piperidine were heated to 120° C. for 4 hours. The mixture was then cooled and the precipitate formed was recrystallised from 30 ml of ethyl acetate. After drying, α-acetyl-β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid dimethylamide of melting point 185° to 187° C. was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Product: COCCOc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(N(C)C)cn4)c(OC)c3)c2cc1OC
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 15, N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide was reacted with 4-chloro-7-(2-methoxyethoxy)-6-methoxyquinazoline. There was thus obtained the title compound in 74% yield; 1H NMR: (CDCl3) 2.93 (s, 6H), 3.5 (s, 3H), 3.75 (s, 2H), 3.88-3.93 (m, 2H), 3.91 (s, 3H), 4.05 (s, 3H), 4.32-4.38 (m, 2H), 6.86 (s, 1H), 6.87 (m, 1H), 7.10 (m, 1H), 7.33 (s, 1H), 7.4 (d, 1H), 7.53 (d, 1H), 7.73 (d, 1H), 8.09 (d, 1H), 8.18 (br s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 534.
Reaction SMILES: N[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:15].N([O-])=O.[Na+]>O>[Br:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:2]([Cl:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: COC(=O)c1cc(Br)cc(OC)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cc(OC)c1Cl
Reaction time: 1 h

Procedure:
To a solution of compound 54 (27.0 g, 103 mmol) in H2O (70 mL) and conc.HCl (70 mL) was added dropwise a solution of NaNO2 (21.5 g, 311 mmol) in H2O (50 mL) at 0° C. After being stirred for 1 hour, a solution of Cu(I)Cl in conc.HCl (80 mL) was added to the reaction mixture dropwise at 0° C. The mixture was stirred at room temperature for 18 hours. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 55 was dried under high vacuum and used without further purification (29.0 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BrH:11].O.BrBr>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)c1ccc(Br)cn1
Reaction time: 1 h

Procedure:
1-(5-bromopyridin-2-yl)ethanone (200 mg, 1.0 mmol) was dissolved in Acetic acid (50 mL) and HBr in Acetic acid (48% solution, 280 uL) was added along with water (100 uL). Warmed to 70 C and added Bromine (51.5 uL, 1.0 mmol) and stirred for 1 hour. The reaction was concentrated to give the desired product (280 mg) containing a small amount of dibrominated product. This material was used as is.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1
Reactant: BrBr
Reactant: CC(C)OC(=O)c1ccc(CCO)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1ccc(CCBr)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Bromine (1.74 mL, 33.9 mmol) was added slowly to a solution of triphenylphosphine (8.9 g, 33.9 mmol) in CH2Cl2 (65 mL) at −40° C. After 1 h at −40° C., a solution of the alcohol from step 1 (6.6 g, 30.8 mmol) and pyridine (2.5 mL, 30.9 mmol) in CH2Cl2 (65 mL) was added via cannula. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo to a brown slurry. The mixture was triturated with hexanes (150 mL) and stirred vigorously. The solids were removed by filtration and the filtrate was concentrated in vacuo to afford 6.2 g (73%) of isopropyl 5-(2-bromoethyl)thiophene-2-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (729 mg, 2.10 mmol) in ethanol (20 mL) was treated with a solution of potassium hydroxide (694 mg, 10.51 mmol) in water (7 mL). The reaction was stirred for 3 h at 25° C., concentrated in vacuo to remove the ethanol, and then was acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting mixture was then extracted with methylene chloride (3×10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (654 mg, 94%) as a white foam: (ES)+-HRMS m/e calcd for C14H17ClO5S (M+Na)+ 355.0377, found 355.0382.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C

Procedure:
To butan-1-ol (76 mL) was added portion wise sodium tert-butoxide (15.2 g) (Note: reaction mixture gets warm). The above was stirred until homogeneous (˜15 min) before 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (10.0 g) was then added to the resultant pale yellow solution. The reaction mixture was then heated to 100° C., overnight. The reaction mixture was stripped to remove as much butan-1-ol as possible before being partitioned between diethyl ether and water. The diethyl ether phase was separated and the aqueous re-extracted further with diethyl ether. Combined organic layers dried over magnesium sulphate (anhydrous). Magnesium sulphate was filtered off and filtrate stripped to give brown viscous oil which was azeotroped with toluene (3 times) and placed under high vacuum overnight, transferred to new flask with dichloromethane and stripped, placed under high vacuum to give the title compound as a brown glass (9.45 g).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25](C)=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2].BrC1N=CC=CN=1.[CH3:42][O:43]C1C(C2N=C(CC)C(N[C@H]3[C@@H](OCC)CNC3)=NC=2CC)=CC=C(OC)N=1>>[CH3:42][O:43][C:25]1[C:24]([C:19]2[N:20]=[C:21]([CH2:22][CH3:23])[C:16]([NH:15][C@H:5]3[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:8][N:7]([C:9]4[N:10]=[CH:11][CH:12]=[CH:13][N:14]=4)[CH2:6]3)=[N:17][C:18]=2[CH2:33][CH3:34])=[CH:29][CH:28]=[C:27]([O:30][CH3:31])[N:26]=1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Agent: Brc1ncccn1
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromopyrimidine and starting with 5-(2,6-dimethoxypyridin-3-yl)-N-[(3R,4S)4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (400 MHz, CDCl3) δ) 8.35, 7.53, 6.52, 6.42, 5.18, 4.90, 4.20, 3.97, 3.93, 3.89, 3.77, 3.52, 2.72, 2.52, 1.33–1.25, 1.18; IR (diffuse reflectance) 2402 (w), 2347 (w), 2307 (w), 2264 (w), 2194 (w), 1601, 1582 (s), 1566, 1547 (s), 1510 (s), 1474 (s), 1395, 1377 (s), 1312 (s), 1022 cm−1 HRMS (ESI) calcd for C25H33N7O3+H1 480.2723. found 480.2715.
Reaction SMILES: [Li].C1(S([C:11]2([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:14][CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[Br:24][CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][C:11]1([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:13][CH2:14]1
Reactant: O=S(=O)(c1ccccc1)C1(S(=O)(=O)c2ccccc2)CCC1
Reactant: BrCCCBr
Agent: [Li]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C1(CCCBr)CCC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A solution of lithium napthtalenide in tetrahydrofuran (4.3M, 60 ml) was added to a stirred solution of 1,1-bis(phenylsulfonyl)cyclobutane (4.15 g, 12.35 mmol) at −78° C. over 20 min. The mixture was stirred for 15 min. and 1,3-dibromopropane (10 ml) was added in one portion. The cold bath was removed and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was treated with saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel to give the title product (2.55 g, 65%).