Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][NH:24][CH2:23]4)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH3-][C:45]#N.[Na+].CC(O)=O.C=O>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][N:24]([CH3:45])[CH2:23]4)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CN(C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (8.3 mg, 0.0136 mmol) in MeOH (0.2 mL), was added NaCNBH3 (1.0 mg, 0.0163 mmol), AcOH (3.85 uL, 0.068 mmol) and formaldehyde (38%) (1.3 uL, 0.0176 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was washed with sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-methyl-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc. 625.2; found=624.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:32](=[O:47])[CH2:33][C@@H:34]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:37]1[CH:38]=[CH:39][C:35]([C@H:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:2][C:3]3[S:4][C:5]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[CH:6][C:7]=3[CH3:8])=[CH:42][CH:41]=2)[CH2:33][C:32]([N:27]2[C@@H:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:30][O:29][C:28]2=[O:31])=[O:47])=[N:36]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 62.7 (0.23 mmol), 7.5 (76 mg, 0.19 mmol), and Cs2CO3 (226 mg, 0.69 mmol) in DMF (2.3 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (15-45% EtOAc/hexane) to afford 62.8 (94 mg, 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])Br>CN(C)C=O>[Br:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[S:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Sc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(Br)C(F)(F)Sc1c(Cl)cccc1Cl
Yield: 35.2 %

Procedure:
In a manner similar to Step A of Example 1, the reaction of 26.0 g (0.25 mole) 2,6-dichlorothiophenol, 20.0 g (0.15 mole) potassium carbonate and 75.4 g (0.30 mole) 1,2-dibromotetrafluoroethane in 200 ml of N,N-dimethylformamide produced 31.5 g of 2-(2-bromo-1,1,2,2-tetrafluoroethylthio)-1,3-dichlorobenzene as an oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=CC(=O)c1cc(Cl)ccc1N
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)CCC(=O)c1cc(Cl)ccc1N
Yield: 86.7 %

Procedure:
A solution of 4.435 g (18.506 mM) of methyl 4-(2-amino-5-chlorophenyl)-4-oxo-2-butenoate in 118 ml of dioxane is hydrogenated in the presence of 887 mg of 10% Pd-C under ordinaly pressure at room temperature. The mixture is concentrated after removal of the catalyst. The resulting residue is chromatographed on a column of silica gel (220 g), eluting with toluene-ethyl acetate (49:1-30:1 v/v) to give 3.877 g (Yield: 86.7%) of methyl 4-(2-amino-5-chlorophenyl)-4-oxobutyrate. This is recrystallized from CH2Cl2 -Et2O-n-hexane to give light yellow scaly prisms melting at 78°-79° C.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>C(O)(=O)C>[NH2:3][C:4]1[CH:12]=[C:11]([Cl:13])[C:10]([Br:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 2.65 mL (52.0 mmol) of bromine in 10 mL of acetic acid was added dropwise over 15 minutes to a solution of 8.89 g (52.0 mmol) of 2-amino-4-chloro-benzoic acid in 60 mL of acetic acid. The mixture was stirred at room temperature for 1 h and poured into 500 grams of ice. The solid was collected by filtration, washed with cold water and dried to produce 11.2 g (86%) of 2-amino-5-bromo-4-chloro-benzoic acid. LCMS: 251 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:40][C:41]([F:61])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:61][C:41]([F:40])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH:59][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:49])=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (53.1 mg, 0.247 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (94 mg, 0.247 mmol) were combined in dichloromethane (2 mL). After 10 minutes, (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (75 mg, 0.224 mmol) from Step A of Example 254 was added. After stirring for 10 more minutes, N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution, extracted with 2 mL of dichloromethane, washed with 0.1 N HCl, and concentrated in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 1-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (501 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.29-8.30 (bs, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.66-7.72 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 4.29-4.32 (m, 1H), 4.06-4.10 (m, 1H), 3.68-3.71 (m, 1H), 3.46-3.51 (m, 1H), 3.34-3.42 (m, 1H), 3.26 (dd, J=9.9, 7.4 Hz, 1H), 3.06-3.17 (m, 2H), 2.55-2.57 (m, 2H), 2.09 (d, J=3.0 Hz, 1H), 1.88-1.98 (m, 3H), 1.80-1.88 (m, 1H), 1.59-1.68 (m, 1H), 1.55 (dd, J=13.2, 8.7 Hz, 1H), 1.50 (s, 9H), 1.25-1.37 (m, 1H); MS (ESI+) m/z 532 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][O:32][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(O)=O>[C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][OH:32])=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1c(CO)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the crude ether from Step 5 in THF (10 mL) at 0° C. was added HOAc, (4 drops) followed by n-Bu4NF (1M, THF, 1.4 mL). The reaction mixture was stirred 2 hr at 0° C. then quenched with a saturated solution of NH4Cl and diluted with Et2O. The organic phase was washed with H2O, brine, dried over MgSO4, and the solvent evaporated. The residue was purified by chromatography on silica gel using hexane/EtOAc 7:3 to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@@H:36]2[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@H:36]3[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
Dimethylformamide (15 ml) was added to 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-hydroxyquinazoline (0.66 g; prepared as described in Example 22-preparation of starting materials), 1-tert-butyl 2-methyl (2S,4S)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1,2-dicarboxylate (0.889 g) and cesium fluoride (0.941 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless gum (0.36 g); Mass Spectrum: (M+H)+ 547.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](=[O:30])C(Cl)(Cl)Cl)=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:30])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2)C(Cl)(Cl)Cl
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2
Yield: 90.9 %

Procedure:
To a solution of 1-{10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-2,2,2-trichloroethanone of Step B (1.80 g, 3.297 mmol) and dimethyl sulfoxide (1.17 mL, 16.487 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.67 mL, 6.595 mmol) and the reaction mixture heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue dissolved in ethyl acetate (100 mL), washed with 1M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane gave the title compound (1.61 g, 91%) as a yellow foam.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Reaction time: 22 h
Yield: 43.5 %

Procedure:
A solution of methyl bromoacetate (0.08 mL, 0.91 mmol) in CH3CN (6 mL) was added, over a period of 15 min, to a solution of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile (0.22 g, 0.82 mmol) and DIPEA (0.28 mL, 1.64 mmol) in CH3CN (8 mL) at −10° C. The reaction was allowed to reach room temperature and stirred for 22 h. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (2-5% MeOH/CH2Cl2) affording 0.12 g of methyl[((trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl)amino]acetate [Rf=0.5 (5% MeOH/CH2Cl2), pale yellow oil, 44% yield].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
5-Benzyloxy-4-tert-butyl-2-formylbenzofuran (700 mg, 2.3 mmol) was dissolved in acetic acid (30 ml) and, after addition of 10% Pd on carbon (700 mg), the solution was stirred under a hydrogen atmosphere (5 atm.) for 8 h. After filtering off the Pd on carbon, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was subjected to silica gel chromatography and eluted with a solvent system consisting of a 4:1 mixture of hexane and ethyl acetate to afford 4-tert-butyl-5-hydroxy-2-methylbenzofuran [320 mg (yield, 68%)] as a pale yellow, fine-grained crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH2:8][CH3:9].[Br:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([I:19])[N:13]=1.O>CN(C)C=O>[Br:11][C:12]1[C:17]([O:18][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=[C:14]([I:19])[N:13]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (1.38 g) and n-propyl iodide (1.13 g) were added to a solution of 2-bromo-6-iodopyridin-3-ol (1.0 g, described in WO 2007088996) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give 2-bromo-6-iodo-3-propoxypyridine as a crude product.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3)CCC2)cc1
Yield: 103.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 300 mg (1.9 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 290 mg of 1-[2-(4-chlorophenyl) cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 72°-74° C.; NMR (CDCl3) d 2.04 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.86 (t, J=7 Hz, 4H) , 7.07-7.21 (m, 8H) .
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([CH3:29])[CH:18]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[C:27]([CH3:28])[C:17]([O:16][CH3:15])=[CH:18][C:19]=3[CH3:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CC)c1=O
Yield: 52.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.9 g (13.9 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.43 g (yield 52%) of Compound 74 as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:18])[C:8]([C:12]3[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:18])[C:8]([C:12]3[CH:16]=[C:15]([NH:17][C:21](=[O:22])[CH2:20][C:19]([O:25][CH2:26][CH3:27])=[O:24])[NH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1nc2ccc(F)cc2nc1-c1cc(N)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(-c2nc3cc(F)ccc3nc2C)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine (45.7 g, 188 mmol) in pyridine (750 mL) was added ethyl hydrogen malonate (5.35 mL, 62.5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.0 g, 282 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h, and then concentrated in vacuo. The residue was triturated with water, ethanol and acetone subsequently to give ethyl 3-{[3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate. MS (APCI): m/z 358 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH3:6].[Cl:7][CH2:8][CH2:9][S:10](Cl)=[O:11]>CCOCC>[Cl:7][CH2:8][CH2:9][S:10]([O:1][CH2:2][CH2:3][S:4][CH2:5][CH3:6])=[O:11]
Reactant: O=S(Cl)CCCl
Reactant: CCSCCO
Solvent: CCOCC
Product: CCSCCOS(=O)CCCl
Temperature: 25 °C

Procedure:
A solution of ethyl 2-hydroxyethyl sulfide (10.6 w) in dry ether (50 v) was slowly added to 2-chloroethanesulfinyl chloride (14.7 w) in dry ether (200 v) maintained at about -10° under a nitrogen atmosphere. Upon warming to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residual oil was passed through a wiped film molecular still to yield 2-(ethylthio)ethyl 2-chloroethanesulfinate (15.4 w) boiling at 95-100° under reduced pressure (1 × 10-4 torr).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:4]2[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][C:5]=2[OH:9])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1ccc(Cc2c(O)cccc2O)cc1
Temperature: 180 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.0 g, 23.4 mmol) and pyridine hydrochloride (21.6 g, 187 mmol) was heated and stirred at 180° C. for 15 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with diluted aqueous hydrochloric acid and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate 80:20) to give 2-(4-ethylbenzyl)resorcinol (5.2 g, 97%) as a light-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].CO.Cl>C1COCC1.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: CSc1ccc(Cl)cc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(Cl)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
5-Chloro-2-methylsulfanyl-benzonitrile (3.9 g, 21.2 mmol) was dissolved in THF (42 mL) and cooled to 0 degrees C. Borane-THF complex (50 mL of a 1M THF solution) was added dropwise. After 10 minutes at 0 degrees C. the reaction was warmed to 65 degrees C. for 4 h. Methanol (approximately 30 mL) was added to the reaction at 0 degrees C. The reaction was warmed to room temperature and stirred for 10 minutes. The reaction solution was concentrated in-vacuo to yield a thick oil which was dissolved in 50% THF/MeOH (30 mL). 4M HCl (30 mL) was added slowly. After 10 minutes, the solution was partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (30 mL) and the organic layers were discarded. The aqueous layer was neutralized to pH9 with 5M NaOH. The solution was extracted with DCM (3×70 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to yield 2.9 g of 5-chloro-2-methylsulfanyl-benzylamine as a pale yellow oil, 1H NMR 400 MHz (CDCl3) δ 7.33 (d, 1H, J=2.4 Hz), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.13 (d, 1H, J=5 8.4 Hz), 3.89 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][CH2:33][C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][CH2:33][C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F
Reaction time: 8 h
Yield: 50 %

Procedure:
[(2R)-3-[2-(2-Chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1677, 0.295 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0715 g, 50%). LCMS: (M+H)+=485.1.