Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (264 mg, 0.95 mmol) [prepared according to the procedure of Example 96], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (306 mg, 0.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (450 mg, 0.96 mmol) in chloroform (7 mL). DIEA (660 μl, 3.78 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.44 mmol, 56%): LC-MS (ES) m/z=607 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O1CCCC1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([CH3:2])[CH:4]=2)=[O:29])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.8 %

Procedure:
3-Methyl-4-methanesulfonylaminobenzylamine hydrochloride (140 mg, 0.56 mmol), 3-(4-t-butylphenyl)acrylic acid (1.1 eq, 0.13 g), and DMTMM (1.1 eq, 0.185 g) were added into 25 ml tetrahydrofuran. The reaction mixture was stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=2/1) to yield a solid (49 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([O:8][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 2-methyl-6-nitro-pyridin-3-ol (0.77 g, 5.00 mmol) in acetone (50.00 ml) was treated with acetic anhydride (1.00 g, 9.80 mmol) and potassium carbonate (2.07 g, 15.00 mmol). The mixture was stirred for 1 h at room temperature then filtered, washing with acetone. The solvent was removed, yielding acetic acid 2-methyl-6-nitro-pyridin-3-yl ester (0.75 g, 77%) as a white solid, MS (ISP): m/e=196.1 (M+), which was used crude.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:2]1[N:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=2[OH:19])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: Oc1cccc(O)c1
Product: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(O)cc3O)n2)c(O)c1

Procedure:
Following the procedure of Example 14, the title compound is prepared by the reaction of 2,4-dichloro-6-phenyl-s-triazine and resorcinol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([O:24][C:25](=[O:28])[CH:26]=[O:27])[CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:28])[CH:26]([OH:27])[CH:15]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:2]([Br:1])[CH:3]=1)[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)c(Br)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(=O)C(c1ccc(OC2CCCCC2)c(Br)c1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3-Bromo-4-cyclohexyloxy-phenyl)-hexan-2-one (7.08 mmol, 2.5 g), oxo-acetic acid ethyl ester solution in toluene (2.8 mL, 50% solution in toluene) and triethylamine (0.5 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with water (3×100 mL), dried the organic layer and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography using mixture of hexanes in ethyl acetate (9:1) to provide 3-(3-bromo-4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (2.0 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:31]=[N:30][N:29]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([C:5]1[N:6]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Solvent: CO
Product: CCCCc1nc(CO)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A solution of (2-butyl-5-chloro-1-{5-[2-(1-trityl-1H-tetrazol-5-yl)-phenyl]-indan-1-yl}-1H-imidazol-4-yl)-methanol (100 mg) in MeOH (10 mL) was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using a gradient of 2% MeOH/CH2Cl2 to 15% MeOH/CH2Cl2 to give 31 mg of a colorless oil. The oil was dissolved in EtOAc (0.5 mL) and hexanes were added to precipitate a solid. The solid was filtered and dried. 1H NMR (250 MHz, d6 -DMSO): d 7.67 (d, 1 H), 7.40 (m, 4 H), 7.05 (s, 1 H), 6.90 (d, 1 H), 6.60 (d, 1 H), 5.95 (t, 1 H), 5.85 (bs, 1 H), 4.18 (s, 2 H), 3.50-2.30 (m), 1.54 (m, 2 H), 1.46 (m, 2 H), 0.90 (t, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OC[C@H]1CCCO1)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.1 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.35 ml (1.35 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 396 mg (1.7 mmol, 1.5 eq.) of (2R)-tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 625 mg (purity 76%, 92% of theory)
Reaction SMILES: [OH:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[N:8]([CH3:9])[CH:7]=[N:6][N:5]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22].[H-].[Na+]>C1COCC1>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([O:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[N:8]([CH3:9])[CH:7]=[N:6][N:5]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1cnnc1CC1(O)C=CC=CC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnnc1CC1(OC(=O)C(C)(C)C)C=CC=CC1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
0.6 g of 3-(1-hydroxy-2'-trifluoromethylbenzyl)-4-methyl-1,2,4-triazole were dissolved in 20 ml THF, with the aid of sonification. An additional 10 ml THF were added to help dissolve the solid material. The solution was cooled to 0° C. 0.56 g of trimethylacetyl chloride were added slowly and the mixture turned cloudy. After 5 minutes, 0.1 g NaH (60%) added in small portions. The ice/water cooling bath was removed and the reaction mixture was stirred overnight. An additional 0.06 g of NaH was added at room temperature and after another 6 hours, there was no major change. 3 drops of water were added to the cloudy reaction mixture (no hydride was present), followed by diethyl ether. The solid was removed by filtration and washed with diethyl ether. The filtrate was dried (MgSO4), filtered and concentrated to an oil. The oil was purified on a silica gel column by elution with 100% ethylacetate to yield 0.4 g of 3-(1-trimethylacetoxy-2'-trifluoromethylbenzyl)-4-methyl-1,2,4-triazole in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[O:5][CH2:6][CH2:7][O:8][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cc(F)cc(F)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A solution of 2-(3,5-difluoro-phenoxy)-ethanol (2.5 g, 14.3 mmol) in pyridine (10 ml) was cooled with an ice bath and treated dropwise with methanesulfonyl chloride (1.7 g, 14.7 mmol). The ice bath was removed and the mixture was stirred for 16 hours at room temperature. The pyridine was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water, with 2N hydrochloric acid then three times with water, dried over magnesium sulfate and concentrated. The residue was crystallised in diisopropyl ether to give methanesulfonic acid 2-(3,5-difluoro-phenoxy)-ethyl ester (1.8 g, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=4)[N:15]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(CC)CC>[Pd]>[F:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[N:6]=[N:7][CH:2]=[CH:3][CH:4]=4)[CH:12]=3)=[CH:14][N:15]2[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccc(Cl)nn3)c2)c2ccc(F)cc21
Agent: [Pd]
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cccnn3)c2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A mixture of 3-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 44; 180 mg; 0.40 mmol), Pd/C(10 mg) and Et3N (40 mg; 0.40 mmol) was stirred for 0.5 hour at r.t. under a hydrogen balloon. The reaction mixture was filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=5/1 to 3/1) to afford 100 mg (60%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[N:26][C:25]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[C@H:30]([CH3:41])[CH2:29]2)=[CH:24][CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[N:27]=[N:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][C@H:30]([CH3:41])[CH2:29]5)=[CH:24][CH:23]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Product: C[C@@H]1CN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nn2)CCN1
Yield: 12 %

Procedure:
Compound 408 was prepared from compound 245 and compound 11 using chemistry similar to that described in example 4. The two step yield is 12%. 1H NMR (500 MHz, CD3OD) δ ppm 9.48 (1 H, s), 8.10-8.14 (2 H, m), 8.00 (1 H, d, J=10 Hz), 8.05 (1 H, d, J=10 Hz), 5.66 (1 H, t, J=9.0 Hz), 4.43-4.49 (2 H, m), 3.52-3.62 (2 H, m), 3.29-3.48 (2 H, m), 3.20 (1 H, dd, J=14.4, 10.8 Hz), 2.45 (2 H, ddd, J=9.2, 7.0, 4.5 Hz), 2.13-2.27 (4 H, m), 1.87-1.88 (2 H, m), 1.46 (3 H, d, J=6.6 Hz); LCMS-ESI (POS), M/Z, M+1: Found 448.1, Calculated 448.2
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (3RS)-3-[N-((1-naphthyloxy)acetyl)valinyl]amino-5-fluoro-4-oxopentanoic acid, tert-butyl ester (0.113 g, 0.23 mmol) in CH2Cl2(2.0 mL)-anisole(0.5 mL) at room temperature under nitrogen was added trifluoroacetic acid (1.0 mL). The resulting clear solution was stirred at room temperature for 1 hr, evaporated to dryness and chased with toluene-CH2Cl2 (1:1). The residue was purified by flash chromatography on silica gel eluting with AcOH—MeOH—CH2Cl2 (0.5:2:100) to give the title compound (0.069 g, 69%) as a white solid. TLC(AcOH—MeOH—CH2Cl2; 1:1:20) Rf=0.38. MS(ES) for C22H25FN2O6 (MW 432.45): positive 433(M+NH); negative 431(M−H). 1H NMR (CD3OD): δ8.32-8.29 (m, 1H), 7.82-7.79 (m, 1H), 7.49-7.46 (m, 3H), 7.38-7.32 (m, 1H), 6.88 (d, 1H, J=7.7 Hz), 4.78-4.73 (m, 2H), 4.55-4.26 (m, 2H), 2.82-2.76 (m, 2H), 2.16-2.03 (m, 1H), 0.94-0.85 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CO.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH2:11][O:10][CH3:9])[CH:3]=1
Reactant: COCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: COCCOc1cccc(Br)c1
Yield: 69.2 %

Procedure:
To a solution of 3-bromophenol (0.865 g, 5 mmol) in MeOH (1.5 ml) was added 2-bromoethyl methyl ether (0.56 ml, 6 mmol) followed by K2CO3 (0.68 g, 5 mmol). The mixture was heated using microwave irradiation in a CEM discover microwave synthesizer (50 W) at 100° C. until the reaction was complete. The reaction was diluted with ether and filtered to remove solid which was washed with further ether. Filtrate concentrated under reduced pressure to give (0.8 g) of product.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16].[OH:18]O>C(O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13](=[O:18])[C:14]=2[CH:1]=1)([OH:17])=[O:16]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1O2
Reactant: OO
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1O2
Reaction time: 17 h

Procedure:
Phenoxathiin-2-carboxylic acid (0.61g) was dissolved in refluxing absolute ethanol (40 ml) and 30% w/v hydrogen peroxide solution (1.50 ml) added. Reflux was maintained for 2 hours, more 30% w/v hydrogen peroxide solution (1.00 ml.) added, and reflux continued for 17 hours. The solution was evaporated to low volume, and the product crystallised out. The solid was filtered, washed and dried to give 2-carboxyphenoxathiin-10-oxide m.p. 223° C. Recrystallisation from absolute ethanol raised the melting point to 237° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) is added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution is stirred 15 minutes at 0° C. and then treated with a 1.6 M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting solution is stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-(4-fluorophenyl)cinnamaldehyde (82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution is stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12 N hydrochloric acid (ca. 20 ml). The reaction mixture is diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts are combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo leaving the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OC)=[O:11])=[C:7]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: COCCOCc1c(C(=O)OC)oc2ccc(F)cc12
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCc1c(CO)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a mixture of methyl 5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-carboxylate (1.54 g) synthesized above, calcium chloride (1.21 g), ethanol (15 mL) and tetrahydrofuran (15 mL) was added sodium borohydride (825 mg) at 0° C., and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.34 g, 97%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:52]1([CH:58]2[CH2:62][CH2:61][NH:60][CH2:59]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:60]3[CH2:61][CH2:62][CH:58]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:59]3)=[O:26])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: c1ccc(C2CCNC2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCC(c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The following was added sequentially to DCM (2 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (50 mg, 0.126 mmol), DIPEA (0.07 mL, 0.378 mmol), EDC (30 mg, 0.151 mmol), HOBT (24 mg, 0.151 mmol), and 3-phenylpyrrolidine (0.023 mL, 0.151 mmol). The mixture was stirred for 36 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×) and brine (1×). The organic phase was dried with magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in EtOAc and precipitated out hexanes, and then collected over a filter and washed with diethyl ether to give the title compound as a slightly yellow solid. (Yield: 21 mg, 0.040 mmol, 32%) 1H NMR (400 MHz, CDCl3) 7.66, 7.41-7.17, 7.06, 6.70, 5.50, 4.41, 4.10-3.39, 2.64, 2.36-0.90
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:27]5[C:32]([O:33][C@H:34]([CH2:36][CH:37]=C)[CH3:35])=[CH:31][CH:30]=[CH:29][C:28]=5[F:39])[C:23]([F:26])=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]2[C:18]3[CH:19]=[C:15]4[N:14]=[C:13]([CH3:40])[C:12]([C@H:41]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])[C:42]([O:44][CH3:45])=[O:43])=[C:11]([N:8]5[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH:2]=[CH:37][CH2:36][C@H:34]([CH3:35])[O:33][C:32]6[C:27]([C:22]=1[CH:21]=2)=[C:28]([F:39])[CH:29]=[CH:30][CH:31]=6)[CH2:10][CH2:9]5)[N:16]4[N:17]=3
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4ccc(F)c(-c5c(F)cccc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cccc(F)c1-c1cc-3ccc1F
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of (2S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′,6-difluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.142 mmol, 1.0 equiv) in DCE (70 mL) was added Hoveyda-Grubbs Catalyst 2nd Generation (8.92 mg, 0.014 mmol, 0.1 equiv) and stirred for 5 h at 90° C. Then, the solvent was evaporated and the residue was used in the next step without further purification. LCMS (M+1)=675.4.