Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.Br[C:23]1[CH:24]=[C:25]([C:29]2([NH:35][CH2:36][C@@H:37]([OH:52])[C@@H:38]([NH:48][C:49](=[O:51])[CH3:50])[CH2:39][C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.[CH3:53][C:54]1[CH:55]=[C:56](B(O)O)[S:57][CH:58]=1.[F-].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:47][C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([F:46])[CH:43]=1)[CH2:39][C@H:38]([NH:48][C:49](=[O:51])[CH3:50])[C@H:37]([OH:52])[CH2:36][NH:35][C:29]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:56]3[S:57][CH:58]=[C:54]([CH3:53])[CH:55]=3)[CH:24]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(Br)c2)CCCCC1
Reactant: Cc1csc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: COCCOC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(-c3cc(C)cs3)c2)CCCCC1
Temperature: 25 °C

Procedure:
Palladium acetate (Pd(OAc)2) (0.82 mgs, 10 mol. Wt. %) and Biphenyl-2-yl-di-tert-butyl-phosphane (2.16 mgs, 20 mol. Wt. %) was added to the reaction vessel (Vessel 1). N-(1S,2R)-[3-[1-(3-Bromo-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide (0.09075 mM) was placed in a separate reaction vessel (Vessel 2) and dissolved in 200 mL DME. 4-Methylthiophene-2-boronic acid and Potassium Fluoride (KF) (3 eq., 6.33 mgs) were added to a separate reaction vessel and dissolved in 200 μL DME (Vessel 3). Solvents in Vessels 2 and 3 were added to Vessel 1 under nitrogen. Vessel 1 was stirred over night at room temperature. Reaction was then concentrated down by vacuum. Crude material purified by Prep-HPLC. Product fractions collected and concentrated down by vacuum. MS (ESI+) for C29H34F2N2O2S m/z 513.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].CCOCC>CC(O)C.C(Cl)Cl>[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1ccc2c(c1)CCN2
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1ccc2c(c1)CCN2c1ncnc2cc(OC)c(OC)cc12
Yield: 95 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 95% yield from 5-methoxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The free-base obtained following column chromatography on silica (45% acetone/hexanes) was dissolved in minimal CH2Cl2 and treated with 1 eq. of methanesulfonic acid in CH2Cl2 followed by dilution with several volumes of ether to precipitate the mesylate salt which was filtered and added in vacuo. (M.P. 285°-292° C. (dec); LC-MS: 338 (MH+); anal. RP18-HPLC RT: 3.82 min.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:38])=[C:16]3[CH3:39])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH:40]1(B(O)O)[CH2:42][CH2:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:40]1([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=3)[C:17]([CH3:38])=[C:16]4[CH3:39])=[O:12])[CH3:9])=[CH:4][CH:3]=2)[CH2:42][CH2:41]1
Reactant: OB(O)C1CC1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C4CC4)cc3)cc12

Procedure:
A mixture of (S)-4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (28 mg, 0.048 mmol), cyclopropylboronic acid (9 mg, 0.10 mmol), Palladium(II) acetate (3.9 mg, 0.017 mmol) tricyclohexylphosphine (10 mg, 0.036 mmol) and potassium phosphate, tribasic, (22 mg, 0.10 mmol) in toluene (2.5 mL) and water (0.3 mL) was heated at 100° C. for 1 h in a Biotage Microwave reactor. The solvent was removed; the residue was filtered and purified by preparative HPLC to yield the title compound as a white solid. ESI-MS (m/z): 543 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: Cc1nnc(Br)s1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(−)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf=0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([S:31]([O-:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.[Na+]>>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: O=S([O-])c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(C(F)(F)F)c4)cc3c2C1
Yield: 33 %

Procedure:
The product of Example 44, step B was coupled with sodium 3-trifluoromethylbenzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 6-chloro-8-(3-trifluoromethylphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (130 mg, 33%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.94-8.06 (m, 1H), 7.86-7.81 (m, 2H), 7.73-7.63 (m, 1H), 4.58 (m, 2H), 3.84 (m, 2H), 2.92 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][C:2](=[O:10])[NH:3][C:4]=2[CH:9]=1)=[O:17]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 57.9 %

Procedure:
Using 1,3-dihydro-2H-benzimidazol-2-one (4.00 g) and 5-chlorovaleryl chloride (9.24 g) according to the same method as that of Reference Example 1, the title compound (4.36 g) was obtained as colorless crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[N:13]([CH3:17])[CH2:14][CH2:15]O>C(Cl)Cl.CN(C=O)C>[Br:12][C:10]1[CH:11]=[C:6]([NH2:5])[C:7]([N:13]([CH2:14][CH2:15][Cl:3])[CH3:17])=[CH:8][CH:9]=1
Reactant: CN(CCO)c1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCl)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Thionylchloride (0.78 g, 6.74 mmol) was added dropwise to a solution of 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (25C) (1.376 g, 5.62 mmol) in DCM (50 mL) and DMF (10 drops) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 hour. Then, the mixture was heated to 35° C. for 2.5 hours, concentrated, diluted with 1N NaOH, and extracted with DCM. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-85:15, to provide 0.611 g (41%) of the desired product 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine (25D): 1H NMR (300 MHz, CDCl3) δ 6.88-6.79 (3H, m), 4.20 (2H, bs), 3.56 (2H, t), 3.17 (2H, t), 2.67 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]=[C:13]([C:17](OC)=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]=[C:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=CCCN(C(=O)OCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC=C(CO)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of the compound of step 1 (2.0 g, 7.33 mmol) in tetrahydrofuran (30 ml) at -20° C. was added DIBAL-H. The mixture was warmed up to 0° C. and stirred at this temperature for 5 hours. Addition of methanol (5 ml) at 0° C. followed by addition of a saturated solution of Rochelle salt (10 ml) resulted in the formation of a white slurry. After stirring for an additional 2 hours, this was filtered; the filtrate was extracted with ether and the organic layer was washed with brine and dried over magnesium sulfate. Upon evaporation, the title compound was obtained as a slightly yellow oil (1.14 g, 4.6 mmol, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccc(Cl)cc1)c1nnc(N)s1
Reaction time: 16 h

Procedure:
Into a 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condensor, was charged with 10.0 grams (0.050 mole) of 2-(4-chlorophenoxy)propanoic acid, (4.6 grams, 0.050 mole) of thiosemicarbazide and 30 ml. of dioxane. The slurry was heated to 90 degrees centigrade and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (8.4 gram, 0.055 mole) was slowly added (for 30 minutes) while maintaining the temperature within 85-90 degrees centigrade. The resulting mixture was refluxed for 75 minutes and stood at ambient temperature for 16 hours. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane) at sixty degrees centigrade and then the solution was cooled. Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off, washed with water, then dried in a vacuum oven at 70 degrees centigrade to white crystals which were recrystallized from the minimum amount of H2O/ethanol mixture, filtered and then dried in a vacuum oven at 80 degrees centigrade to white crystals of 5-[1-(4-chlorophenoxy) ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 162-166 degrees centigrade).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([CH3:11])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc2sccc2c(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(C)cc3sccc23)cc1
Temperature: 170 °C
Reaction time: 4 h

Procedure:
A mixture of 7.0 g of 4-chloro-6-methylthieno[3,2-c]pyridine and 28 ml of 4-methoxybenzylamine was stirred at 170° C. for 4 hours. After being cooled, the reaction mixture was diluted with 400 ml of chloroform, washed with water and saturated saline, dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 10 g of the title compound as a yellow oily material.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:1][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1cnccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2ccncc2-c2ccnn2C(C)C)cn1
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (79 mg, 0.52 mmol, 1.5 eq.), 4-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (crude above, 0.35 mmol), and K2CO3 (145 mg, 1.05 mmol, 3 eq.) in DMF (10.0 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on RP-HPLC (Gemini 21.2×150 mm) twice using a mixture of CH3CN/water (0.1% HCOOH) as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 5%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.52 (d, J=1.7 Hz, 1H), 6.96 (s, 1H), 6.15 (d, J=1.8 Hz, 1H), 4.87 (s, 2H), 4.06 (sep, J=6.6 Hz, 1H), 3.75 (s, 3H), 1.31 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([O:28]C)=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:14])(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([OH:28])=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2O)C(=O)O)cc1
Yield: 85.4 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 35 (6.0 g), 1 mol/L of an aqueous sodium hydroxide solution (38 mL), and methanol (300 mL), to give the captioned compound (4.4 g, 85%) as an amorphous solid product.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].C(=O)([O-])[O-:18].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:18])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 93.4 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,4,5,6-tetrafluorophthaloyldifluoride separated by distillation from the mixture of Example 2, 43.8 g (0.413 mol) of sodium carbonate and 200 g of xylene were charged, and the mixture was reacted at 130° C. for 1.5 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was separated by distillation to-obtain 84.9 g of tetrafluorophthalic anhydride. The yield was 93.4%.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](C(N=[N+]=[N-])=O)=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[N-:19]=[C:20]=[O:21]>C1(C)C=CC=CC=1>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([N:19]=[C:20]=[O:21])=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=NC(=O)c1c[nH]c2cc(OC(F)F)ccc12
Reactant: [N-]=C=O
Solvent: Cc1ccccc1
Product: O=C=Nc1c[nH]c2cc(OC(F)F)ccc12

Procedure:
To a suspension of 1-carbamoyl-6-difluoromethoxy-1H-indole-3-carboxylic acid (180 mg, 0.66 mmol) in THF (6 mL) was added Et3N (111 μl, 0.8 mmol) and the resulting solution was stirred at RT under nitrogen for 10 min. DDPA (220 μl, 0.8 mmol) was added and the reaction was further stirred at RT under nitrogen for 3 h. TLC indicated consumption of the starting material. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 4:1 to 1:1) to give 6-difluoromethoxy-1H-indole-3-carbonyl azide (MS: 251 [M−H]−; tR (HPLC conditions k): 3.57 min) and 1-carbamoyl-6-difluoromethoxy-1H-indole-3-carbonyl azide (MS: 251 [M−CONH2]−; 268 [M−N2]+; tR (HPLC conditions k): 3.46 min). 6-Difluoromethoxy-1H-indole-3-carbonyl azide intermediate was suspended in toluene (6 mL) and refluxed under nitrogen for 3 h until completion of the reaction. The crude isocyanate was used as was in the next step.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 101.4 %

Procedure:
2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of CuI (200 mg). The slurry was refluxed for 1 hour. Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.BrCC(C1C2OCCCC=2C=CC=1)=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(O)C>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc2c(c1)CCCO2
Agent: O=C(CBr)c1cccc2c1OCCC2
Solvent: CCO
Product: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Temperature: 60 °C
Yield: 64 %

Procedure:
A solution of the 80/20 mixture of 2-bromo-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (19a) and 2-bromo-1-(3,4-dihydro-2H-1-benzopyran-8-yl)ethan-1-one (450 mg, 1.76 mmol) and 2-aminopyridine (166 mg, 1.76 mmol) in ethanol (10 mL) was heated at 60° C. overnight. The mixture was concentrated in vacuo. A 1M solution of sodium hydroxide (10 mL) and ethyl acetate (10 mL) were added. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired imidazo-pyridine (19b) (228 mg, 0.91 mmol, 64%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:33][C@@H:34]([C:36]1([C:41]#[N:42])[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([C:36]1([C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH3:35])[CH2:40][CH2:39][CH2:38][CH2:37]1)#[N:42]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)C1(C#N)CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
In a flask were combined 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol), 1-((R)-1-amino-ethyl)-cyclopentanecarbonitrile hydrochloride (48 mg, 0.27 mmol), EDC (120 mg, 0.63 mmol) and HOBt (106 g, 0.63 mmol). DMF (3 mL) was added followed by i-Pr2NEt (0.28 mL, 1.63 mmol). The reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc. The organics were washed with 10% citric acid, sat'd NaHCO3, sat'd LiCl, and sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20-100% EtOAc/heptane) to give 140 mg (92%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([NH:56][CH3:57])[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([N:56]([CH3:57])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCCC2)[C@@H](C)OC(C)(C)C)ccc1F
Yield: 17.9 %

Procedure:
4-Fluoro-3-methylbenzoic acid (101 mg, 0.66 mmol), TBTU (232 mg, 0.72 mmol) and DIPEA (0.172 mL, 0.99 mmol) was stirred in DCM (2 mL) for 1 h. (2R,3R)-3-tert-butoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M7) (150 mg, 0.66 mmol) was added and the resultant mixture was stirred at rt overnight. The reaction mixture was washed with NaHCO3 (8% aq., 2 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (43 mg, 18%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.94, 1.05-1.15, 1.55-1.72, 2.20, 2.21-2.28, 2.31-2.45, 2.60-2.66, 2.77, 2.83, 2.90, 3.27, 3.44-3.50, 3.70-3.77, 3.87-3.93, 4.51-4.58, 7.08-7.22, 7.23-7.28, 7.37.