Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:27])[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:5]=2[NH:4][N:3]=1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:27])[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:9]=[C:10]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC1(C)OB(c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)OC1(C)C
Reactant: Clc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2c(-c3ncccn3)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (179 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (21.6 mg), potassium acetate (116 mg) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 110° C. under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-5-(2-chlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (277 mg). A mixture of 3-amino-5-(2-chlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (277 mg), 2-chloropyrimidine (131 mg), tripotassium phosphate (365 mg), tetrakis(triphenylphosphine)palladium(0) (99.0 mg), toluene (5.0 mL), ethanol (1.0 mL) and water (1.0 mL) was stirred overnight at 120° C. under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (47.0 mg).
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:56]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:56][CH2:2][C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)=[O:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of Example 100 in THF (5 mL) was cooled to −78° C. and treated with diisopropylethyl amine (0.424 mL, 2.57 mmol) followed by trimethylsilyltriflate (0.421 mL, 2.177 mmol). The reaction was allowed to warm to rt over 30 min, then cooled again to −78° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (62 mg, 0.218 mmol). The reaction was allowed to stir for 1 h at −78 C, then warmed to rt and quenched with methanol (200 uL) and diluted with ethyl acetate and 1N sodium sulfite solution. The organic layer was separated, washed with 1 N bisulfate buffer (pH 2), dried with sodium sulfate and passed thru a silica plug. Evaporation of the solvent gave a yellow solid which was triturated with Et2O:hexanes (1:1) to provide the title compound as a yellow solid (154 mg, 70% Yield). 1H-NMR (DMSO-d6) 9.18 (s, 1H), 8.45 to 8.48 (m, 1H), 8.02 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.27 (s, 1H), 7.20 to 7.37 (m, 4H), 4.77 (s, 2H). MS [M+H]+=551.2; LCMS RT=3.63.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][C@H:9]([CH3:11])[O:8][C@H:7]([CH3:12])[CH2:6]1.O.[NH2:15][NH2:16]>CO>[CH3:12][C@H:7]1[O:8][C@@H:9]([CH3:11])[CH2:10][N:5]([CH2:4][C:3]([NH:15][NH2:16])=[O:2])[CH2:6]1
Reactant: NN
Reactant: COC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
Methyl[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetate (5.05 g, 27.0 mmol, see Journal of Fluorine Chemistry (1998) 193-201 for literature preparation) was dissolved in methanol (20 ml) and hydrazine hydrate (2.013 ml, 27.0 mmol) added. The reaction mixture was heated to 70° C. for 18 h. The solvent was partially concentrated in vacuo to remove the methanol and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried and concentrated to afford the title compound as a yellow solid (3.35 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])[CH2:17][CH2:16]2)=[CH:7]1.[CH2:33](Br)[CH:34]=[CH2:35]>CN(C=O)C>[CH2:35]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])[CH2:19][CH2:20]2)=[CH:7]1)[CH:34]=[CH2:33]
Reactant: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCO)c3ccccc23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
To a suspension of 0.012 g (0.04 mmol) of a dispersion of 60% NaH in 0.5 mL of DMF, a solution of 0.042 g (0.01 mmol)of 2-(2-{4-[1-(2-hydroxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid in 0.5 mL of DMF was added. After stirring at room temperature for 30 minutes as solution of 0.014 g (0.12 mmol) of allyl bromide in 0.3 mL of DMF was added. The crude mixture was stirred at room temperature for 15 hours. The solvent was evaporated at reduced pressure and the crude mixture was dissolved in 1 mL of ethanol. 0.2 mL of an aqueous 2N NaOH solution were added and the mixture was heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and after addition of 1 mL of water, the mixture was neutralised with 2N HCl and extracted with chloroform. The crude was purified by chromatography over silica gel affording 0.015 g (33% of yield) of the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc(S(N)(=O)=O)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2ccccc2O)s1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A 70 ml CH2Cl2 suspension of 5-(2-methoxyphenyl)thiophene-2-sulfonamide (1.0 g, 3.7 mmol) is stirred under N2 at −75° C. as boron tribromide (1.1 ml, 12 mmol) is syringed into the reaction mixture. The amber solution is stirred for 30 minutes at −75° C., then at 0° C. for 2–3 hours. The reaction is quenched with ice, extracted with CH2Cl2. The extracts are washed with brine, dried (Na2SO4), filtered, and the filtrate is concentrated. The residue is purified by chromatography (SiO2, ethyl acetate/hexane gradient) to give 720 mg of 5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Temperature: 90 °C
Yield: 46.5 %

Procedure:
A mixture of Example 77A (1.559 g, 3.34 mmol), 4-pyridylboronic acid (0.431 g, 3.51 mmol) and Na2CO3 (0.37 g, 3.51 mmol) in THF/methanol/water (12 mL:2.4 mL:4 mL) was degassed by bubbling nitrogen through the solution for 15 minutes, then treated with Pd(dppf)Cl2 (136 mg, 0.17 mmol). The reaction vessel was sealed and heated to 90° C. for 17 hours. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, concentrated, and the residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide 0.65 g (46%) of the desired product. MS (ESI(+)) m/e 419 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:30][CH2:31][OH:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCO
Temperature: 80 °C
Yield: 25.9 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinoline (500 mg, 1.7 mmol), potassium carbonate (232 mg, 1.7 mmol) and 2-bromoethanol (1181l, 1.7 mmol) in DMF (15 ml) was heated at 80° C. for 5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(2-hydroxyethoxy)-6-methoxyquinoline (160 mg, 26%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:19]([OH:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([I:15])[CH:17]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C(O)c1cccc(I)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1C(=O)C(=C(O)c2cccc(I)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10.5 g 1-acetyl-6-chloro-2-indolinone (educt V.1), 13.6 g 3-iodobenzoic acid and 17.7 g TBTU are placed in 100 ml of dimethylformamide, 35 ml triethylamine are added and the mixture is stirred for 12 hours at ambient temperature. After this time the solvent is eliminated, the residue is combined with water, suction filtered and washed with a little water, methanol and ether and dried in vacuo at 100° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2=[C:38]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=[C:36]2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:38]1[C:37]2[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[N:34][S:35][C:36]=2[CH:41]=[CH:40][CH:39]=1)(=[O:44])=[O:43])([CH3:49])([CH3:48])[CH3:47]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCN)c12
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCNC(=O)c3ccc(I)cc3)c12
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 4-iodobenzoic acid (210 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (120 μL, 0.8 mmol) and 4-methylmorpholine (172 μL, 1.6 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-4-sulfonamide (243 mg, 0.7 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 1:1 ethyl acetate:hexanes, followed by 7:3 ethyl acetate:hexanes provided N-(3-(4-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (365 mg) as a yellow foam. 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (dd, 1H), 7.80 (d, 2H), 7.59 (d, 2H), 7.43-7.49 (m, 2H), 6.10 (t, 1H), 4.98 (s, 1H), 3.71 (dd, 2H), 3.59 (dd, 2H), 1.92-2.00 (m, 2H), 1.25 ppm (s, 9H). MW=572 confirmed by LC-MS, tr=13.85 min (Method Y) MH+=573.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K2O3 (3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=114-116° C.
Reaction SMILES: Cl.C(O[C@H](C)C([N:13]1[C:21]2[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH3:23])=O)C1C=CC=CC=1.ClC1N=C(Cl)C=C(OC)N=1>C(O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH:14]([CH3:23])[NH:13]2
Reactant: CC1Cc2c(F)cccc2N1C(=O)[C@@H](C)OCc1ccccc1
Agent: COc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(F)cccc2N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 68.7 %

Procedure:
8.2 ml of concentrated hydrochloric acid are added to a solution of 1.69 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (2) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 200 ml of water, alkalinized with concentrated sodium hydroxide until the pH is 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.56 g of (−)-4-fluoro-2-methylindoline is thus obtained in the form of a very pale yellow oil, the characteristics of which are the following:
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11])C)C.Cl>O1CCCC1>[OH:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: CCOC(C)OCC#CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C#CCO)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5.7 g (23 mmol) of 4-(1-ethoxyethoxy)-1-(4-methylphenyl)-2-butyn-1-one in 80 ml of tetrahydrofuran was treated at room temperature with 23 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded 4-hydroxy-1-(4-methylphenyl)-2-butyn-1-one of melting point 74°.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:35]([NH:40][NH2:41])(=[O:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([NH:41][NH:40][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:15])=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Reactant: CC(C)C(=O)NN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(=O)C(C)C)cnc21
Reaction time: 0.25 h

Procedure:
Intermediate 3 (0.060 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and stirred under nitrogen for 15 minutes. Isobutyric acid hydrazide (0.027 g) was then added and the mixture stirred under nitrogen for 18 h. Solvents were removed in vacuo and the residue partitioned between DCM and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo and applied to an SPE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo afforded Intermediate 10. LCMS showed MH+=359; TRET=2.70 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.10 g, 0.25 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.25 mmol), DIEA (0.064 g, 0.50 mmol), DMAP (0.033 g, 0.27 mmol), and THY (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give (0.82 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.41 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.02-6.97 (m, 2H), 5.26 (s, 1H), 5.01-4.99 (m, 1H), 4.56-4.53 (m, 1H), 4.16-4.08 (m, 1H), 3.01 (s, 3H), 1.52 (d, J=7.0 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 480. Found: [M+H]+ 481.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13]>CCOCC.II>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)C=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a suspension of magnesium (2.98 g, 0.123 mol) in ether (30 mL) was added iodine (0.165 g, 0.000651 mol). To this was slowly added a solution of 4-chlorobenzyl bromide (24.00 g, 0.1168 mol) in ether (100 mL). Upon addition of approximately 1 mL of solution an exotherm was noted and the mixture reached reflux. The addition of solution was slowly continued to maintain a gentle reflux (˜90 min). On completion of addition, the reaction was heated for 30 minutes at 45° C. The reaction was then cooled to 0° C. Isobutyraldehyde (12.7 mL, 0.140 mol) in ether (10 mL) was then added slowly over 2 hours. On completion of the addition the reaction was allowed to warm to 23° C. and stirred overnight. The reaction was quenched with ice (˜200 g) and acidified with 2M HCl (˜100 ml). This was extracted twice with ether and the organic phase was evaporated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to afford the title compound (9.89 g, 43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(O[C@@H]3CCOC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (6.3 g, 28.5 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.8 g, 28 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.1 (M+). Found: 291.1 (M++1).