Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][C:8]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[N:6]=[CH:5][C:4]=2[C:3]1=O.[CH3:22][C:23]1[N:28]=[C:27]([NH:29][C:30]([NH2:32])=[S:31])[CH:26]=[CH:25][CH:24]=1>CCO.Cl>[CH3:22][C:23]1[N:28]=[C:27]([NH:29][C:30]2[S:31][C:2]3[CH2:10][CH2:9][C:8]4[NH:7][N:6]=[CH:5][C:4]=4[C:3]=3[N:32]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(NC(N)=S)n1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCC(Br)C3=O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)n1
Yield: 86.7 %

Procedure:
According to Scheme 3 Step 4: A solution of 5-bromo-1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (0.90 mmol, 331 mg) and of 1-(6-methylpyridin-2-yl)thiourea (0.90 mmol, 150 mg) in EtOH (10 mL) and HCl (35%, 1 mL) was stirred at 80° C. for 5 hours. The reaction was quenched with the addition of a saturated solution of NaHCO3 at room temperature until pH=8. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was washed with Et2O and dried to yield N-(6-methylpyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.78 mmol, 220 mg, 87%) as a white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]([CH3:15])=[O:14].OS(O)(=O)=O>CCOCC>[CH3:12][C:13]([OH:14])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 8.8 g. (0.37 mol.) of magnesium turnings and 150 ml of dry ether was placed in a 3-necked flask fitted with a nitrogen inlet, a reflux condenser and an addition funnel containing 73.7 g (0.37 mol) of 1-bromo-3-phenylpropane. A small amount of the bromo compound was added to the reaction mixture and the mixture warmed in order to initiate reaction. The reaction mixture was treated with 150 ml of dry ether and then the bromo compound was added at such a rate as to maintain gentle reflux. The reaction mixture was heated at reflux for a further 15 minutes and then treated slowly with 21.5 g (0.37 mol) of acetone. The mixture was heated at reflux for a further 30 minutes, cooled and then poured slowly into 300 g of crushed ice. The resultant white precipitate was dissolved by the addition of 20% H2SO4. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo. The residue was distilled (120° C.; 6 mm) to give the captioned compound as a colorless oil. PMR (CDCl3): δ 1.18 (6H, s), 1.44-1.53 (2 H, m), 1.62-1.72 (2H, m), 2.61 (2H, t, J~7.6 Hz), 7.16-7.30 (5H, m).
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4](C)=[O:5].C[O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=O.[CH3:15]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)(=O)C.O>[CH3:13][O:12][CH:10]([C:9](=[O:8])[CH2:14][C:4](=[O:5])[CH3:3])[CH3:15]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: COC(=O)C(C)OC
Reactant: CC(C)=O
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(C)C(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 10.1 g (259 mmol) of sodium amide, and the flask was purged with argon. Then, 120 mL of methylcyclohexane was placed in the flask. Subsequently, 7.40 g (127 mmol) of acetone was slowly dropped into the ice-cooled mixture in the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 15.0 g (127 mmol) of methyl 2-methoxypropionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, made acetic with acetic acid, and subjected to extraction with hexane. The hexane extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (66° C., 1.38 kPa) to give 9.63 g (yield: 53%) of 2-methoxy-3,5-hexanedione as colorless liquid.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2I)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:2]2[CH2:3][CH2:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:1]2=[O:14])[CH2:17][CH2:16]1
Reactant: O=C1NCCc2sc3ccccc3c21
Reactant: Ic1cnccc1C1CC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2c(sc3ccccc23)CCN1c1cnccc1C1CC1
Yield: 29.7 %

Procedure:
3,4-Dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-9d: 100 mg, 0.491 mmol) was reacted with 4-cyclopropyl-3-iodo-pyridine (I-73c: 133 mg, 0.65 mmol), 1,4-dioxane (3 mL), copper iodide (9.31 mg, 0.049 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (313.3 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 46.8 mg of the product (29.8% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[OH2:2].[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1cccc(F)c1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1cccc(F)c1)CCC3
Product: O
Reaction time: 1 h
Yield: 154.6 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(3-fluorobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (500 mg, 1.14 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was treated with 1 M aqueous lithium hydroxide (25 mL) at room temperature for 18 h. The resulting suspension was concentrated in vacuo and the residue diluted with water and adjusted to pH 2 with concentrated hydrochloric acid. After stirring for 1 h, the resulting precipitate was collected via vacuum filtration to provide 390 mg (77%) of the title compound as a solid. Recrystallization (methanol/water) of the residue provided an analytical sample as a yellow-green fibrous solid: mp 250-252° C. 1H NMR (DMSO-d6) δ 12.87 (bs, 1H), 7.71 (s, 1H), 7.42 (s, 1H), 7.37 (m, 1H), 7.10 (dt, J=10.6, 2.2 Hz, 1H), 6.77 (d, J=9.9 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 5.56 (s, 2H), 4.62 (s, 2H), 2.93 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.41 (s, 3H), 1.97 (quintet, J=7.3 Hz, 2H); MS ES− m/e 423 (p−1); IR (KBr, cm−1) 3438, 1617, 1376.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][Br:5].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[Br-:5].[C:3]([CH2:4][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:2][CH3:1])=[O:6]
Reactant: c1ccncc1
Reactant: COC(=O)CBr
Solvent: CC(C)=O
Product: COC(=O)C[n+]1ccccc1
Product: [Br-]

Procedure:
Carbomethoxymethylpyridinium bromide is synthesized by reacting bromoacetic acid methylester with dry pyridine in acetone at room temperature. The product precipitates out as a white crystalline solid during the reaction and can be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-])=O)=[N:9]2)=[CH:4][CH:3]=1>C(O)C.[Pt].ClCCl>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C1CC(c2ccccc2[N+](=O)[O-])=NN1c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccccc1C1=NN(c2ccc(Cl)cc2)C(=O)C1

Procedure:
The starting material is prepared thus: 2 g if 1-(p-chlorophenyl)-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one are catalytically hodrogenated in 100 ml of ethanol over 200 mg of 5% platinum on carbon at room temperature and 3 atmospheres. Since the product crystallizes from the mixture as it is formed, the mixture is diluted with dichloromethane to dissolve said crystalline product. It is filtered, the filtrate evaporated, and the dried residue recrystallized from ethanol, affording the 3-(o-aminophenyl)-1-(p-chlorophenyl)-4,5-dihydropyrazol-5-one melting at 199°-201°.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:19]=2)=[O:17])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(Cc2cccc(C(=O)c3c[nH]c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A mixture of 3-[3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indole (442 mg), ethyl 4-bromobutyrate (185 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 4 hours. Ethyl 4-bromobutyrate (185 mg) and potassium carbonate (120 mg) were added, and resulting mixture was stirred at 20° C. for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give ethyl 4-[3-[3-[2,2-bis(4isobutylphenyl)ethyl]benzoyl]indol-1-yl]butyrate (480 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (6.0 g, 17 mmol), as prepared in step 2 of Example 1, in methylene chloride (12 mL) was added trifluoroacetic acid (12 mL) and the reaction stirred at ambient temperature. After 30 minutes the reaction was concentrated in vacuo, dissolved in methylene chloride, and diluted with hexane. The precipitated product was collected by filtration and dried in vacuo giving a quantitative yield of white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.36 (s, 1H), 7.74 (d, 1H, J=7.5 Hz), 7.35 (m, 5H), 6.18 (d, 1H, J=7.7 Hz), 5.15 (s, 2H), 4.77 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.O>[O:30]1[CH2:31][CH2:32][N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCOCC3)nccc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.200 g, 0.614 mmol) and potassium carbonate (0.424 g, 3.07 mmol) were dissolved in DMF (4.09 ml). Morpholine (0.535 ml, 6.14 mmol) was added and the reaction was stirred overnight at 110° C. The reaction was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to a pH of about 1 with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol) (Biotage AB, Uppsala, SE), then the column was washed several times with methanol. The product was liberated with ammonia solution in methanol. The process was repeated with the aqueous filtrate and a new SCX column. The product-containing filtrates were combined and concentrated to afford crude product as an orange solid. The material was purified by silica gel chromatography (40 g column, gradient elution 0-10% MeOH:DCM) to afford 1-morpholino-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.86 (br. s., 1H), 8.38 (d, J=1.9 Hz, 1H), 8.28-8.19 (m, 2H), 7.86 (dd, J=1.9, 8.9 Hz, 1H), 7.62 (d, J=5.5 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.88-3.80 (m, 4H), 3.35-3.26 (m, 4H). m/z (ESI) 377.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].[NH2:13]C(N)=O.S1(CCCC1)(=O)=O.C(=O)=O>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:13][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2c(F)cccc21
Agent: O=C=O
Solvent: O=S1(=O)CCCC1
Product: O=C1NC(=O)c2c(F)cccc21
Reaction time: 0.25 h

Procedure:
A mixture of 49.8 parts (0.3 mole) of 3-fluorophthalic anhydride and 9.9 parts (0.165 mole) of urea in 126 parts of sulfolane is heated at 125°-130° C., while stirring. The mixture is stirred for 30 minutes, when the evolution of carbon dioxide is complete, after which stirring is continued for a further 15 minutes at 168° C. The solvent is distilled off (98 parts) at a bath temperature of 130°-160° C. under 0.3 mbar. A gas chromatogram shows that it contains 2.75 parts of 3-fluorophthalimide. The distillation residue is triturated with water, and the product is filtered off under suction, washed and dried, 44.5 parts of 3-fluorophthalimide of melting point 179°-182° C. being obtained. The total yield is 47.25 parts (95.3% of theory) of 3-fluorophthalimide.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C(O)C>[C:11]1([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(F)c(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(-c2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
4-bromo-2,5-difluoroaniline (10 mmol), benzeneboronic acid (12 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL), H2O (10 mL) and ethanol (5 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 4-phenyl-2,5-difluoroaniline (2.2 g) is yielded.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CCOC(C)=O.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)[CH:27]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC(c2cc(N)ccc2F)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(c2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)ccc2F)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (167 mg, 0.500 mmol), 4-fluoro-3-(1-methylpiperidin-4-yl)-phenylamine (149 mg, 0.600 mmol), N,N-dimethylformamide (3 mL), and trifluoroacetic acid (385 μL, 5.18 mmol) in a sealed tube was heated at 100° C. for 15 h. The mixture was concentrated in vacuo, charged with sodium bicarbonate (504 mg, 6.00 mmol), di-tert-butyldicarbonate (120 mg, 0.550 mmol), and N,N-dimethylformamide (2 mL), and stirred at rt under N2 for 24 h. After that time, the mixture was filtered, and the filtrate was concentrated in vacuo to obtain a brown oil, which was dissolved in EtOAc (30 mL) and washed with water (3×20 mL). The organic phase was concentrated in vacuo to obtain a light-brown oil that was purified by HPLC to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.51 (s, 9H), 1.87 (brs, 4H), 2.13-2.20 (m, 2H), 2.32 (s, 3H), 2.54 (brs, 2H), 2.83-2.91 (m, 1H), 2.99-3.01 (m, 2H), 3.65 (brs, 2H), 4.12 (brs, 2H), 6.27 (brs, 1H), 6.56 (s, 1H), 7.03 (t, 1H, J=8.8 Hz), 7.57-7.60 (m, 2H), 8.19 (s, 1H). MS (ES+): m/z 507.17 (75) [MH+]. HPLC: tR=2.16 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH:39]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:38]2)[CH:34]=[N:33][CH:32]=1)CCC>CN(C=O)C.C(Cl)Cl.O.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.[Cu]I>[C:46]([O:45][C:44]([NH:43][CH:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35]2[N:36]=[C:31]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[CH:10]=4)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=3)[CH:32]=[N:33][CH:34]=2)[CH2:38]1)=[O:50])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3c(F)cccc3F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (350 mg, 0.769 mmol), tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (436 mg, 0.769 mmol), Pd(PPh3)4 (89 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) in DMF (6 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate. MS (ESI, pos. ion) m/z: 606 (M+1). To a solution of tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (466 mg, 0.769 mmol) in DCM (6 mL) was added TFA (4 mL) and the reaction was stirred at RT for 3 h, then solvent was removed. The residue was diluted with DCM and washed with saturated NaHCO3 aqueous solution twice. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-3-amine as a light brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CC)C(C)C)(C)C.[CH2:14]([O:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([Br:32])=[C:27]([CH3:33])[CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:14]([O:21][CH2:22][CH2:23][N:24]([C:25]1[CH:26]=[C:27]([CH3:33])[C:28]([Br:32])=[C:29]([CH3:31])[CH:30]=1)[C:1]([Cl:4])=[O:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(NCCOCc2ccccc2)cc(C)c1Br
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N(CCOCc2ccccc2)C(=O)Cl)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Phosgene (3.5 ml, 6.64 mmol, 20% solution in toluene) and N,N-diisopropylethylamine (1.2 ml, 6.64 mmol) were added to a solution of N-(2-(benzyloxy)ethyl)-4-bromo-3,5-dimethylaniline (740 mg, 2.21 mmol) in anhydrous toluene (11 ml) at 0° C. The reaction solution was gradually warmed to room temperature and stirred at the same temperature for three hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane) to give N-(2-(benzyloxy)ethyl)-N-(4-bromo-3,5-dimethylphenyl)carbamic acid chloride (860 mg, 98%).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH:21]OS([O-])=O.[K+].[OH2:27]>CO>[CH:1]([S:4]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:12]2)=[CH:7][CH:6]=1)=[O:21])([CH3:3])[CH3:2].[CH:1]([S:4]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:12]2)=[CH:7][CH:6]=1)(=[O:21])=[O:27])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: O
Reactant: CC(C)Sc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [K+]
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc2cc(NC(=O)C3CC3)ncc2c1
Product: CC(C)S(=O)c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.7 %
Yield: 25.2 %

Procedure:
To a solution of N-(7-(isopropylthio)isoquinolin-3-yl)cyclopropanecarboxamide (see, Example 80) (85.8 mg, 0.35 mmol) in methanol (15 mL) was added a solution of Oxone (1 eq) in water (15 mL) at 0° C. It was warmed to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by prep-TLC to give the products N-(7-(isopropylsulfinyl)isoquinolin-3-yl)cyclopropanecarboxamide (26.1 mg, 24.7%) and N-(7-(isopropylsulfonyl)isoquinolin-3-yl)cyclopropanecarboxamide (28.1 mg, 25.2%).