Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)C(C)C)(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CS(OS(C)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][S:11][C:12]3=[N:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]23)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc(SCC(O)c2ccc(C#N)cc2)[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2n1C(c1ccc(C#N)cc1)CS2
Reaction time: 24 h

Procedure:
To a solution of alcohol from Step B (6.95 g, 21.9 mmol) and N,N-diisopropylethylamine (11.4 mL, 65.7 mmol) in methylene chloride (300 mL)/DMF (50 mL) was added di-tert-butyl dicarbonate (6.69 g, 30.7 mmol) at 0° C. The reaction was stirred for 24 hours, then methanesulfonic anhydride (7.63 g, 43.8 mmol) was added in one portion. The reaction was stirred for 3 hours at 25° C. and 16 hours at reflux. The reaction was poured onto saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (50→70% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1)=O.FC(F)(F)C([NH:15]OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1)#[N:15]
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Reactant: NC(=O)c1ccc(C=O)s1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(N)=O)s1
Yield: 39.5 %

Procedure:
5-Formyl-2-thiophenecarboxylic acid (2.64 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (30 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (2.2 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was dissolved in ethyl acetate (50 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (50 ml) and ethyl acetate (200 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature, and then the organic layer was collected. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give 5-formyl-2-thiophenecarboxamide (1.77 g). A mixture of 5-formyl-2- thiophenecarboxamide (1.55 g), N,O- bis(trifluoroacetyl)hydroxyamine (3.5 g), pyridine (2 ml) and toluene (110 ml) was stirred under reflux for 1 hour, and then cooled, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-cyano-2-thiophenecarboxamide (0.6 g).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:27]C(=O)OC(C)(C)C)([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:15]=3)[CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CN2CC3C(=CC=C(CCCCCCCC)C=3)C2)CO1>>[NH2:27][C:5]([CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2c(c1)CCN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Agent: CCCCCCCCc1ccc2c(c1)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Product: CCCCCCCCc1ccc2c(c1)CCN(CC(N)(CO)CO)C2
Yield: 68 %

Procedure:
When the product of Step F is substituted for tert-butyl 2,2-dimethyl-5-((5-octylisoindolin-2-yl)methyl)-1,3-dioxan-5-ylcarbamate in Example 2, Step G, the identical process afforded the title compound in 68% yield., as a colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.26 (m, 10H); 1.54 (m, 2H); 2.48-3 (m, 3H); 3.54 (s, 4H); 3.76 (s, 2H); 6.7 p-7.06 (m, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([OH:48])=O)[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:31]1([CH:37]2[CH2:42][N:41]3[CH:43]=[C:44]([C:46]([N:60]4[CH2:59][CH2:58][N:57]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([C:50]([F:63])([F:64])[F:49])[CH:52]=5)[CH2:62][CH2:61]4)=[O:48])[N:45]=[C:40]3[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cn2c(n1)CCC(c1ccccc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1cn2c(n1)CCC(c1ccccc1)C2)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (276 mg; 0.86 mmol) and N-methylmorpholine (237 μl; 218 mg; 2.15 mmol) were added to a solution of 6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (200 mg; 0.72 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (162 μl; 198 mg; 0.86 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 191 mg (59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([CH2:13][CH:14]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)#[N:12].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:32]2[CH:31]=[N:30][N:29]([CH:14]([CH2:13][C:11]#[N:12])[CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[CH:33]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1cnc(Cl)nc1Cl
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
To a mixture of 2,4-dichloro-5-methoxypyrimidine (0.967 g, 0.00540 mol), and tert-butyl 4-{3-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propyl}piperidine-1-carboxylate (from example 1 step 3, 2.00 g, 0.00450 mol) in 1,4-dioxane (40 mL, 0.5 mol) was added a 1 M solution of sodium carbonate (0.954 g, 0.00900 mol) in water (8.99 mL, 0.499 mol) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.0003 mol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to provide the desired product (1.59 g, 76.64%). LCMS (M+Na) 483.4.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[N:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[N:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[CH:23]1([C:20]2[N:21]=[CH:22][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[N:19]=2)[CH2:24][CH2:25]1
Reactant: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(Br)c3CCN12
Reactant: OB(O)c1ccc(F)nc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 99.7 %

Procedure:
Example 95-2. 9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (5.7 g, 14.31 mmol), (6-fluoropyridin-3-yl)boronic acid (4.03 g, 28.6 mmol) and a solution of Na2CO3 (7.58 g, 71.6 mmol) in water (28 mL) was treated with DME (114 mL). The suspension was degassed, Pd(PPh3)4 (2.48 g, 2.15 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 70% AcOEt in heptane for 3 min, then from 70% AcOEt in heptane to 100% AcOEt in heptane in 50 min, 100% AcOEt in heptane for 10 min) to yield a beige foam (5.91 g). The residue was dissolved in DCM (100 mL) and MP-TMT resin (4.0 g, 0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol (50 mL) to afford the title compound as white crystals (4.8 g). UPLC-MS: MS 415.4 (M+H+); UPLC rt 1.02 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.87 (m, 2 H), 0.89-0.99 (m, 2 H), 1.98-2.07 (m, 1 H), 2.87 (t, J=6.11 Hz, 2 H), 3.72 (t, J=6.11 Hz, 2 H), 4.30 (s, 2 H), 7.05 (s, 1 H), 7.31 (dd, J=8.44, 2.57 Hz, 1 H), 7.47-7.56 (m, 2 H), 7.89-7.97 (m, 1 H), 8.07 (td, J=8.13, 2.57 Hz, 1 H), 8.30 (d, J=2.45 Hz, 1 H), 9.00 (s, 1 H).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 92.1 %

Procedure:
A slurry of 5.00 g (15.6 mmoles) of methyl 4-(4-phenoxyphenoxy)benzoate from Example A, 0.28 g (50.0 mmoles) of potassium hydroxide, 50 ml of methanol and 50 ml of deionized water is refluxed for 48 hours Methanol is added until the mixture is homogeneous. Aqueous hydrochloric acid is added until the solution is strongly acidified, and the slurry is cooled. The resulting precipitate is filtered, washed with 300 ml of deionized water and dried in air. It is recrystallized from a minimum volume of hot 2-1 by volume methanol and water solution to yield 4.40 g (92 percent yield) of 4-(4-phenoxyphenoxy)benzoic acid having a melting point of 185° C. as measured by DSC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].O.ClC(OCC)=O>[CH2:18]([O:17][C:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[O:16])[CH3:19]
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(=O)OC)ccc1C=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.4 %

Procedure:
To a mixture of methyl 3-amino-4-formylbenzoate (110 mg, 0.614 mmol) in 6 mL THF plus 4 mL saturated NaHCO3 and 1 mL H2O at rt was added ethyl chloroformate (0.070 mL, 0.737 mmol) at the reaction stirred at rt. After 50 min, an additional 0.5 mL saturated NaHCO3 and 5 drops ethyl chloroformate was added. At 17.5 hours the mixture was heated to 60° C., 1 mL saturated Na2CO3 added, and 5 drops ethyl chloroformate added. Then to push reaction to completion, a small scoop of solid Na2CO3 was added and additional ethyl chloroformate added drop-wise until the reaction was approximately 80% complete (45 hours total reaction time). The reaction was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The solid was crystallized from hexane/EtOAc and the filtrate chromatographed eluting with 2.5% MeOH/CHCl3. The impure products from crystallization and chromatography were combined and then recrystallized from hexane/EtOAc to give the title compound as a light yellow solid (63.8 mg, 41%). 1H NMR (CDCl3) δ: 10.53 (br. s, 1H), 10.00 (d, J=0.6 Hz, 1H), 9.11-9.12 (m, 1H), 7.80-7.84 (m, 1H), 7.72-7.76 (m, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:25]=1.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:14][CH:15]=3)=[C:7]([C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:6]=2[CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2oc3ccc(Cl)cc3c2C(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 4(i) (1 g, 2.8 mmol) in dry DCM was stirred at 0° C. under nitrogen. Anisoyl chloride (4.9 mmol) was added followed by a solution of SnCl4 (1M DCM, 4.9 mmol). An immediate red colour occurred and stirring was continued for 2 hours. The reaction mixture was added carefully to 100 ml of ice-water and the aqueous was extracted with ethylacetate (3×100 Ml). The organic extracts were combined, dried (Na2SO4) and evaporated to give a bright yellow oil. This was purified by flash chromatography (silica flash) to give the title compound as a pale yellow solid. (0.8 g 58%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C(O)C1CCCC1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C2CCCC2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (76 mg, 0.2 mmol), cyclopentyl carboxylic acid (27 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 30 min. The crude was purified by HPLC to give title compound (20 mg, 21%) as a brown solid as TFA salt. 1H NMR (CD3CN, 400 MHz) δ 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m, 2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, 3H), 3.74-3.80 (m, 2H), 3.82-3.96 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, J=9.09 Hz, 11), 7.55 (d, J=2.53 Hz, 1H), 7.57 (s, 1H), 7.76 (dd, J=2.78, 9.35 Hz, 1H), 8.38 (s, 1H). Exact mass calculated for C22H2979BrN4O3 476.1. found 477.3 (M+H 79Br, 100), 479.3 (M+H 81Br, 98).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Reactant: CCOC(=O)CCCCCCCBr
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCCC(=O)O)C(=O)CC3)cc1

Procedure:
The titled compound was prepared from 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 12.1 step 1) and ethyl 8-bromooctanoate analogously to Example 1.1 steps 1 and 2;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1cnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N2CC(NC(=O)OC(C)(C)C)C2)s1
Yield: 59.9 %

Procedure:
A solution of 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromothiazole-5-carboxylate (0.29 mL, 1.92 mmol) and diisopropylethylamine (0.61 mL, 3.48 mmol) in DMF (17 mL) was stirred at 70° C. for 10.5 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 341 mg of the title compound as a pale yellow solid (60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:38]=[C:37]([F:45])[C:36]=1[C:46]1[N:51]=[C:50]([C:52](O)=[O:53])[CH:49]=[CH:48][C:47]=1[F:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:19]([O:18][C@@H:14]1[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:52]([C:50]3[CH:49]=[CH:48][C:47]([F:55])=[C:46]([C:36]4[C:35]([F:34])=[CH:40][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:38][C:37]=4[F:45])[N:51]=3)=[O:53])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12][C@H:13]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21]
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (200 mg, 0.418 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (130 mg, 0.418 mmol), HATU (318 mg, 0.836 mmol) in DMF (1.5 mL) and DIPEA (218 μL, 1.25 mmol) was stirred at room temperature for 2 h. After quenched with water, the mixture was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%), to yield an amide intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]([NH:15][S:16]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:18])=[O:17])=[O:14])[CH:9]=[CH:8][C:7]=1[N:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([F:37])=[C:30]([NH:35][CH3:36])[CH:31]=2)[C:26]1=[O:38])(=O)C.C(O)(C(F)(F)F)=O>>[Cl:24][C:21]1[S:20][C:19]([S:16]([NH:15][C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:7]([N:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][C:29]([F:37])=[C:30]([NH:35][CH3:36])[CH:31]=4)[C:26]3=[O:38])=[C:6]([CH2:5][OH:4])[CH:11]=2)=[O:14])(=[O:17])=[O:18])=[CH:23][CH:22]=1
Reactant: CNc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3COC(C)=O)c(=O)c2cc1F
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3CO)c(=O)c2cc1F

Procedure:
This analog compound was obtained from hydrolysis of the intermediate, Boc protected compound of Example 62, then followed by TFA deprotection to give 5-chloro-N-({[4-[7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]-3-(hydroxymethyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+=537, 539(Cl).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[C:61]([F:69])=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63](Cl)=[O:64]>>[Cl:59][C:60]1[C:61]([F:69])=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: O=C(Cl)c1cccc(Cl)c1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Cl)c4F)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 204 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chloro-2-fluoro benzoyl chloride.