Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:4]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: CCOC(=O)Cc1cc2c(c(OC)c1)C(=O)c1ccccc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)cc2c1C(=O)c1ccccc1CC2

Procedure:
Ethyl 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-acetate is refluxed in water (20 ml) and methanol (5 ml) containing sodium hydroxide (0.5 g) for 2 hours. The solution is cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated. The residue is recrystallized from ethyl acetate-hexane to afford 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid, mp 189°-199°.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Si:9]([O:16][C@H:17]([CH2:23][C:24](=[O:32])[CH2:25]P(OC)(OC)=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)C>[Si:9]([O:16][C@H:17]([CH2:23][C:24](=[O:32])/[CH:25]=[CH:1]/[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:14])([CH3:13])[CH3:15])([CH3:11])[CH3:10]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)C[C@@H](CC(=O)/C=C/c1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
In 5 mL of isopropanol (water content: 10,000 ppm) were dissolved 140 mg (1.3 mmol.) of nicotinaldehyde (pyridin-3-aldehyde) and 500 mg (1.3 mmol.) of methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate (optical purity: 99% ee) to give an alcoholic solution. To the alcoholic solution was added 181 mg (1.3 mmol) of potassium carbonate, and the mixture was stirred for 3 hours at room temperature (22° C.). To the resulting reaction mixture was added 20 mL of ethyl acetate, and the mixture was stirred and washed with 10 mL of water. The washing was repeated twice. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered to give a filtrate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=1/1, volume ratio) to give 469 mg (yield: 99%) of methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-7-(pyridin-3-yl)-6-heptenoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1>O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Na+].C(C(CC)=O)C>[CH2:3]([C:2]1([CH2:11][CH3:10])[NH:12][C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1)[CH3:4]
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCC(=O)CC
Solvent: O
Product: CCC1(CC)Nc2cccc3cccc(c23)N1
Reaction time: 5 h
Yield: 1769.7 %

Procedure:
With 1.58 g of 1,8-diaminonaphthalene, 10.8 g of diethyl ketone and 25 mg of sodium p-toluenesulfonate monohydrate were mixed. The mixture was heated and stirred for 5 hours in a steam bath. The resulting mixture was extracted with 100 ml of ethyl acetate and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled out to obtain 20 g of 2,2-diethyl-2,3-dihydroperimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(Cl)cc4)n3c2)cc1

Procedure:
The title compound, off-white solid (43 mg, 34%), MS (ISP) m/z=389.4 [(M+H)+], mp 171° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-phenyl)-imidazo[1,2-a]pyridine (intermediate F) (0.1 g, 0.325 mmol) and 1-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:23][C@:22]3([CH3:36])[C@@H:24]([CH3:35])[CH2:25][CH2:26][C@H:27]4[C:28]([CH3:34])([CH3:33])[C@@H:29]([OH:32])[CH2:30][CH2:31][C@@:21]34[O:20][C:11]=2[C:12]2[C@H:13]([CH3:19])[NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:10]2[CH2:23][C@:22]3([CH3:36])[C@@H:24]([CH3:35])[CH2:25][CH2:26][C@H:27]4[C:28]([CH3:34])([CH3:33])[C@@H:29]([OH:32])[CH2:30][CH2:31][C@@:21]34[O:20][C:11]=2[C:12]2[C@H:13]([CH3:19])[NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1
Reactant: C[C@@H]1NC(=O)c2cc(OCc3ccccc3)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NC(=O)c2cc(O)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Reaction time: 2.5 h
Yield: 70.9 %

Procedure:
To Compound (66a) (28 mg, 0.06 mmol) dissolved in 15 ml of methanol containing 10% water was added 20 mg of 10% palladium-carbon, followed by catalytic reduction for 2.5 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 5 g; ethyl acetate: methanol=19:1) and by crystallization from diethyl ether-n-hexane to give 17 mg (74%) of Compound (67a). Melting point: 280°-285° C. (decomp.) Elemental analysis for C24H33NO4.5/2 H2O Calcd.: C, 64.84%; H, 8.62%; N, 3.15% Found: C, 64.53%; H, 8.94%; N, 3.28%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH2:19][CH2:18]2)[C:13]([N+:28]([O-:30])=[O:29])=[CH:12][N:11]=1.[CH:31](OC)(OC)OC>CO.C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:31][N:9]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[CH2:19][CH2:18]4)[C:13]([N+:28]([O-:30])=[O:29])=[CH:12][N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1
Reactant: COC(OC)OC
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2ccccc21

Procedure:
A solution of (R)-4-(2-(2-amino-5-fluorophenylamino)-5-nitropyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (120 mg) and CH(OMe)3 (2.5 mL) in MeOH/THF (2.5 mL/10 mL) was stirred at room temperature overnight. Volatiles were removed in vacuo and the residue was purified by PTLC (EtOAc) to afford 80 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:4]([CH:5]=C(C)C)[C@H:3]1[C:9]([O:11][CH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=1[F:23])=[O:10].CO.O=O.[O:29]=[O+][O-]>O.C(OCC)(=O)C>[CH:5]([C@@H:4]1[C@@H:3]([C:9]([O:11][CH2:12][C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=2[F:23])=[O:10])[C:2]1([CH3:24])[CH3:1])=[O:29]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Reactant: O=[O+][O-]
Agent: O=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Temperature: -78 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A mixture of 1.27 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate, 20 ml of methanol and 20 ml of ethyl acetate was cooled to -78° C. Oxygen-containing ozone was bubbled into the mixture while stirring until the reaction mixture was colored blue. Then, nitrogen gas was bubbled into the blue reaction mixture to remove the excess ozone. Thereafter, 5 ml of dimethyl sulfide was added thereto. The resulting mixture was heated to room temperature. The reaction mixture, after having been allowed to stand for one day, was concentrated under reduced pressure. 20 Milliliters of acetone, 2 ml of water and 0.2 g of p-toluenesulfonic acid monohydrate were added to the resultant residue. The resulting reaction mixture, after having been allowed to stand at room temperature for 2 hours, was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain 0.98 g (yield: 82%) of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-3-formyl-2,2-dimethyl-cyclopropanecarboxylate, m.p. 43.2° C.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=[C:14]([OH:16])[CH:15]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.CCOCC.[ClH:32]>C(O)(=O)C>[ClH:32].[CH3:19][N:20]1[CH2:21][CH:22]=[C:23]([C:13]2[C:12]([O:17][CH3:18])=[CH:11][C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][C:14]=2[OH:16])[CH2:24][CH2:25]1
Reactant: CN1CCC(=O)CC1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(OC)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(C)C(C)c1cc(O)c(C2=CCN(C)CC2)c(OC)c1

Procedure:
5-(1,2-Dimethylheptyl)-3-methoxyphenol (10.0 g) of Example V, and N-methyl-4-piperidone (4.45 g) were dissolved in 20 ml acetic acid and saturated with HCl gas. Ether was added and the resulting solid recrystallized from isopropyl alcohol-ether. Yield 7.32 g, m.p. 96°-97°.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Li+].[CH3:16]C([N-]C(C)C)C.CI.Cl>CCOCC>[CH3:16][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)CC(=O)C(C)C(=O)OCC
Temperature: -15 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
This compound was synthesized according to U.S. Pat. No. 6,833,471. To 20 mL of dry THF that had been purged with Ar(gas) was added diethyl 3-oxopentanedioate (5 mL, 27.54 mmol) and the solution was cooled to −15° C. prior to the dropwise addition of LDA (2M) (15 mL, 30 mmol). The reaction was maintained under Ar(gas) at −15° C., and MeI (3 mL, 48.2 mmol) was added slowly. The reaction was allowed to reach room temperature gradually over 3 hours, and the stirring was continued overnight. After 18 hours, the reaction mixture was poured into 140 mL of a 1:1 mixture of 0.5 N HCl (aq) and Et2O. The organic layer was separated, and the aqueous layer was extracted twice with Et2O (15 mL×2). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to give an yellow oil, which was flash chromatography purified (SiO2, Hexane:EtOAc=8:2 (v:v)) to afford a colorless/light yellow oil as the title compound. (1.37 g, 23% yield). MW m/z: 215.3 (MW−1, low intensity). 1H NMR (CDCl3, 300 Hz) δ ppm 4.20 (q, 4H), 3.68 (q, 1H), 3.60 (dd, 2H), 1.37 (d, 3H), 1.26 (t, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:17])[CH3:16])=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=3[NH:14][C:15](=[O:17])[CH3:16])=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1cc(C(C)C)ccc1C(=O)CCl
Agent: Cl
Product: CC(=O)Nc1cc(C(C)C)ccc1C(=O)CN1CCN(c2nsc3ccccc23)CC1
Yield: 72.7 %

Procedure:
Starting with N-[2-(2-chloro-acetyl)-5-isopropyl-phenyl]-acetamide (0.30 g, 1.182 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.302 g, 1.182 mmol) and following the procedure as outlined in Example 517, N-{2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-5-isopropyl-phenyl}-acetamide (0.375 g, 0.859 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=73%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.36 (bs, 1H), 8.14 (d, J=8.24 Hz, 1H), 8.09 (d, J=8.24 Hz, 1H), 7.78–7.72 (m, 2H), 7.58 (t, J=7.56 Hz, 1H), 7.45 (t, J=7.56 Hz, 1H), 7.18 (d, J=8.24 Hz, 1H), 5.00 (s, 2H), 4.13–4.01 (m, 2H), 3.68–3.44 (m, 6H), 3.40 (s, H2O), 2.93 (heptet, J=6.95 Hz, 1H), 2.08 (s, 3H), 1.19 (d, J=6.95 Hz, 6H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[N:16](COCC[Si](C)(C)C)[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[N:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[NH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[N:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccsc3)n2)c2cnc(NCCN3CCOCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(NCc2ccsc2)nc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of crude (2-morpholin-4-yl-ethyl)-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (149 mg, crude) in dichloromethane (2 mL) was added CF3COOH (2 mL). This mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was washed with dichloromethane (2 mL) to give (2-morpholin-4-yl-ethyl)-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-amine as a white solid. (Yield 46 mg, 18% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(OCC)(=O)C>CN(C=O)C.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:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:13]=1[NH:12][C:4]1[C:5]([CH3:11])=[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)[C:19]#[N:20]
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3ccccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 60 °C
Yield: 15 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (122 mg, 0.3 mmol) in DMF (4 mL) was added 2-benzofuranboronic acid (162 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) under nitrogen atmosphere and the reaction mixture was heated at 60° C. overnight. After the solution was cooled to room temperature, ethyl acetate was added, and the organic phase was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-(1-benzofuran-2-yl)-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (18 mg, 15%). HPLC retention time: 13.4 min.(g); MS: 399.3 (M+H); and HRMS: 399.1009.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C1COCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][O:30][CH2:31][C:32]([CH3:40])([CH3:39])[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].[Cl-].[Na+]>>[C:34]([C:33]1([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31][O:30][CH:29]1[C:28]1[CH:41]=[CH:42][CH:43]=[C:26]([O:25][CH3:24])[CH:27]=1)([CH3:36])([CH3:37])[CH3:35]
Reactant: COc1cccc(COCC(C)(C)C(=O)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
In nitrogen atmosphere, 1.50 ml (11.4 mmol) of diisopropylamin and 6.60 ml (10.6 mmol) of 1.6 M butyllithium hexane were added to 15 ml of THF anhydride at a room temperature, and the mixture was stirred for 30 minutes. Adding 10 ml of THF dissolving 1.48 g (5.32 mmol) of 1-(3-methoxybenzyloxy)-2,2,4,4-tetramethyl-3-pentanon (Compound [49]) at −78° C., the mixture was stirred for 2 hours. The reaction mixture was stirred for 200 minutes with increasing the temperature to a room temperature gradually. The mixture was added to saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, then dried with magnesium sulfate anhydride and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=1:2) to obtain 1.30 g of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (Compound [50]). Yield 87.8%.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[H-].[Na+]>C1COCC1>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NCCCl)Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1cccc(C(F)(F)F)c1
Yield: 104.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloro-ethyl)-3-(3-trifluoromethyl-phenyl)-urea (I-36a: 3.2 g, 12.02 mmol) was reacted with sodium hydride (870 mg, 18.03 mmol) in dry THF (35 mL to give 2.9 g of product (95%)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:24]([NH:23][CH3:22])=[O:25])(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OCCCl
Temperature: 25 °C

Procedure:
5.9 g of triethylamine is added dropwise to a suspension of 11.0 g of 2-(2-cloroethoxy)-phenylsulfonamide, 50 ml of methylene chloride and 3.3 g of methyl isocyanate within 10 minutes at a temperature of 20°-25° C. The resulting clear solution is stirred for a further hour at room temperature and evaporated to dryness. The residue is solved in 5% aqueous sodium carbonate. After acidification of this solution with 10% hydrochloric acid 12.5 g of N-[2-(2-chloroethoxy)-phenylsulfonyl]-N'-methylurea precipitate therefrom, m.p. 218°-222° C.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[NH2:12].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([NH:18][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[NH2:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1N
Solvent: CO
Product: CC(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1N
Temperature: 64 °C
Yield: 90 %

Procedure:
To a 100 mL round-bottom flask, 0.1 mol of 2-amino-3,5-dichlorobenzoic acid methyl ester having a structure as shown in VIII-1, 100 mL of methanol, and 0.4 mol of tert-butylamine were added, heated to 64° C. and reacted for 5 hours, after treatment 23.5 grams of N-tert-butyl-2-amino-3,5-dichlorobenzamide having a structural formula of III-1 was obtained, and the yield was 90.4%;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=O)[CH:19]=[C:18]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C-]#[N:36].[K+].O>[OH-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([NH2:36])=[O:25])[CH:19]=[C:18]([CH2:28][O:29][CH2:30][C:31]([F:33])([F:34])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: [C-]#N
Reactant: CCOC(=O)Cc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CC(N)=O)n2)ccc1-n1cnc(C)c1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
Ethyl 2-(2-{[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}-6-[(2,2,2-trifluoro-ethoxy)methyl]pyrimidin-4-yl)acetate (140 mg, 0.30 mmol, 1.0 eq) was suspended in ammonium hydroxide (3 mL) with few crystals of potassium cyanide in a sealed tube. The mixture was stirred 4 days at 65° C. The reaction mixture was cooled down to rt, water was added and the aqueous layer was extracted with DCM (5×). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel cartridge eluting with 0% to 10% MeOH/DCM (1% ammonium hydroxide) to give the title compound as a solid, 68 mg (50%).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:37]([C@@H:32]([NH:31][C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[CH2:33][C:34]([NH2:35])=[O:36])=[O:38])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: CC(C)(C)C(=O)N[C@@H](CC(N)=O)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)C(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-pivaloyl-L-asparagine (65 mg, 0.3 mmol) which was prepared in step A this example. The final product was purified by preparative HPLC to yield 21 mg (12%) of the desired material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH2:36]C)[CH2:34]C)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[CH3:34][N:33]([CH3:36])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]5[S:38][CH:42]=[CH:41][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 57 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 57% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.8 (s, 5H) 3.8 (d, J=0.9 Hz, 3H) 3.9 (s, 1H) 4.2 (s, 1H) 6.5 (d, J=5.3 Hz, 1H) 6.6 (s, 1H) 6.9 (m, 6H) 7.1 (s, 3H) 7.2 (s, 1H) 7.4 (m, 1H) 7.6 (s, 1H) 7.7 (s, 1H) 7.9 (s, 1H) 8.2 (d, J=5.5 Hz, 1H) 8.5 (s, 1H) 8.8 (m, 1H) 9.6 (s, 1H) 10.4 (s, 1H). ES-LC/MS m/z 590 [M+H]+.