Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccn1
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(c1ccc(-c2ccccc2)cc1)c1ccccn1)C(C)C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of 50.0 g (0.16 mole) of 2-(4-phenylphenyl)-4-[N,N-bis(1-methylethyl)amino]butanenitrile and 29.7 g of potassium hydride (about 0.26 mole as a 35% dispersion in oil) in 1000 ml of toluene was heated at 65°. A solution of 32 g (0.20 mole) of 2-bromopyridine in 450 ml of toluene was added slowly. After addition was complete, the mixture was stirred an additional 30 minutes, cooled in an ice bath, and treated with 750 ml of water. The toluene layer was separated and extracted with 10% aqueous hydrochloric acid. The acidic aqueous layer was neutralized with a slight excess of aqueous sodium hydroxide and extracted wih dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, giving 56.5 g of the title compound as an oil having the expected NMR spectrum. The intermediate nitrile was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:19])[NH2:18])=[N:9]2)=[CH:5][CH:4]=1.C[N:23](C)[CH:24](N(C)C)[CH:25]([O:28][CH3:29])[C:26]#N.N1CCCCC1>CC(C)CCO>[CH3:29][O:28][C:25]1[C:24]([NH2:23])=[N:19][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=3)[N:9]=2)=[N:18][CH:26]=1
Reactant: COC(C#N)C(N(C)C)N(C)C
Reactant: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: CC(C)CCO
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
6.45 g of 1-(4-methoxybenzyl)-1H-indazole-3-carboximidamide (23.0 mmol, 1 eq.), 5.40 g of 3,3-bis(dimethylamino)-2-methoxypropanenitrile (1-2-1, 31.5 mmol, 1.37 eq.) and 0.455 ml of piperidine (4.60 mmol, 0.2 eq.) were dissolved in 82.7 ml of dry 3-methylbutan-1-ol, put under a nitrogen atmosphere and stirred at 100° C. for 3 days. The mixture was cooled down at room temperature and stirred for 18 hours for crystallization. The resulting suspension was filtered off. The crystals were washed with cold methanol and dried in vacuo at 50° C. The crystallization was repeated twice with cold methanol to receive 2 further filter cakes and a combined yield of 6.87 g (19 mmol, 82.5%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
2,2,2-Trifluoroethyliodide (15.2 g) and potassium carbonate (10.0 g) were added to a solution of 4-bromo-2-chlorophenol (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 80° C. for 20 hours. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give 4-bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene as a colorless oil (3.0 g, 43%).
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]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[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]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile (106 mg, 0.25 mmol) in THF (3 mL) and EtOH (1 mL) was added 1-methylpiperazine (75 mg, 0.75 mmol) and acetic acid (75 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the reaction mixture and the solution was stirred at room temperature overnight, and concentrated. Aqueous 1N HCl was added and the aqueous phase was extracted with ethyl acetate, basified to pH of 10 by adding sodium carbonate, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl}nicotinonitrile as a yellow solid (68 mg, 53%). HPLC retention time: 7.0 min.(g); and MS: 511.5 (M+H).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>O.C(O)(=O)C>[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH:9]([N+:1]([O-:3])=[O:2])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)CC(C)C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)CC(C)C)[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (232 g, 3.36 mol) in water (560 mL) was added drop-wise over 1.5 hours to a solution of methyl 5-methyl-3-oxohexanoate (400 g, 2.53 mol) in glacial acetic acid (510 mL) at 20 to 25° C. Stirring was continued at room temperature for 2 hours. Water (1.3 L) was added, and the reaction mixture was stirred for an additional 18 hours. The mixture was then extracted with ethyl acetate (3×2.5 L), and the combined organic layers were washed sequentially with water (2.5 L), with aqueous sodium bicarbonate solution (2.5 L), and with saturated aqueous sodium chloride solution (1.0 L). After drying over sodium sulfate, the organic extracts were concentrated in vacuo to afford the product as a yellow liquid, which was used directly in the next step. Yield: 456 g, 2.24 mol, 89%.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][CH:48]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:49]1[CH:54]=[CH:53][C:52]([P:55](=[O:62])([O:59][CH2:60][CH3:61])[O:56][CH2:57][CH3:58])=[CH:51][CH:50]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][CH:48]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:49]2[CH:54]=[CH:53][C:52]([P:55](=[O:62])([O:56][CH2:57][CH3:58])[O:59][CH2:60][CH3:61])=[CH:51][CH:50]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (309 mg, 1.5 mmol) in MeCN (10 ml) were added HATU (599 mg, 1.58 mmol), Et3N (159 mg, 1.58 mmol) and diethyl 4-(amino(phenyl)methyl)phenylphosphonate, 2-c, (479 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with sat. NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide the product, 8-1, (150 mg, 20%). 1H NMR (CD3OD, 300 MHz,): δ 10.39 (br, 1H), 8.56 (s, 1H), 8.47 (m, 1H), 7.81 (m, 1H), 7.62 (m, 2H), 7.40 (m, 2H), 7.25 (m, 5H), 6.54 (m, 1H), 6.26 (m, 1H), 3.96 (m, 4H), 1.18 (m, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:32]([O:34]C)=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH2:10][C@H:9]1[C:32]([OH:34])=[O:33])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)COC(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Methyl (2S,4S)-1-BOC-4-{[3-(acetoxy)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidine-2-carboxylate (0.88 g, 1.77 mmol) obtained in Step A was dissolved in MeOH (8 mL) and water (1.6 mL). NaOH (213 mg, 5.31 mmol) was added thereto. The reaction solution was stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, acidified with 1N HCl and extracted with EtOAc. The extracted organic solution was washed with 1N HCl solution, dried over MgSO4 and concentrated in vacuo to give the title compound (0.74 g, 95%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2C=CC=CC=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.C([OH:24])(C)C>>[N:14]1([C:2]2[C:7]([CH:8]=[O:24])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Clc1ncccc1-c1ccccc1
Reactant: CC(C)O
Reactant: C1CNCCN1
Agent: Cl
Product: O=Cc1cccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-pyridinecarboxaldehyde (VI; 6.4 g, 0.05 mole) and piperazine (19.4 g, 0.23 mole) was refluxed 5 hr in isopropanol (250 mL). The reaction mixture was concentrated in vacuo to a syrup which was partitioned between methylene chloride and water. The organic phase was isolated, washed with water (3×500 mL), dried (MgSO4), filtered, and concentrated in vacuo to a syrup which was flash chromatographed (10% methanol-methylene chloride). The appropriate fractions were combined, concentrated in vacuo, dissolved in ethanol and treated with 1 equivalent of ethanolic HCl. Crystallization of the crude hydrochloride salt gave 8.8 g (87%) of the appropriate IIIc intermediate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Product: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) in accordance with the general method of example 1, step 6 using 3,5-Difluorophenylboronic acid instead of 3-Fluorophenylboronic acid to yield the final compound as a white crystalline solid, MS (ISP): m/e=278.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:10]=1.[O:27]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]1.Cl[C:34]([O-])=[O:35].C(N(CC)CC)C>C(Cl)Cl.O>[O:27]1[CH2:31][CH2:30][CH:29]([O:32][C:34]([N:7]2[CH2:6][CH2:5][N:4]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[C@H:3]([CH2:2][OH:1])[CH2:8]2)=[O:35])[CH2:28]1
Reactant: Cc1ccc2c(N3CCNCC3CO)nc(-c3ccccc3O)nc2c1
Reactant: O=C([O-])Cl
Reactant: O[C@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)OC4CCOC4)C[C@H]3CO)nc(-c3ccccc3O)nc2c1

Procedure:
To 2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (69.2 mg, 0.19 mmol) in 650 μL of CH2Cl2 at 0° C. was added (S)-tetrahydro-furan-3-ol-chloroformate (26.8 mg, 0.17 mmol), followed by triethylamine (30 μL, 0.22 mmol). The reaction mixture was stirred for an hour and then diluted with 5 mL of CH2Cl2 and 5 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was subjected to purification using 30-100% EtOAc-hexanes to give the desired product. LC/MS: m/z 465.2 (M+H)+ at 2.5 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:19][CH3:20])[C:17]([NH2:18])=[C:13]2[CH:12]=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](O[C:38](=O)[CH3:39])OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.CCC(=O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:19][CH3:20])[C:17]([NH:18][CH:2]([CH2:7][CH2:38][CH3:39])[CH2:3][CH3:4])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC(=O)CC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(CC)Nc1c(CC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
After dissolving [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (30 mg) in acetic acid (1 mL), 3-hexanone (0.024 mL) and sodium sulfate (139 mg) were added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (41.5 mg) was then added, and stirring was continued for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (21 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([CH2:21]Cl)[CH:19]=[CH:20][C:15]=2[S:14][C:13]2[N:23]=[CH:24][CH:25]=[N:26][C:12]1=2.O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][O:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([CH2:21][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[CH:19]=[CH:20][C:15]=2[S:14][C:13]2[N:23]=[CH:24][CH:25]=[N:26][C:12]1=2
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCN1c2cc(Cn3cccn3)ccc2Sc2nccnc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
To a solution of 100 mg of pyrazole in N,N-dimethylformamide was added in a nitrogen atmosphere 60 mg of sodium hydride (oily 60%) under ice cooling and the resulting mixture was stirred for 10 minutes. Subsequently, 240 mg of 10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was added to the reaction mixture, which was then heated to 80° C. for 10 minutes. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue thus obtained was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 150 mg of the title compound as a yellow powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC#N>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:20]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.4 %

Procedure:
Sodium carbonate (1.27 g) was added to a solution of homopiperazine (5.99 g; 5 eq.) and ethyl bromoacetate (2.0 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give [1,4]diazepan-1-yl-acetic acid ethyl ester (1.794 g), which was carried on for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.15 (m, 2H), 3.39 (s, 2H), 2.91 (m, 4H), 2.81 (m, 4H), 1.76 (m, 3H), 1.25 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4]([C:7]([O:9]CC)=O)=[N:5][N:6]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4]([C:7](=[O:9])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:5][N:6]=1
Reactant: CCOC(=O)c1nnc(C)n1-c1ccccc1C
Reactant: Cl[Mg]Cc1ccccc1
Agent: N
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1c(C)nnc1C(=O)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 10C (1.0 g, 4.1 mmol) in toluene cooled by an ice bath, benzylmagnesium chloride (2M in THF) (3.0 mL, 6.0 mmol) was added dropwise. After one hour, ammonia chloride solution was added to the mixture and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated and used without further purification. MS (m/z) 292 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:25][N:26]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:11]2[N:10]=1.O>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:25][N:26]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:11]2[N:10]=1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 74 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-trimethylsilanylethynyl-2H-pyrazolo[4,3-c]isoquinoline in 5 ml of THF, 0.22 cm3 of tetrabutylammonium fluoride is added, and the mixture is stirred at RT for 30 min. It is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and AcOEt (85/15 by vol.), to give 47 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline (lemon yellow solid). MS (E/I): m/z=611 (M+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[O:13])=[CH:7][CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.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>[N:16]1([CH2:15][CH2:14][S:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[O:13])[CH:20]=[CH:19][N:18]=[N:17]1
Reactant: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A solution of 1.00 g (3.43 mmol) 1-[2-(4-allyloxy-phenylmethanesulfinyl)-ethyl]-1H-[1,2,3]triazole in 60 ml dichloromethane was added to a solution of 1.61 g (10.3 mmol) 1,3-dimethylbarbituric acid and 102 mg (0.09 mmol) Pd(PPh3)4 in 30 ml dichloromethane and stirred for 5 h at 50° C. The mixture was extracted with 3×50 ml sat. NaHCO3-solution and 20 ml water. The organic phase was discarded and the aqueous phase acidified with 2M HCl to pH=4, concentrated to a volume of 50 ml and adjusted to pH=1. After five extractions with ethyl acetate, the organic extracts were combined and dried over MgSO4. After evaporation the residue was purified by chromatography on silica gel (dichloromethane/methanol 100:2) to yield 0.84 g (97%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.O>CN(C)C=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:3][CH:4]=1
Reactant: Nc1ncnc2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-aminoquinazoline (11.6 g) and diethyl ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml) was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0° C. to precipirate crystals. To the mixture was added small volume of water with stirring. The crystals were separated by filtration, washed with water, dried overnight under reduced pressure and dissolved in ethyl acetate. The resultant solution was dried over anhydrous magnesium sulfate and recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl [(4-quinazolinylamino)methylene]propanedioate (22.7 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:15])[N:4]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[CH2:10][O:9][C:7]1[CH:6]=[C:5]([CH3:15])[N:4]=[C:3]([N:2]([CH3:1])[C:25]([NH:24][S:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)(=[O:22])=[O:23])=[O:26])[N:8]=1
Reactant: O=C=NS(=O)(=O)c1cccs1
Reactant: CNc1nc(C)cc(OCC(F)(F)F)n1
Solvent: ClCCl
Product: Cc1cc(OCC(F)(F)F)nc(N(C)C(=O)NS(=O)(=O)c2cccs2)n1

Procedure:
To a dry stirred solution of 22.1 parts of 2-methylamino-4-(2,2,2-trifluorethoxy)-6-methylpyrimidine in 250 parts of methylene chloride at ambient temperature was added 18.9 parts of 2-thiophenesulfonyl isocyanate. That mixture was stirred and refluxed for 2 hours. The methylene chloride was removed under reduced pressure, and the resulting solid was triturated with toluene to yield 19 parts of N-[N-[4-(2,2,2-trifluoroethoxy)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-thiophenesulfonamide.