Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:30][C:31]1[N:32]=[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]2[CH:39]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][C:31]3[N:32]=[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]4[CH:39]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: ClCc1cn2ccccc2n1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3cn4ccccc4n3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 using methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-(chloromethyl)imidazo[1,2-a]pyridine. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.33-8.40 (m, 1H) 8.18-8.25 (m, 1H) 8.10-8.17 (m, 1H) 7.70-7.79 (m, 1H) 7.59-7.65 (m, 1H) 7.51-7.56 (m, 1H) 7.44-7.50 (m, 2H) 7.34-7.41 (m, 1H) 7.29-7.34 (m, 1H) 6.18-6.25 (m, 1H) 6.00-6.05 (m, 1H) 5.88-5.98 (m, 1H) 5.35 (s, 1H) 3.67 (s, 3H) 1.02 (s, 9H); LCMS (m/z) ES+=519 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:21][CH3:22])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-nitrosalicylic acid (10.8 g) in ethanol (100 ml) was added concentrated sulfuric acid (92.0 g) with stirring at room temperature, and the resulting mixture was refluxed for 7.5 hours. After cooling to room temperature, the reaction mixture was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, 0.5N hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (10.7 g, yield: 85%) as a pale yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]([CH3:30])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)[N:14]=1)[CH3:8])(C)(C)C.[ClH:32].C(O[CH2:37][CH3:38])(=O)C>C(OCC)C>[ClH:32].[CH3:8][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([C:20]2[NH:21][N:22]=[C:37]([CH3:38])[CH:19]=2)[CH2:18][C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=2)[N:14]=1)([CH3:30])[C:6]([OH:5])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNCc2cnn(-c3ccccc3)c2)cs1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cnn(-c3ccccc3)c2)[nH]n1

Procedure:
A compound obtained using 2-methyl-2-{[4-(2-{[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester synthesized in Example 451-2, and by an operation similar to that of Example 446 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CNc1ccc(OC)cc1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Product: CCOC(=O)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from ethyl 4-chloroquinazoline-2-carboxylate and (4-methoxy-phenyl)-methylamine by using the procedure described for example 1b. 1H NMR (CDCl3): 7.98-8.02 (m, 1H), 7.61 (ddd, J=1H, 8.1, 6.9, 1.5), 7.08-7.17 (m, 3H), 7.01-7.05 (m, 1H), 6.91-6.96 (m, 2H), 4.56 (q, J=2H, 7.2), 3.84 (s, 3H), 3.71 (s, 3H), 1.50 (t, J=2H, 7.2).
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]2[O:16]C3C=C(O)C=C(O)C=3C[C@@H]2O)=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.[CH2:22](O)C>>[O:16]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]([OH:21])=[C:4]([O:20][CH3:22])[CH:5]=1
Reactant: CCO
Reactant: Oc1cc(O)c2c(c1)O[C@@H](c1ccc(O)c(O)c1)[C@@H](O)C2
Product: COc1cc(C=O)ccc1O

Procedure:
Standard epicatechin solution: Prepare fresh epicatechin stock solution at 1.0 mg/ml in 50% ethanol.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C(O)CCC>CO>[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[N:23]=[C:22]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: Clc1nccc(N2CCc3ccccc32)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 219 mg, 0.77 mmol) in methanol (2 ml) was added to a solution of 2-chloro-4-(indolin-1-yl)pyrimidine (Method 3, 200 mg, 0.86 mmol) in ii-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica (1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (201 mg, 61%). NMR: 2.19 (s, 6H), 2.21-2.3 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.25 (m, 2H), 3.8-4.1 (m, 5H), 5.75 (m, 1H), 6.2 (m, 2H), 6.8-6.9 (m, 3H), 7.0-7.1 (m, 1H), 7.15-7.25 (m, 1H), 7.5-7.6 (m, 2H), 8.05-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.95 (s, 1H); MS (MH+): 406.5.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:13][C:12]([NH2:14])=[N:11][C:9](=O)[CH:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:13]=[C:12]([NH2:14])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(=O)cc(-c2ccccc2)[nH]1
Product: Nc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
To 10.0 g (53 mM) of 6-phenylisocytosine is added 80 ml of phosphorus oxychloride. The mixture is heated to reflux, and refluxed until solution is complete (about 30 minutes). The solution is then cooled and evaporated to dryness under vacuum at 45° C. The resulting oil is poured into 300 ml of ice water, with vigorous stirring, and the remaining oil washed into the aqueous mixture with additional 100 ml of water. The entire aqueous mixture is neutralized to pH 8 with concentrated ammonium hydroxide, filtered, and solids washed well with water until water wash is neutral. Dry at 60° in a vacuum oven to yield 9.2 g of 4-chloro-6-phenyl-2-pyrimidinamine.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH3:3].[CH3:19][C:20]([CH3:22])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:19][C:20]1([CH3:22])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16](=[O:17])[NH:18]1
Reactant: CC(C)=O
Reactant: CCCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.130 g, 0.500 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate), then washed with ethyl acetate to afford the title compound (0.094 g, 62%) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[NH2:4].[C:29]([O-])([O-])(OCC)[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2[N:4]=[C:29]([CH3:30])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: CS(=O)(=O)Oc1ccc(Oc2ccc(CNc3cccc(F)c3N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(F)cccc2n1Cc1ccc(Oc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of 2-fluoro-6-[4-(4-methylsulfonyloxyphenoxy)benzylamino]aniline (300 mg) and ethyl ortho-acetate (181 mg) was heated at 150° to 160° C. for 24 hours while stirring. The reaction mixture was cooled to room temperature, toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, and the resultant mixture was stirred for 10 minutes The toluene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene. The residue was purified by silica gel column chromatography to give 4-fluoro-1-[4-(4-methylsulfonyloxyphenoxy)benzyl]-2-methylbenzimidazole (243 mg) as white crystals m.p., 48°-56° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].[CH2:26](S)[CH2:27]C>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][CH2:13][CH2:26][CH3:27])=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: CCCS
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (500 mg, 1.4 mmol) in EtOH (15 mL) was added NaOH (0.71 mL of a 4 M solution, 2.8 mmol) followed by propanethiol (255 μL, 2.8 mmol). The mixture was stirred at room temperature for 2 h then evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was triturated with ether and the colourless solid (380 mg, 77%) collected by filtration. mp 117-119° C. C18H25NO2S2 requires: C, 61.50; H, 7.17; N, 3.98%. Found: C, 61.48; H, 7.02; N, 3.97%. 1H NMR (250 MHz, CDCl3) δ1.04 (6H, s), 1.10 (3H, t, J=7.3 Hz), 1.87 (2H, sextet, J=7.3 Hz), 1.93-1.99 (4H, m), 2.40 (2H, s), 2.83 (2H, s), 3.00 (2H, t, J=7.3 Hz), 3.57-3.63 (4H, m). MS (ES+) 352 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29]C(=O)OCC1C=CC=CC=1)[CH2:25][CH:26]([CH3:28])[CH3:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCOC(C)=O>[Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:27])[CH3:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A flask containing a solution of the Cbz-protected amine 11b (460 mg, 0.846 mmol) in a 5:1 MeOH/EtOAc mixture (12 mL) was purged and filled 3 times with argon, then 10% Pd/C (50 mg) was added. The flask was purged and filled 3 times with H2, and the resulting black suspension was stirred at rt under H2 (1 atm). Since the reaction did not reach completion after 3 h, an additional amount of 10% Pd/C (30 mg) was added and stirring under H2 was continued for 5 h. The reaction mixture was then filtered through a pad of Celite, the Celite washed with MeOH and AcOEt, and the solution concentrated in vacuo to yield 317 mg (92%) of the crude title compound as a pale yellow oil, that was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:3]=1.[NH3:28]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:28])=[O:10])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:3]=1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: N
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylic acid (Example 32) with 2 M ammonia in MeOH.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([N:9]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]([O:17][CH3:18])=[N:11][C:10]1=O)[CH3:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]([CH2:7][CH3:8])[S:14](=[O:16])(=[O:15])[N:13]=[C:12]([O:17][CH3:18])[N:11]=1
Reactant: CCN1C(=O)N=C(OC)NS1(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN1C(Cl)=NC(OC)=NS1(=O)=O
Reaction time: 2 h
Yield: 91 %

Procedure:
154 parts of phosphorus pentachloride were added, in the course of 2 minutes, to a stirred mixture of 128 parts of 6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide and 840 parts of phosphorus oxychloride at 25° C. The reaction mixture was then stirred for 51/2 hours under reflux, after which it was evaporated down under reduced pressure. The oil which remained was taken up in 300 parts of 1,2-dichloroethane and the solution was chromatographed over neutral alumina (Activity I). After evaporating down, 127.5 parts (91% of theory) of 5-chloro-6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 63°-70° C., were obtained (Compound No. 2).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][O:64][CH2:65][CH2:66][NH2:67]>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:67][CH2:66][CH2:65][O:64][CH3:63])=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
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: COCCNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 2-Methoxyethylamine (54.3 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was purified by reverse phase preparative HPLC to yield white solid (0.029 g, 50%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][NH:15][CH:16]3[C:25]4[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:21][C:20]=4[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:31][CH:30]=2)[CH:16]2[C:25]3[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COC(=O)c1ccc2c(c1)C(NCc1ccc(C#Cc3ccc(F)cc3)cc1)CCC2
Product: COC(=O)c1ccc2c(c1)C(N(Cc1ccc(C#Cc3ccc(F)cc3)cc1)C(=O)CCC1CCCC1)CCC2

Procedure:
The titled compound was prepared following the procedure B using methyl 8-({4-[(4-fluorophenyl)ethynyl]benzyl}amino)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate and 3-cyclopentylpropionyl chloride as a white powder (80%). 1H NMR (CDCl3, 300 MHz) δ 1.06 (m, 2H), 1.41-2.10 (m, 11H), 2.27-2.60 (m, 2H), 2.77 (m, 2H), 3.87 (s, 3.4H), 4.07 (d, J=17.9 Hz, 0.6H), 4.52 (d, J=18.5 Hz, 0.6H), 4.86 (d, J=15.6 Hz, 0.4H), 5.10 (m, 0.4H), 6.06 (m, 0.6H), 7.00-7.20 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 7.48 (m, 3H), 7.66 (d, J=10.4 Hz, 1H), 7.78 (m, 1H). HPLC, Rt: 5.83 min (Purity: 99.4%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)=[O:11])#[N:2].[CH2:24]([NH:26][CH3:27])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:12]1[CH:13]=[CH:14][C:15]([C:16](=[O:18])[N:26]([CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1)#[N:2]
Reactant: N#Cc1cccc(OCCNC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCN(C)C(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1

Procedure:
258 mg (0.83 mmol) of 4-[N-[2-(3-cyanophenoxy)ethyl]carbamoyl]benzoic acid, 53 mg (0.9 mmol) of N-ethyl-N-methylamine, 129 mg (0.83 mmol) of 1-hydroxybenzotriazole (hydrous, 87%) and 159 mg (0.83 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 10 ml of dichloro ee at room temperature overnight. The resultant mixture was diluted with 1 N hydrochloric acid. After the extraction with dichloromethane, the organic layer was washed with 1 N aqueous sodium hydroxide solution and then with saturated aqueous NaCl solution and dried over anhydrous magnesium-sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:26][N:27](C=O)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:26]#[N:27])[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCSC1
Temperature: 50 °C

Procedure:
To a solution of Example 17B (16.55 g, 44 mmol) in dry DMF (100 mL) under nitrogen was added tetrabutylammonium cyanide (50 g, 200 mmol). The mixture was heated to 50° C. for 60 hours and then poured into cold water and extracted with ethyl acetate (3×250 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with 50% ethyl acetate/50% hexane to provide the titled compound (12 g). MS (ESI) m/e 312 (M+H)+, 310 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.44 (m, 9 H) 2.10 (m, 1 H) 2.79 (m, 1 H) 3.05 (m, 1 H) 3.17 (m, 1 H) 3.33 (m, 1 H) 3.57 (dd, 1 H) 3.83 (m, 2 H) 3.96 (m, 1 H) 4.48 (m, 1 H) 4.65 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.Cl>O>[CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)ncc12
Agent: Cl
Solvent: O
Product: Cc1nccn2c(C3CCNCC3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
Benzyl 4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (3.71 mmol, 1.30 g) was dissolved in 37% hydrochloric acid (240 mmol, 20 ml). The reaction mixture was stirred at room temperature for two hours, then poured in water and washed twice with diethyl ether. The aqueous layer was concentrated in vacuo and co-evaporated with toluene and ethanol. The residue was dissolved in methanol and eluted twice over a column of Si-Carbonate (Silicycle, Loading 0.7 mmol/g) to give 8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.93 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[OH-].[K+]>CCOC(C)=O.O>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Chloroacetyl chloride (1.05 mL, 13.1 mmol) is added in one portion to a biphasic mixture of N-methyl-4-nitroaniline (1.0 g, 6.57 mmol), KOH (1.11 g, 19.7 mmol) in 12 mL EtOAc and 12 mL H2O, cooled to 0° C. The resulting mixture is stirred at this temperature for 5 min, then the ice bath was removed and it was allowed to warm to RT. The reaction was stirred for an additional one hour at RT.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:17])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1CCN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1CCNC(=O)c1ccc(Cl)cc1
Yield: 70.2 %

Procedure:
1-Amino-2-(2-methylphenyl)ethane (13.5 g) was dissolved in 80 ml of pyridine. While the solution was cooled with stirring, 18 g of 4-chlorobenzoyl chloride was added dropwise. They were reacted at room temperature for 5 hours. Pouring of the reaction mixture into cold water gave a precipitate of crystals. The crystals were washed in water, dried, and recrystallized from cyclohexane to afford 19.2 g of 1-(4-chlorobenzoylamino)-2-(2-methylphenyl)ethane having a melting point of 95° to 96° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH2:10]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:9])[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2ccc(N)cc2F)c1
Yield: 88.5 %

Procedure:
The title compound (241 mg) was prepared from 4-bromo-3-fluoroaniline (200 mg, 1.05 mmol) and 3-butoxyphenylboronic acid (265 mg, 1.4 mmol) as a colourless liquid.