Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=O)[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([N:30]2[CH2:34][C@H:33]([CH2:35][NH2:36])[O:32][C:31]2=[O:37])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([NH:36][CH2:35][C@@H:33]3[O:32][C:31](=[O:37])[N:30]([C:20]4[CH:21]=[CH:22][C:23]([N:24]5[CH2:25][CH2:26][S:27][CH2:28][CH2:29]5)=[C:18]([F:17])[CH:19]=4)[CH2:34]3)=[O:16])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: COc1ccc2cc(C(=O)O)c(C)nc2c1
Product: COc1ccc2cc(C(=O)NC[C@H]3CN(c4ccc(N5CCSCC5)c(F)c4)C(=O)O3)c(C)nc2c1
Yield: 43 %

Procedure:
It was prepared following the same procedure as in Example 1, starting from 370 mg of 7-methoxy-2-methylquinoline-3-carboxylic acid and 350 mg of N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]amine. After similar work-up, 244 mg were obtained corresponding to the desired 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-quinolinecarboxamide (Yield=43%).
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=O.[CH2:24]([OH:27])[CH2:25][OH:26]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]1[O:27][C:5]([O:7][CH2:8][CH3:9])([CH2:4][CH2:3][C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:26][CH2:25]1
Reactant: OCCO
Reactant: CCCCCCCCCCCCCCC(=O)CCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC(=O)CCC1(OCC)OCCO1
Yield: 71.5 %

Procedure:
A mixture of 9.25 g (28 mmol) of ethyl γ-ketooctadecanoate and 9.00 g of ethylene glycol (145 mmol) was refluxed for 5 hours in 300 ml of toluene in the presence of a small amount of p-toluenesulfonic acid catalyst while removing water by means of Dean-Stark apparatus. The resulting mixture was washed with an aqueous saturated sodium bicarbonate solution and then with an aqueous saturated solution of sodium chloride. An oily product obtained by removing the solvent under reduced pressure was subjected to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to give 7.42 g (71% yield) of ethyl γ-ketooctadecanoate ethylene ketal.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[C:3]([NH2:12])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CNCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
The title compound was made using a procedure described in Collins, et. al., Tetrahedron, Vol. 48, No. 37, pp 7887-7898, 1992. To a solution of 1-fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.64 mL, 5.7 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH2Cl2 and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:35][C:34]([N:33]([CH3:38])[CH3:32])=[O:37]
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(=O)N(C)C)c3ccccc32)cc1
Yield: 6.9 %

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), N,N-dimethyl-2-chloroacetamide (0.19 g) and potassium carbonate (0.22 g) is refluxed for 24 hours. The reaction solution is concentrated and water is added to the resulting residue. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(dimethylaminocarbonylmethyl)amino]-1-[4-(2-methylbenzoyl amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.05 g) as colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:19]=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccnc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 14.7 %

Procedure:
A solution of 2-fluoropyridine (306 mg, 3.15 mmol) in THF (1 mL) was added to a solution of lithium diisopropylamide in THF (0.20 M, 17 mL, 3.4 mmol) at −78° C. The solution was stirred at −78° C. for 4 h, then DMF (0.73 mL, 9.4 mmol) was added dropwise and stirring was continued at −78° C. for 2.5 h. Saturated NH4Cl(aq) (2 mL) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with EtOAc (20 mL), and the organic phase was washed with saturated NaHCO3(aq) (20 mL) and brine (10 mL), then dried (MgSO4) and concentrated in vacuo. Purification of the crude material by chromatography on silica gel (10% EtOAc/hexanes) gave the title compound as a yellow liquid (58 mg, 15%). 1H NMR (CDCl3) □ 7.39 (m, 1H), 8.32 (m, 1H), 8.48 (m, 1H), 10.33 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([OH:18])=[C:13]([N:19]=O)[CH:12]=[CH:11]2>CCCCCC>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]([C:14]([Cl:2])=[O:18])=[C:10]([CH:9]=1)/[CH:11]=[CH:12]\[C:13]#[N:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=Nc1ccc2cc(Cl)ccc2c1O
Solvent: CCCCCC
Product: N#C/C=C\c1cc(Cl)ccc1C(=O)Cl

Procedure:
To a rapidly stirring suspension of phosphorus pentachloride, 68.0 g, 0.326 mole in dry hexane (1.6 liters) is added 78.03 g (0.322 mole) of 6-chloro-2-nitroso-1-naphthol (I). The mixture is stirred at room temperature for 3 hours, the refluxed for 2 hours. The warm solution is then decanted and the residue in the reaction vessel refluxed for another hour with 1.0 liter of dry hexane. The hexane extracts are combined and evaporated to dryness. Yield: 75.0 g semi-solid brown residue. This crude product is recrystallized by taking it up in 2.0 liters of hot hexane, evaporating the solution down to a minimum volume (ca 300 ml) and cooling in an ice-water bath. Yield 31.0 g (42.59%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([OH:28])[CH:22]=2)=[O:18].[O:29]1[CH2:32][CH:31](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:28][CH:31]1[CH2:32][O:29][CH2:30]1)[CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(O)cc5[nH]4)c3N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(OC6COC6)cc5[nH]4)c3N)ccc2[nH]1
Temperature: 80 °C
Reaction time: 144 h
Yield: 28.8 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl)-methanone (21 mg, 0.056 mmol), toluene-4-sulfonic acid oxetan-3-yl ester (19 mg, 0.084 mmol), and potassium carbonate (13 mg, 0.095 mmol) were dissolved in anhydrous N,N-dimethylformamide (DMF), and heated at 80° C. with stirring under a nitrogen atmosphere for six days. After cooling to room temperature, the reaction mixture was combined with water, and extracted with an ethyl acetate/methanol (10/1) solution. The organic layer was isolated, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/3) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-(oxetan-3-yloxy)-1H-indol-2-yl]-methanone as a yellow solid (6.9 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43](Cl)=[O:44]>C1COCC1.Cl>[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=[CH:5]2)=[O:44]
Reactant: Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Reactant: O=C(Cl)CC1CC2CCC1C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1CC2CCC1C2)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 78 mg (0.22 mmol) of 5-amino-N-phenyl-1-(2-phenylethyl)-1H-indole-2-carboxamide (Example LI) are dissolved in 2 ml of THF, and 24.4 mg (0.24 mmol) of triethylamine are added. The solution is cooled to 0° C., and a solution of 37.9 mg (0.22 mmol) of bicyclo[2.2.1]hept-2-ylacetyl chloride in 0.2 ml of THF is added dropwise. The reaction mixture is stirred at RT for 2 h and then diluted with 1-molar hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution and once with sodium bicarbonate solution, dried over sodium sulphate and filtered. The residue obtained after removal of the solvent under reduced pressure is purified chromatographically on silica gel (mobile phase: dichloromethane/ethyl acetate). 31.5 mg (29% of theory) of the product are obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([C:16]([N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:18])=[CH:19][CH:20]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 63 %

Procedure:
As described in example 52g, 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (45 mg, 0.15 mmol) was converted, using thiomorpholine-1,1-dioxide instead of cyclobutylamine, to the title compound (39 mg, 63%) which was obtained as a light yellow oil. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:27][CH2:28]2)[CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(Cc2cc(Cl)ccc2Cl)C2CC2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(2,5-dichloro-benzyl)-amine
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][O:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: COCCl
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A 10 g quantity of 1-(2-hydroxyphenyl)ethanone was dissolved in 100 ml of dimethylformamide, and 11.2 ml of chloromethyl methyl ether and 25.4 g of potassium carbonate were added. The mixture was stirred at 50° C. for 6 hours and then at room temperature for 4 days. After insolubles were removed from the reaction mixture by filtration, ice water was added to the filtrate and extraction with ethyl acetate was performed. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 6.26 g of colorless oily 1-(2-methoxymethoxyphenyl)ethanone.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])=[CH:17][C:16]=1[CH3:28]>C1C=CC=CC=1>[CH2:1]([NH:7][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:26]=[CH:27][C:15]([Cl:14])=[C:16]([CH3:28])[CH:17]=1)[CH2:24][CH3:25])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCC(Oc1ccc(Cl)c(C)c1)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC(Oc1ccc(Cl)c(C)c1)C(=O)NCc1ccco1
Yield: 27.1 %

Procedure:
In 50 ml of benzene were dissolved 1.5 g (0.015 mole) of furfurylamine and 4.0 g (0.051 mole) of pyridine, and thereto was added dropwise a solution of 3.0 g (0.012 mole) of 2-(4-chloro-3-methylphenoxy)-butyroyl chloride in 20 ml of benzene at room temperature with stirring, followed by stirring for further 5 hours. Subsequently, after the same procedure as in Synthesis Example 4 and 5 was followed, the resultant crude crystals were recrystallized from ethanol to give 1.0 g of N-furfuryl-2-(4-chloro-3-methylphenoxy)-butyramide melting at 100°~102° C. as pale brown needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:28])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>C(O)C.O.CS(C)=O>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14](=[O:28])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Yield: 50.9 %

Procedure:
6 g (15 mmol) of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-(4-ethoxycarbonylphenoxy)ethanone (from Example 5) were stirred with 5 g of potassium hydroxide in 90 ml of ethanol/water/dimethyl sulfoxide (5:3:1) at 80° C. for 5 min and poured into ice-water, the alkaline solution was extracted with ether and the extract was discarded, and then the pH was adjusted to 3 with concentrated hydrochloric acid, and the acid solution was extracted with ethyl acetate. The latter extract was washed with water, dried over magnesium sulfate and evaporated. Recrystallization of the residue from ethanol provided 2.8 g of the title compound of melting point 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[Li]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)([OH:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1ccco1
Product: CC(O)(c1ccco1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 2-furyl lithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.6 (m, 1H), 7.08 (dd, J=2.73, 10.91 Hz, 1H), 6.8 (d, J=2.73 Hz, 1H), 6.56 (d, J=8.18 Hz, 1H), 6.45-6.38 (m, 2H), 6.14 (s, 1H), 5.3 (s, 2H), 1.76 (s, 3H); MS (ES) m/z 280/282 ([M−H]−, 30%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14](=[S:22])[C@H:13]([NH:23]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[NH2:23][C@@H:13]1[CH2:12][CH2:11][C@@H:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=2[F:2])[CH2:16][N:15]([CH2:17][C:18]([F:20])([F:21])[F:19])[C:14]1=[S:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 3 mL, 12.0 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]carbamate (105 mg, 0.239 mmol) in 1,4-dioxane (3 mL). After 1 h, the reaction was concentrated to give the title compound as a bis hydrochloride salt (96 mg). MS 339.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:11]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(C(=O)OC)cc2C1=O
Yield: 83 %

Procedure:
A solution of 8 g of 6-methoxycarbonyl-1-indanone, 8 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 80 ml of 2,2-dimethoxy-propane was boiled under reflux for 28 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 3:1). In addition to 1.3 g of educt, there were obtained 8.5 g (83%) of (RS)-2-(2-buten-1-yl)-6-methoxycarbonyl-1-indanone as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(Cl)Cl.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O.O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)n1cc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
To a mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (500 mg), ethynyl(trimethyl)silane (255 mg), PdCl2(PPh3)2 (46 mg), CuI (12 mg), and CH2Cl2 (10 ml), was added NEt3 (0.2 ml) under ice-bath cooling. The mixture was allowed to warm to 25° C. and stirred for 15 hours. Water and EtOAc were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel; CH2Cl2—MeOH), recrystallized from EtOH, and dried in vacuo to give 5-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-1-isopropyl-2(1H)-pyridone (373 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1.CCOC(C)=O>C(Cl)(Cl)Cl>[Br:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
4-Ethylphenylamine (1.00 g, 7.52 mmol, 1 equiv) was dissolved in chloroform (40 mL) and placed into an ice bath. NBS (1.34 g, 1 equiv) was then added into the solution in small portions. The mixture was warmed to room temperature and stirred for 2 hours. EtOAc (˜200 mL) was added and the mixture was filtered. The filtrate was washed with saturated aqueous K2CO3 (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexanes to afford the title compound as light brown oil (1 g). MS (ES) m/z 200.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1F
Temperature: 80 °C
Yield: 44.2 %

Procedure:
A solution of 4-fluoro-3-methoxyphenylboronic acid (61 mg, 0.36 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.30 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA62 (40 mg, 44% yield). ESI-MS (M+H)+ m/z calcd 302, found 302.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:19])[C:7]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:14]([CH2:13][N:9]1[C:10]([CH3:12])=[CH:11][C:6]([S:1][CH2:2][CH2:3][OH:4])=[C:7]([N+:20]([O-:22])=[O:21])[C:8]1=[O:19])=[O:15])[CH3:18]
Reactant: OCCS
Reactant: CCOC(=O)Cn1c(C)cc(Cl)c([N+](=O)[O-])c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc(SCCO)c([N+](=O)[O-])c1=O

Procedure:
2-Mercaptoethanol (0.168 mL, 2.4 mmol) was added to a stirred mixture of 4-chloro-1-ethyloxycarbonylmethyl-6-methyl-3-nitro-2-pyridinone (the product of Example 3, Step B, 549 mg, 2.0 mmol) and triethylamine (0.613 mL, 4.4 mmol) in ethanol (4 mL) and the mixture was heated to reflux for 15 min. The reaction was cooled and evaporated to a solid which was purified by flash column chromatography on silica gel (eluting with ethyl acetate), to give the title compound as a pale yellow crystalline solid: