Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])=[O:19])[C:10]([O:12]C)=[O:11])=[O:4].O.[Li+].[OH-].Cl>C1COCC1>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])=[O:19])[C:10]([OH:12])=[O:11])([OH:4])=[O:2]
Reactant: COC(=O)COc1cc(C(=O)OC)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cc(C(=O)O)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
The crude product from step a) is converted in analogy to examples 1b) to 1d) into methyl 3-methoxycarbonylrnethoxy-4-[3-(2-chloro-4-fluorobenzoyl)ureido]-benzoate, of which 50 mg (0.11 mmol) are dissolved in 5 ml of THF, and 1 ml of water is added. To this are added 27 mg (1.1 mmol) of LiOH, and the reaction is stirred at room temperature until the precursor has reacted completely. The reaction is monitored by LC-MS. After completion of the reaction, the mixture is acidified with dilute hydrochloric acid and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4, filtered and concentrated in a rotary evaporator, and the residue obtained in this way is purified in a preparative HPLC system (column: Waters Xterra™ MS C18, 5 μm, 30×100 mm, mobile phases: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 28 mg (0.068 mmol) of the desired product are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.O1CCCC1.[C].[Pd]>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC(O)CC2)cc1

Procedure:
The 4-hydroxy-N-(4-nitrophenyl)piperidine (11.1 g, 50 mmol) obtained in Example 1(1) was dissolved in methanol (100 ml) and tetrahydrofuran (50 ml), and 10% palladium-carbon (8.0 g) was added thereto, followed by stirring at room temperature in an atmosphere of hydrogen gas for 7 hours. After the insoluble material was filtered with Celite, the filtrate was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the precipitate was collected by filtration, thereby obtaining 4-hydroxy-N-(4-aminophenyl)piperidine (9.25 g, 94%) as a reddish-purple solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33](=[N:35]O)[NH2:34])=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]>C(Cl)Cl.CN(C=O)C>[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33]2[N:34]=[C:16]([C:9]3[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[O:18][N:35]=2)=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 408 mg (1.5 mmol) of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid and 1 mL of oxalyl chloride in 5 mL of CH2Cl2 was treated with 5 drops of DMF. The resulting mixture was stirred at rt for 1 h, then concentrated. The crude acid chloride and 291 mg (1.5 mmol) of 4-(carbomethoxy)benzamidoxime were dissolved in 7 mL of 6:1 v/v xylenes/pyridine. The resulting solution was heated at 140° C. for 1 h, then cooled. The mixture was partitioned between 50 mL of 1:1 EtOAc/ether and 50 mL of 1 N HCl. The organic layer was separated, washed with 3×50 mL of 1 N HCl, 50 mL of sat'd NaHCO3, dried and concentrated. Chromatography on a Biotage 40 M cartridge using hexanes (1L), then 20:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 423 mg (65%) of the title compound: 1H NMR (500 Mhz) δ0 3.97 (s, 3H), 7.48 (app s, 5H), 7.92 (s, 1H), 8.18 (app d, J=8.5, 2H), 8.23 (app d, J=8.5, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.S1(CCCC1)(=O)=O.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[K+]>>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:2]3[CH:3]=[C:4]4[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]4=[CH:11][CH:12]=3)=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C1OC(=O)c2cc(Oc3ccc(-c4ccccc4)cc3)ccc21
Reaction time: 5 h

Procedure:
To a solution of 0.66 parts (0.004 mole) of 4-fluorophthalic anhydride in 3 parts of sulfolane, was added 0.68 parts (0.004 mole) of p-phenylphenol and 0.23 parts (0.004 mole) of potassium fluoride. The mixture was heated and maintained at a temperature of about 175°-200°, with stirring for a period of about 5 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].B.C1COCC1.C1COCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]([OH:16])[CH3:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(C)=O)cc([N+](=O)[O-])c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An oven-dried round bottom flask fitted with a magnetic stirring bar was charged with compound methyl 5-nitro-3-acetylbenzoate (0,5 g), prepared in step 1 of Intermediate 13, BH3THF (1 M solution in THF, 5 mol equiv.), and anhydrous THF. After stirring at room temperature for 24 h, H2O (20 mL) was added and the solution was concentrated in vacuo. The residue was taken in H2O (20 mL) and extracted with CHCl3 (3×100 mL). The combined CH2Cl2 extracts were washed with saturated Na2CO3 solution (20 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo to afford product. This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:9][C:3]2[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=2)=[O:23])=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A 3.00 g quantity of 5-chloro-4-hydroxy-2-pyridone was suspended in 100 ml of pyridine. To the suspension was added 5.59 g of 4-benzyloxybenzoyl chloride with stirring at room temperature. The reaction mixture was stirred at 90° C. for 1.5 hours. The solvent was distilled off and ethyl acetate was added to the residue. The mixture was stirred at room temperature overnight. The ethyl acetate layer was concentrated and the residue was subjected to silica gel column chromatography using as an eluent 2% methanol-chloroform, giving 770 mg of the title compound in a yield of 10.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH:30]1[C:34]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)=[N:33][N:32]=[N:31]1>ClC(Cl)C.CN(C=O)C>[NH:33]1[C:34]([C:35]2[CH:36]=[C:37]([NH:41][C:14]([C:11]3([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH:38]=[CH:39][CH:40]=2)=[N:30][N:31]=[N:32]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CC1
Reaction time: 0.67 h
Yield: 70 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (100 mg, 0.41 mmol) in dichloroethane (2.0 mL) were added DMF (2 drops) and pyridine (0.13 g, 1.6 mmol), followed by oxalyl chloride (57 mg, 0.45 mmol). The mixture was stirred for 40 minutes, and 3-(1H-tetrazol-5-yl)-phenylamine was added. The mixture was stirred for 2 hours, and a pink precipitate formed. The mixture was filtered, and the filtrate was washed with 1.0 N aq. HCl and brine, dried over MgSO4, and concentrated to give the title compound in 70% yield. MS (ES+) [M+H]+=387.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][C:27]=2F)[C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:14]2)=[O:12])=[C:5]([CH3:7])[N:6]=1.CC1C(C)=C(C2C(F)=CC(C)=C(C=2)C([N:43]2[CH2:46][CH:45](C3C=CC(C#N)=CC=3)[CH2:44]2)=O)NN=1>>[N:43]1([C:27]2[CH:26]=[CH:25][C:10]([C:11]([N:13]3[CH2:16][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)[CH2:14]3)=[O:12])=[CH:9][C:8]=2[C:4]2[NH:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2F)[nH]1
Reactant: Cc1cc(F)c(-c2[nH]nc(C)c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Product: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2N2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 377, except 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)azetidin-3-yl)benzonitrile (compound 376.2) was used instead of 4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 377.2). m/z (ES+) 412 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:27](Cl)(=[O:29])[CH3:28]>N1C=CC=CC=1.C(Cl)Cl>[C:27]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 1) (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added acetyl chloride (58 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 48 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with NaHCO3 (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (30-60% EtOAc in hexanes) to provide the title compound as a colourless solid (217 mg, 98%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.01 (dm, J=8.0 Hz, 2H), 7.60-7.49 (m, 3H), 7.41 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.58 (pentet, J=6.1 Hz, 1H), 5.16 (d, J=8.0 Hz, 1H), 5.02 (dd, J=5.9, 8.0 Hz, 1H), 2.32 (s, 3H), 2.13 (s, 3H), 1.38 (d, J=6.4 Hz, 3H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:21]([CH2:23][N:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[S:25]([CH3:28])(=[O:27])=[O:26])#[N:22]>CN(C=O)C>[C:21]([CH2:23][N:24]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:31][CH:30]=1)[S:25]([CH3:28])(=[O:27])=[O:26])#[N:22]
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)N(CC#N)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC#N)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 11 from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-cyanomethyl-N-methylsulphonyl-amino)-aniline in DMF.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>C(Cl)Cl>[Cl:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1Cl
Reaction time: 1 h
Yield: 38 %

Procedure:
To a suspension of 4-hydroxy-6-(3-morpholin-4-yl-propoxy)-[1.5]naphthyridine-3-carbonitrile in anhydrous CH2Cl2 (150 ml) was added oxalyl chloride (2.7 ml, 31.8 mmol) and DMF (0.1 ml, 20%) at room temperature under nitrogen. The suspension became a clear dark brown solution. The resulting mixture was stirred for an additional 1 hr. The solvent was removed by rotary evaporation. The residue was dissolved in ice-water mixture, made basic with (NH4OH), and extracted with CH2Cl2. The extracts were washed (brine), dried (Na2SO4), and concentrated to give the title compound (400 mg, 38%). H-NMR δ(DMSO-d6): 1.88 (2H, m), 2.26-2.29 (6H, m), 2.51 (2H, m), 3.49 (2H,m), 4.34 (2H, m), 6.834 (1H, d, C7-H), 8.147 (1H, d, C8-H), 8.711 (1H, s, C2-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:25])[CH3:24])[C@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[O:13][CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].B(O)O.CCCC[N+:45]([CH2:54][CH2:55][CH2:56][CH3:57])(CCCC)CCCC.[F-]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:25])[CH3:24])[C@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:56]3[CH:55]=[CH:54][NH:45][CH:57]=3)[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(-c3cc[nH]c3)cc21
Temperature: 65 °C

Procedure:
To a solution of N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide (0.300 g, 0.58 mmol) and anhydrous THF (5 mL) was added Pd(dppf)Cl2 (0.030 g, 0.03 mmol) and K3PO4 (2.9 mL, 5.80 mmol). To this mixture was added boronic acid (0.310 g, 1.16 mmol) (J. Org. Chem. 1992, 57, 1653) and the reaction mixture was heated to 65° C. overnight under nitrogen with stirring. Reaction was quenched with deionized water and then extracted with ethyl acetate. Organic layers were washed with brine, then dried with MgSO4, filtered, and concentrated in vacuo. The TIPS-protected compound (0.100 g, 0.16 mmol) was dissolved in THF (3 mL) and then 0.1M solution of TBAF in THF (0.32 mL, 0.32 mmol) was added. Reaction mixture was stirred for 2 h, then concentrated in vacuo. Dissolved in ethyl acetate, filtered through silica gel plug, then concentrated in vacuo to give the desired product as an amber oil (130 mg), which is purified by reverse phase prep-HPLC. HRMS (ESI); calcd for C25H27N3O3F2+H1 456.2099, found 456.2092.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:13][C:14]3[C:15]([F:25])=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:12])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11])[C:6]([S:13][C:14]2[C:15]([F:25])=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]1[CH3:12])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Sc2c(C)n(CC(=O)OC(C)(C)C)c3c(F)c(Cl)ccc23)c1F
Reaction time: 1 h
Yield: 112 %

Procedure:
To a stirred solution of compound 4 (140 mg, 0.36 mmol) in DMF (3 mL) under inert atmosphere were added tert-butyl 2-bromoacetate (0.08 mL, 0.54 mmol), Cs2CO3 (238 mg, 0.73 mmol), Bu4NBr (5.9 mg, 0.018 mmol) at RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude compound 5 (200 mg) as a pale green semisolid. 1H NMR (500 MHz, CDCl3): δ 7.61 (t, J=7.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.09 (t, J=8.5 Hz, 1H), 6.90 (t, J=8.5 Hz, 1H), 6.74 (t, J=6.5 Hz, 1H), 4.95 (s, 2H), 4.40 (q, 2H), 2.44 (s, 3H), 1.52 (s, 9H), 1.42 (t, J=7.5 Hz, 3H); LC-MS: 96.7%; 513.6 (M+H2O); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.72 min. 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCOCC1c1cc(F)cc(F)c1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)COC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
The mixture of 3-(3,5-difluorophenyl) dihydro-2H-pyran-4(3H)-one (Preparation X2) (800 mg, 3.77 mmol) and carbonisocyanatidic chloride (557 mg, 5.28 mmol) was heated in a sealed bottle at 55° C. for 1 h and then at 130° C. for 2 h. The mixture was cooled to RT. Partition between EtOAc and saturated NaHCO3 solution. Extracted with EtOAc (×3 times). The combined organic layers was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to give 8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (230 mg, 0.818 mmol, 21.69% yield). LC-MS (M+H)+=282.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.94 (br, s., 1H) 6.85-7.01 (m, 2H) 6.81 (tt, J=8.81, 2.17 Hz, 1H) 4.70 (d, J=15.56 Hz, 1H) 4.49 (dd, J=15.56, 2.14 Hz, 1H) 4.03-4.12 (m, 2H) 3.68 (br. s., 1H)
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:30]1[C:34]2=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]2[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:39][C:38]1[N:37]=[CH:36][N:35]=[C:34]2[N:30]([CH:2]([C:4]3[O:5][C:6](=[O:29])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)(=[O:22])=[O:21])[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:31]=[CH:32][C:33]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1)n1ncc2c(N)ncnc21
Yield: 53.9 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate C9, 90 mg, 0.188 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.8 mg, 0.376 mmol) and K2CO3 (52 mg, 0.376 mmol) in DMF (1 ml) at 80° C. for 2 hrs to give the title compound (54 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]=2[CH:10]=1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)CC1
Yield: 22 %

Procedure:
1.67 g of 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine and 3 g of ethyl piperidine-4-carboxylate are heated at 130° for 3 hours. After cooling, the residue is dissolved in methylene chloride and the solution is worked up in the customary manner. 0.5 g of ethyl 1-[6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine-2-yl]-piperidine-4-carboxylate is obtained.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[NH2:7][CH:8]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)[CH2:10][CH2:9]1>C1C=CC=CC=1.C(N(CC)CC)C.O>[C:1]([NH:7][CH:8]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)[CH2:10][CH2:9]1)(=[O:4])[CH2:2][CH3:3]
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)NC1CCc2cc3c(cc2C1)OCC3

Procedure:
A solution of propionyl chloride in 50 ml of benzene is added dropwise to a solution of 5 g of the compound of Example 2 in 100 ml of benzene and 4.2 ml of triethylamine. After one and a half hours' refluxing, the cooled mixture is diluted with water, separated off after being left to settle and extracted with benzene, and the organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The dry residue is recrystallized in acetonitrile.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([Cl:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:3][C:16]([C:15]1[C:6]([Cl:5])=[C:7]([CH:12]=[CH:13][C:14]=1[Cl:19])[C:8]([O:10][CH3:11])=[O:9])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Yield: 100 %

Procedure:
2 drops of dimethylformamide and 11.90 g (0.1 mol) of thionyl chloride were added to a solution of 5.00 g (0.02 mol) of methyl 2,4-dichloro-3-hydroxycarbonylbenzoate and 50 ml of dry toluene. The solution was heated under reflux for 4 hours. Removal of the solvent by distillation gave 5.35 g of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[C:9]3[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (1.90 g, 7.30 mmol), iron powder (4.10 g, 73.4 mmol), and ammonium chloride (0.200 g, 3.65 mmol) were suspended in a 4:1 solution of ethanol/H2O. The mixture was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and filtered through a plug of silica gel. The silica gel was rinsing with triethylamine/ethyl acetate (1/4) and combined filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.78), 4.34 (t, 2H, J=6.78), 5.73 (s, 2H), 6.13 (m, 1H), 6.66 (m, 1H), 7.01 (m, 1H), 8.05 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.