Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH3:8])[NH:6][CH3:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH3:8])[N:6]([C:10](=[O:12])[CH3:11])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@@H](C)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)N(C)C(C)=O
Reaction time: 24 h

Procedure:
In 300 ml of chloroform was dissolved 33.7 g (0.22 mol) of N-methyl-L-alanine methyl ester hydrochloride, followed by addition of 65 ml of acetic anhydride and 110 ml of triethylamine. The mixture was allowed to stand at room temperature for 24 hours and, after the excess acetic anhydride was decomposed with water, the solution was neutralized with sodium bicarbonate. The chloroform layer was separated and the water layer was extracted with ethyl acetate (120 ml×5). The chloroform and ethyl acetate layers were combined and concentrated under reduced pressure. The brown-colored oily residue was dissolved in chloroform and washed with an aqueous solution of sodium hydrogen carbonate, followed by concentration under reduced pressure. By the above procedure was obtained 31.8 g of N-acetyl-N-methyl-L-alanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:42][CH2:41][CH2:40][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[S:31])=[CH:18][CH:17]=1
Reactant: NCCN1CCCCC1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCN4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 2-(1-piperidinyl)ethylamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (35 mg, yield 45%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C:33]([NH2:37])([CH3:36])[CH2:34][CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C:33]([CH3:36])([CH3:32])[CH2:34][CH3:35])=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 8 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 1,1-dimethylpropylamine (1 ml) for 40 h at 60° C. and for 43 h at 110° C. under nitrogen. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography using from ethyl acetate/heptane 1:2 as eluent followed recrystallisation from ethyl acetate/heptane 1:2 to give 25 mg (8%) of the title compound. Mp 205-207° C. 1H NMR (200 MHz, CDCl3): δ=0.98 (t, 3H), 1.54 (s, 6H), 1.68 (q, 2H), 7.10 (s, 2H), 7.53 (d, 2H), 7.60 (s, 1H), 7.81 (d, 2H); EI SP/MS: 539 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:20]([C:19]1[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1c(O)ccc2c1CC(CO)O2
Reaction time: 48 h
Yield: 87.2 %

Procedure:
5-Benzyloxy-4-tert-butyl-2-formylbenzofuran (5.0 g, 16 mmol) was dissolved in a 25:1 mixed solution (260 ml) of ethyl acetate and acetic acid. After adding 10% Pd on carbon (5.0 g), the solution was stirred under a hydrogen atmosphere for 48 h. After filtering off the Pd on carbon, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was subjected to silica gel chromatography and eluted with a solvent system consisting of a 4:1 mixture of hexane and ethyl acetate to afford 4-tert-butyl-5-hydroxy-2-hydroxymethyl-2,3-dihydrobenzofuran [3.1 g (yield, 87%)] as a colorless oil. Mass 222(M+), 207, 57
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N:5]1([CH2:11][C:12]2[CH:26]=[CH:25][C:15]3[NH:16][C:17]([C:19]4[C:23]([NH2:24])=[CH:22][NH:21][N:20]=4)=[N:18][C:14]=3[CH:13]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:5]1([CH2:11][C:12]2[CH:26]=[CH:25][C:15]3[NH:16][C:17]([C:19]4[C:23]([NH:24][C:1]([N:27]5[CH2:32][CH2:31][S:30][CH2:29][CH2:28]5)=[O:2])=[CH:22][NH:21][N:20]=4)=[N:18][C:14]=3[CH:13]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: C1CSCCN1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (20% in toluene) (0.3 ml) was added at 0° C. to a solution of 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol) in a mixture of toluene/DCM (1:1). The reaction was stirred at ambient temperature for 1 hour then the excess phosgene was blown off by a stream of nitrogen. Thiomorpholine (35 mg, 0.33 mmol) was added and the reaction was stirred at ambient temperature for 1 hour then at 60° C. for 1 hour. The mixture was then concentrated in vacuo and the residue purified by preparative LC/MS to give thiomorpholine-4-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (LC/MS Polar: Rt 2.58, [M+H]+428).
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=O)[CH2:15]Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:18][C:19]([NH2:21])=[S:20].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:21][C:19]1[S:20][CH:15]=[C:14]([C:8](=[N:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:18]=1
Reactant: CCCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 52.1 %

Procedure:
Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.), sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.), were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.7 g.), mp. 86° to 88° C.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1(Cl)[NH:12][C:11]([Cl:13])=[CH:10][S:9]1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:15][NH2:16]>>[CH:1]([N:4]([NH:16][CH3:15])[S:5]([C:8]1[S:9][CH:10]=[C:11]([Cl:13])[N:12]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reactant: CN
Product: CNN(C(C)C)S(=O)(=O)c1nc(Cl)cs1
Yield: 78 %

Procedure:
In analogy to Example 5, the N-isopropyl-2-N-methylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-isopropyl-2,4-dichlorothiazole-sulphonamide from Example 3 with 30% strength aqueous methylamine solution. Following recrystallization from toluene, the product of m.p. 187-8° C. was obtained in a yield of 78% of the theoretical yield.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(I)ccc1C(=O)O
Product: COc1cc(I)ccc1C(=O)Cl

Procedure:
A mixture of 4-iodo-2-methoxybenzoic acid (750 mg) and thionyl chloride (7 ml) was stirred at reflux for 15min and then evaporated to give 4-iodo-2-methoxybenzoyl chloride. A solution of Intermediate 6 (629 mg) in THF (30 ml) was treated with a solution of sodium hydroxide (227 mg) in water (10 ml), followed by the 4-iodo-2-methoxybenzoyl chloride, and the mixture stirred at 23° under nitrogen for 24 h. 5M-Hydrochloric acid (1.5 ml) was added, followed by aqueous saturated sodium bicarbonate (10 ml), and the mixture evaporated. The residue was treated with water (50 ml), extracted with ethyl acetate (10×100 ml), and the combined, dried organic extracts were evaporated. The residue was adsorbed from hot ethanol (ca. 40 ml) onto silica gel (Merck 7734, 10 ml), and purified by FCC eluting with System A (945:50:5) to give a solid (780 mg). Crystallisation from ethanol (10 ml) gave the impure title compound, a portion of which (102 mg) was recrystallised from ethanol to give the pure title compound as fine white crystals (37 mg), m.p. 168°-170°.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:17]2[C@H:13]([NH:14][O:15][CH2:16]2)[CH2:12][C@H:11]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1.[C:26]([O:34][C@@H:35]1[C@@H]2[C@@H](NOC2)C[C@H]1OCC1C=CC=CC=1)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[O-].[Na+].C(=O)([O-])[OH:55].[Na+].ClC(OOCC1C=CC=CC=1)=O>CO>[CH2:19]([O:18][C@@H:11]1[CH2:12][C@@H:13]2[N:14]([C:35]([O:34][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:55])[O:15][CH2:16][C@@H:17]2[C@H:10]1[OH:9])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])O
Reactant: O=C(O[C@@H]1[C@@H]2CON[C@@H]2C[C@H]1OCc1ccccc1)c1ccccc1
Reactant: O=C(O[C@@H]1[C@H]2CON[C@H]2C[C@H]1OCc1ccccc1)c1ccccc1
Agent: C[O-]
Agent: O=C(Cl)OOCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1OC[C@@H]2[C@@H](O)[C@H](OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
The compound (4.08 g, 12.0 mmol) synthesized in Example 6 (6 g) was dissolved in methanol (40 mL) and sodium methoxide (696 μL, 3.61 mmol) was added thereto, followed by stirring of the mixture at room temperature for 2 hours. After Dowex 50W×8 was added thereto until the reaction mixture became neutral and it was filtered, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (40 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL) and benzyloxy chloroformate (2.4 mL, 16.8 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at the same temperature for 1 hour and 30 minutes. The organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 2:1-1:1, V/V) to obtain the desired title compound (789 mg, yield 18%) as a pale yellow solid and its diastereomer (1.62 g, yield 36%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reaction time: 48 h
Yield: 44.8 %

Procedure:
A solution of 4-bromo-2-methoxyaniline (8.096 g, 40.04 mmol) in dichloromethane (100 mL) was treated with triethylamine (6.06 g, 60.06 mmol), then hydrocinnamoyl chloride (7.08 g, 42.04 mmol). The reaction mixture was stirred for 48 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added. The precipitate was filtered, and the filtrate was evaporated to a solid under reduced pressure. The solid was dissolved in ethyl acetate, and washed with 5 N hydrochloric acid solution, 5 N sodium hydroxide solution, water and brine. The crude material (two spots by thin layer chromatography) was triturated with methanol. The un-dissolved solid was filtered to give 6 g (50%) of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 7.92-7.90 (m, 1H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 7.09-7.07 (m, 1H), 3.83 (s, 3H), 2.90-2.86 (m, 2H), 2.72-2.69 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.491 min (97%).
Reaction SMILES: [H-].[Na+].[N+](C1[CH:11]=[CH:10][C:9]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])=[CH:8]C=1)([O-])=O.C1(O)CCC1.O>O1CCCC1>[CH:9]1([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])[CH2:10][CH2:11][CH2:8]1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCC2)CC1
Reaction time: 0.08 h
Yield: 13.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 10 mg, 0.25 mmol) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (Example 123; 60 mg, 0.13 mmol) in anhydrous tetrahydrofuran (1 mL) under argon. The mixture was stirred for 5 min and then cyclobutanol (11 μL, 0.14 mmol) was added and the mixture was stirred at room temperature for 7 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a Silicycle 4 g column, eluting with 0-4% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclobutyl ester (7 mg, 14%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:40](=[O:41])[CH2:39][CH2:38][N:37]([CH2:43][CH2:44][OH:45])[C:35](=[O:36])[O:34][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00013 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000163 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.000163 mol), N,N-diisopropylethylamine (0.031 g, 0.00024 mol) and 1-hydroxy-7-azabenzotriazole (0.018 g, 0.00013 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.050 g, 0.000083 mol).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.O>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
A stirred solution of di-tert-butyl malonate (1.5 mL, 6.70 mmol) in N,N-dimethylformamide (15 mL) at 0° C. under argon was treated portionwise over 10 minutes with sodium hydride (276 mg of 60% oil dispersion, 6.90 mmol) and stirred at 0° C. for 15 minutes before allowing to warm to room temperature over 1 hour. A white precipitate was produced. The stirred mixture was cooled to 0° C. and treated with a solution of 4-fluoro-3-nitrotoluene (1.0 g, 6.45 mmol) in N,N-dimethylformamide (2 mL) and a deep purple colour was immediately formed. This mixture was stirred at room temperature for 28 hours then heated at 70° C. for 6 hours. The mixture was cooled, then diluted with water (100 mL) and extracted with Et2O (2×50 mL). The combined extract was washed with water (70 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with toluene to afford the title compound as a yellow oil (660 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=[O:29])C.[Na+].C(OO)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([O:29][CH2:9]2)[CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC1(CC)C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(CC2(c3cccc(Cl)c3)CO2)C(=O)c2ccccc2C1=O
Yield: 149.1 %

Procedure:
To the mixture of 1.62 g of 2-[2-(3-chlorophenyl) propen 3-yl]-2-ethylindan-1,3-dione, 0.34 g of sodium acetate trihydrate and 10 ml of chloroform was added-2.85 g of 40% peracetic acid. After refluxing for 3 hours, excess peroxide was decomposed with 10% sodium thiosulfate aqueous solution, and the organic layer was washed with water, neutralized with a saturated sodium bicarbonate aqueous solution, washed with water and with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to obtain 1.27 g of the compound No. 53 shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:28][C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OCC(=O)N5CCOCC5)cc4c3n21
Temperature: 75 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and 2-bromo-1-morpholin-4-yl-ethanone (462 mg, 2.03 mmol). After stirring overnight at 75° C., the brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 272 mg of the title compound as an off-white solid, mp 226-228° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH2:22][CH3:23])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OC(C)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Yield: 80 %

Procedure:
To a solution of 2-(4-acetamidophenoxy)propionic acid (0.5 g, 2.2 mmol) in ethanol (10 mL) is added a drop of concentrated sulfuric acid and refluxed for 4 hours. The reaction is concentrated to dryness to give a residue. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is collected, dried (MgSO4), and concentrated to give ethyl 2-(4-acetamidophenoxy)propanoate (0.44 g) (yield 80%): 1H NMR (CDCL3) delta 1.27 (t, J=7.0 Hz, 3H), 1.60 (d, J=7.0 Hz, 3H), 4.25 (q, J=7.0 Hz, 2H), 4.76 (q, J=7.0 Hz, 1H), 6.84 and 7.46 (dd, J=9.0 Hz, 4H), and 8.02 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2.[I:24]I>ClC1C=CC=CC=1>[I-:24].[F:13][C:14]1[CH:23]=[CH:22][C:21]2[N+:20]3[CH:12]=[C:7]4[CH:6]=[CH:5][C:4]5[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=5[N:8]4[C:19]=3[CH:18]=[CH:17][C:16]=2[CH:15]=1
Reactant: II
Reactant: Fc1ccc2ncccc2c1
Reactant: Cc1ccc2cc(F)ccc2n1
Solvent: Clc1ccccc1
Product: Fc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Product: [I-]

Procedure:
A mixture of 16.1 g. of 6-fluoroquinaldine, 58.9 g. of 6-fluoroquinoline, 70 ml. of chlorobenzene and 50.8 g. of iodine is stirred at 20°-25° C. for 1 hour, then heated at 95°-100° C. for 4 days. The precipitate is collected and suspended in 300 ml. of methanol. The methanol suspension is treated with 17 ml. of 85% hydrazine hydrate and the resulting solid 3,10-difluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. >360° C., after crystallization from methanol.