Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8](OC)=[O:9])[CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1
Reactant: COC(=O)C[C@@H]1COC(C)(C)O1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)OC[C@@H](CCO)O1
Reaction time: 12 h
Yield: 93.2 %

Procedure:
To a solution of 1.0 g of methyl 2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate in 29 ml of diethyl ether, 110 mg of lithium aluminum hydride was added under cooling with ice, followed by 12 hours' stirring at the same temperature. Sodium sulfate decahydrate was added to the reaction liquid which was then stirred for 30 minutes and filtered with Celite. Distilling the solvent off under reduced pressure, 782 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CC(O)C>[F:11][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1F
Solvent: CC(C)O
Product: COc1cc(CCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 56.3 %

Procedure:
To 5-ethenyl-4-fluoro-2-nitrophenyl methyl ether (1.0 g, 5.1 mmol) in 10 mL of iPrOH was added, piperidine (1.3 g, 15.2 mmol). The mixture was heated to 180° C. 17 min in the microwave. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.81 g, 2.87 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.97 Hz, 1H), 7.01 (d, J=5.86 Hz, 1H), 3.92 (s, 3H), 2.82-2.88 (m, 2H), 2.53-2.58 (m, 2H), 2.40-2.48 (m, 4H), 1.55-1.61 (m, J=5.49, 5.49, 5.49, 5.49 Hz, 4H), 1.40-1.47 (m, 2H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:7]([C:12]2[N:25]([CH3:26])[C:15]3=[N:16][CH:17]=[C:18]([S:20][C:21]([F:24])([F:23])[F:22])[CH:19]=[C:14]3[N:13]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:6]1[C:7]([C:12]2[N:25]([CH3:26])[C:15]3=[N:16][CH:17]=[C:18]([S:20]([C:21]([F:24])([F:22])[F:23])=[O:35])[CH:19]=[C:14]3[N:13]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS(=O)(=O)c1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1-c1nc2cc(S(=O)C(F)(F)F)cnc2n1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a mixture of 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (500 mg) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (429 mg) while ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 50° C. for 2 hours. To the reaction mixture were poured aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfinyl-3H-imidazo[4,5-b]pyridine (353 mg), which is hereinafter referred to as “the present compound 20”.
Reaction SMILES: C(OC(C([C@@H:17]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:18]([NH:20][N:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22](=[O:43])[C@@H:23]([CH3:42])[NH:24][C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])=[O:19])C/C=C/C1SC=CC=1)=O)(C)(C)C.Br>ClCCl.C(O)(=O)C>[CH2:44]([N:21]([C:22](=[O:43])[C@@H:23]([CH3:42])[NH:24][C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[NH:20][C:18](=[O:19])[CH2:17][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:45]([CH3:46])[CH3:47]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C/C=C/c1cccs1)C(=O)OC(C)(C)C
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of 1.04 g of (E)-2(R)-[1(RS)-[(tert.butyloxy)carbonyl]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in 50 ml of dichloromethane was treated with 1.0 ml of a 33% solution of hydrogen bromide in acetic acid at −15° C. The mixture was stirred at this temperature for 1.5 hours and then washed with water and dried over anhydrous magnesium sulfate. Evaporation was followed by addition of hexane and filtration of the resulting precipitate. The precipitate was dried to give 0.665 g of (E)-2(R)-[1(RS)-(carboxy)]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in the form of a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]3[N:12]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[C:11]([CH3:23])=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Diethyl 7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-2,6-dicarboxylate (200 mg, 0.52 mmol), 3-(trifluoromethyl)phenylboronic acid (199 mg, 1.05 mmol, 2 eq.), anhydrous copper(II) acetate (190 mg, 1.05 mmol, 2 eq.) and molecular sieve (500 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (5 ml), pyridine (170 μl, 2.10 mmol, 4 eq.) and triethylamine (146 μl, 1.05 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (32.7 mg, 12% of theory).
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>CN(C)C=O>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][O:6][CH:3]([CH3:5])[CH3:4])=[CH:10][CH:9]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCc1ccc(Br)cc1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
60% Sodium hydride in mineral oil (0.96 g, 24 mmol) was added to a solution of isopropanol (7.59 mL, 36 mmol) in dry N,N-dimethylformamide (30 mL) at 0° to 5° C. under argon atmosphere. After the mixture was stirred for about 25 minutes, 4-bromo-benzyl bromide was added and the mixture stirred at 20° C. for an additional 1 hour. The solution was partitioned between saturated ammonium chloride (50 mL) and diethyl ether (50 mL). The aqueous phase was extracted with diethyl ether (3×20 mL), and the combined organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The crude product was filtered over silica gel to give pure 1-bromo-4-isopropoxymethylbenzene (2.33 g, 85%) as clear oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=O.N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: O=CCCc1ccccc1Cl
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccccc2Cl)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 738 mg (4.4 mmol) of 3-(2-chlorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.37 g (96.5%, yellow oily substance) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]1([C:25]2[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:20]1([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C2CCCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C3CCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 1-cyclopentyl-4-methoxy-benzene via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[CH:6][CH2:5]2)[O:3]C1>[Pd].C(OCC)(=O)C>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1
Reactant: Fc1cccc(C2=CCC3(CC2)OCCO3)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC(c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 43 h
Yield: 53.3 %

Procedure:
First, 39.4 g of 4-(2,3-difluorophenyl)-3-cyclohexenone ethylene ketal, 150 ml of ethyl acetate, and 1.0 g of 10% Pd-C were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 43 hours under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, 225 ml of 1,4-dioxane, 675 ml of water, and 1 g of p-toluenesulfonic acid monohydrate were added to the residue. The mixture was stirred under reflux for 2 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=19:1) and distilled under reduced pressure to obtain 17.5 g of 4-(2,3-difluorophenyl)cyclohexanone (Y: 72%). The compound thus obtained had a purity of 98.9% by GC and a b.p. of 125° C. to 128° C./0.6 mmHg.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9](N)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:7]2[N:8]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1nc2ccccn2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-Bromo-[1,2,4]triazolo[1,5-a]pyridine. A suspension of [1,2,4]triazolo[1,5-a]pyridin-2-amine (0.500 g, 3.73 mmol, obtained from pyridin-2-amine following an analogous procedure as the one described for 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine) in 48% HBr (5 mL) was cooled to 0° C. and slowly treated with a solution of sodium nitrite (0.386 g, 5.59 mmol) in water (2 mL) resulting in a dark brown suspension with brown gas evolution. The mixture was stirred for 1 h. A dark purple solution of copper(I) bromide (0.642 g, 4.47 mmol) in 48% HBr (2 mL) was added and the reaction mixture was stirred overnight at room temperature. The purple suspension was poured into water (15 mL) and the resulting yellow-orange suspension was collected and dried to give an orange solid which was further purified by column chromatography (eluting with 100% dicholomethane) to afford 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (0.455 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.96 (dt, 1H), 7.81-7.91 (m, 1H), 7.68-7.79 (m, 1H), 7.27 (td, J=1.37, 6.93 Hz, 1H); MS (ESI) m/z 197.9 [M]+and 200.1 [M+2]+.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.Cl[CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:39][C:40]4[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=4)[CH:29]=3)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(O)c3)cc1)n2C1CCCCC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(OCc4ccncc4)c3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Ethyl 1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)phenyl]-benzimidazole-5-carboxylate (78 g) obtained in Example 28 was suspended in dimethylformamide (800 ml), and sodium hydride (60% oil, 14 g) was added under ice-cooling. The mixture was stirred for 1 hr at room temperature. After the reaction mixture was ice-cooled, 4-chloromethylpyridine hydrochloride (29 g) was added and the mixture was stirred for 30 min. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture and the precipitated crystals were collected by filtration. The resulting crystals were recrystallized from ethyl alcohol to give the title compound (77 g, yield 82%).
Reaction SMILES: C(SC[C:11]1[C:12](=[O:48])[C:13]([CH2:38][S:39][C:40](=O)C2C=CC=CC=2)=[C:14](CSC(=O)C2C=CC=CC=2)[C:15](=[O:27])[C:16]=1[CH2:17][S:18][C:19](=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)CO>[CH:38]1[S:39][CH:40]=[C:14]2[C:15](=[O:27])[C:16]3[C:11]([C:12](=[O:48])[C:13]=12)=[CH:19][S:18][CH:17]=3
Reactant: O=C1C(CSC(=O)c2ccccc2)=C(CSC(=O)c2ccccc2)C(=O)C(CSC(=O)c2ccccc2)=C1CSC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C1c2cscc2C(=O)c2cscc21
Reaction time: 5 h
Yield: 72.9 %

Procedure:
48.5 g (68.5 millimoles) of 2,3,5,6-tetra-(benzoylthiomethyl)-p-benzoquinone were suspended in 450 ml of ethylene glycol, and 32.8 g (411 millimoles) of 50% strength sodium hydroxide solution were added, while stirring thoroughly. A strong jet of compressed air was then passed through the reaction mixture, and the latter was slowly heated up. At an internal temperature of 70° C., the dark mixture became homogeneous. The internal temperature was increased to 90°-100° C., and thorough stirring was continued at this temperature for 5 hours, while compressed air was continuously passed through. The mixture was cooled, 700 ml of water were added and stirring was continued for a further 0.5 hour, while cooling with ice. The solid material was filtered off under suction and washed with a large amount of water. 11.0 g (73%) of 4,8-dihydrobenzo[1,2-c:4,5-c']dithiophene-4,8-dione of melting point 340° C. were isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: OC[C@H]1CCCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2C)cn1
Yield: 13 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 13% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.61-1.67 (m, 2H), 1.77-1.82 (m, 1H), 2.19 (s, 3H), 2.32-2.36 (m, 1H), 2.43 (s, 3H), 2.55-2.60 (m, 1H), 2.77-2.80 (m, 1H), 3.15 (br t, 1H), 3.25-3.29 (m, 2H), 3.37-3.42 (m, 1H), 4.40 (t, 2H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.63-7.66 (m, 2H), 8.16 (s, 1H), 8.28 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2ccc(Cl)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (120 mg, 0.47 mmol) was added 0.3 mL (4.7 mmol) of iodomethane, 130 mg (2 eq) of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gavel 19 mg (94% yield) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[CH:9]=[C:10]([NH:13][C:14](=[O:34])[C:15]([OH:33])([C:29]([F:32])([F:31])[F:30])[CH2:16][C:17]([C:20]3[C:28]4[O:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH3:18])[CH:11]=[CH:12][C:7]=2[C:6](=[O:35])[O:5][N:4]=1)[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCOCC1>[CH2:1]([C:3]1[C:8]2[CH:9]=[C:10]([NH:13][C:14](=[O:34])[C:15]([OH:33])([C:29]([F:32])([F:31])[F:30])[CH2:16][C:17]([C:20]3[C:28]4[O:27][CH:26]=[CH:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH3:18])[CH:11]=[CH:12][C:7]=2[C:6](=[O:35])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc4c3OCC4)C(F)(F)F)cc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc4ccoc34)C(F)(F)F)cc12
Yield: 87.5 %

Procedure:
930 mg of (±)-4-ethyl-6-[4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-2,3-benzoxazin-1-one and 680 mg of 2,3-dichloro-5,6-dicyano-p-benzoquinone in 90 ml of dioxane are refluxed for 20 hours, mixed with water and suctioned off. After chromatography on silica gel (hexane/ethyl acetate 1.5+1), 810 mg of (±)-4-ethyl-6-[4-(7-benzofuranyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-2,3-benzoxazin-1-one is obtained. Flash point 212° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:58])([CH3:57])[C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]4)=[O:49])([CH3:58])[CH3:57])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methyl-propionyl)-4-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:8](COC(=O)C(C)(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:29]=1[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].ClCCl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.O>[NH2:27][C:28]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:35][C:29]=1[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]
Reactant: CN(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1cccnc1-c1nn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccnc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Yield: 38.8 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-(3-methoxy-pyridin-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (570 mg, 1.36 mmol), 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (570 mg, 1.96 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex in dichloromethane (1:1, 111 mg, 0.136 mmol), tetrahydrofuran (3 ml), acetonitrile (6 ml), water (3 ml), and saturated sodium bicarbonate (3 ml) were combined and irradiated in a microwave reactor for 20 minutes at 120° C. Water was added to the reaction mixture, and this was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-100% [10% methanol in ethyl acetate] in hexanes) to give 205 mg (31%) 2-amino-5-[3-(3-methoxy-pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide. MS: m/z 503.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O.CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
10 g (50.6 mmol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 2 hours with 5.82 g (50.6 mmol) of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallised from ethyl acetate. There is obtained (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 264°-266° C. (b) A solution of 4.0 g (16 mmol) of (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10)-dione in 30 ml of dimethylformamide is treated under an argon atmosphere with 0.57 g (16 mmol) of sodium hydride (60 percent oil dispersion) and stirred at room temperature for 1 hour. 3.02 g (17.5 mmol) of diethylchlorophosphate are added dropwise to the thus-obtained suspension at -20° C. and the mixture is stirred at this temperature for 10 minutes.