Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH:9]=[C:10]([N+:12]([O-])=O)[CH3:11])[C:6](OC)=[C:5]([CH3:17])[C:4]=1[CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.C(#N)C.O>[CH3:11][CH:10]1[CH2:9][C:7]2[C:6](=[C:5]([CH3:17])[C:4]([CH3:18])=[C:3]([OH:2])[CH:8]=2)[NH:12]1
Reactant: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c(C)c1C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(O)cc2c(c1C)NC(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 1,4-dimethoxy-2,3-dimethyl-5-(2-nitro-1-propenyl)benzene (2.51 g, 9.99 mmol) in THF (35 mL) was added lithium aluminum hydride (1.0 g, 26 mmol) under ice-cooling, and the mixture was heated to reflux for 6 hours. Hyflo Super-Cel® (5 g) was added to the reaction mixture, and water (1.5 mL) was added dropwise under ice-cooling. The resulting mixture was suspended in ethyl acetate, filtered, concentrated under the reduced pressure to obtain an oil. This was dissolved in acetonitrile (10 mL), a solution of diammonium cerium (IV) nitrate (10.9 g, 19.9 mmol) in acetonitrile (20 mL) and water (20 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, neutralized with sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the solid. This was dissolved in ethyl acetate, mixed with an aqueous solution of sodium hydrosulfite, shaken, and the precipitated solid was filtered to obtain 0.79 g of 2,3-dihydro-2,6,7-trimethyl-1H-indole-5-ol.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:7]=[N:8][N:9]([OH:11])[CH:10]=1>C(#N)C>[CH3:1][NH:2][C:3](=[O:4])[O:11][N:9]1[CH:10]=[C:6]([Cl:5])[CH:7]=[N:8]1
Reactant: On1cc(Cl)cn1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)On1cc(Cl)cn1
Reaction time: 12 h

Procedure:
8 g of methyl isocyanate, dissolved in 50 g of acetonitrile, are added to 15 g of 4-chloro-1-hydroxypyrazole and 150 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours, after which the reaction mixture is evaporated down and the residue is digested 3 times with a total of 150 g of petroleum ether. 17.8 g (80% of theory) or 4-chloropyrazol-1-yl N-methylcarbamate of melting point 125° C. are obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:19]1[C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:29][C:28](=[O:30])[CH2:27][C@H:19]1[C:20]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A solution of 1.21 g (15.51 mmol) of dimethyl sulfoxide in 5 ml of methylene chloride was added to a solution of 0.98 g (7.72 mmol) of oxalyl chloride in 20 ml of methylene chloride at -50° to -60° C. After 5 minutes, a solution of 2.0 g (7.00 mmol) of (4R)-1-t-butoxycarbonyl-4-hydroxy-N-t-butyl-L-prolinamide (prepared as described in Preparation 5) in 40 ml of methylene chloride was added to the resulting mixture. The mixture was stirred for 15 minutes, after which 3.5 g (35.00 mmol) of triethylamine were added, and the mixture was stirred for a further 5 minutes. The temperature of the reaction mixture was then allowed to rise to room temperature, and the mixture was stirred for a further 1 hour. At the end of this time, the reaction mixture was poured into ice-water and extracted with methylene chloride. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 1.47 g of the title compound as colorless crystals, melting at 147°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:20](=[O:22])[CH3:21])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(OC2CNC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-(4-bromophenoxy)azetidine (207 mg, 0.91 mmol) in CH2Cl2 (10 mL) was added triethylamine (276 mg, 2.73 mmol) and acetic anhydride (186 mg, 1.82 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a yellow oil. The crude product was diluted with ethyl acetate (20 mL), washed with 1N HCl and saturated NaHCO3, dried over sodium sulfate, and concentrated in vacuo to give 1-[3-(4-bromophenoxy)azetidin-1-yl]ethanone (245 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 2H), 6.61 (d, 2H), 4.89 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.17 (m, 1H), 4.03 (m, 1H), 1.90 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:28]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:28])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 5-benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 27) (1.3 g, 4.2 mmol) and sodium acetate (2 g) in acetic acid (10 mL) at 100° C., a solution of the bromine (1.32 g, 8.4 mmol) in acetic acid (10 mL) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at that temperature for 30 min and cooled and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 mL), water (100 mL), brine (100 mL) and dried over Na2SO4. Concentration of the organic layer provided 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (1.61 g, 99%) as white crystalline solid. m/z 392, 394 (MH+), 1H NMR (300 MHz) δ 0.54 (d, 3H), 1.11 (d, 3H), 2.62-2.76 (m, 1H), 2.83 (s, 3H), 4.42 (d, 1H), 4.80 (d, 1H), 6.22 (d, 1H), 7.12-7.42 (m, 5H).
Reaction SMILES: N[C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I:21]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[I:21][C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1N
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1I
Temperature: 25 °C
Yield: 48.4 %

Procedure:
1-tert-Butyl 4-methyl 3-amino-2,5-dimethylterephthalate (0.444 g, 1.59 mmol) was dissolved in THF (10 mL), and the mixture was sparged with nitrogen for 10 minutes. Copper (I) iodide (302 mg, 1.59 mmol) and diiodomethane (0.64 mL, 7.93 mmol) were added followed by isoamyl nitrite (0.63 mL, 4.74 mmol), and the mixture was stirred at reflux for 20 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to provide an oil which was purified by column chromatography (silica gel, 2-10% ethyl acetate in hexanes). The clean fractions were combined and concentrated, and the residue was partitioned between ethyl acetate and 1: I saturated sodium bicarbonate solution: 1 M sodium thiosulfate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford 1-tert-butyl 4-methyl 3-iodo-2,5-dimethylterephthalate (300 mg, 0.769 mmol, 48% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42 (s, 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.31 (s, 3H), 1.59 (s, 9H); GCMS for C15H19IO4: 359 ([M-OCH3]+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH2:34][CH3:35]>N1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:37]([NH:36][CH2:33][CH2:34][CH3:35])=[O:38])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCCN=C=O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
In 10 mL of pyridine, 300 mg (0.62 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 1.58 g (18.6 mmol) of propyl isocyanate was added thereto and the mixture solution was stirred at 50° C. for eight hours. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water, and the organic layer was washed with a saturated sodium chloride solution, dried and concentrated. The residue was triturated with n-hexane:ethyl acetate=1:1, collected by filtration and vacuum dried to obtain 210 mg (64%) of 1-(9-(4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl)-9H-purin-6-yl)-3-propylurea (Table 1, Compound No. 119) as a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>C1COCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (60.83 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (5% MeOH, 95% CHCl3) providing the title compound in 50% yield (75 mg, 0.155 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O.[OH-].[Li+].Cl>CO.O>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoate (80.0 mg, 0.19 mmol) and lithium hydroxide monohydrate (16.0 mg, 0.37 mmol) in methanol (3.0 mL) and water (1.0 mL) was stirred at RT for 4 h. The mixture was adjusted with 1N HCl to pH=5. The volatiles were removed under reduced pressure, and dried in-vacuo to give a crude product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=415.0.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:36][O:37][C:38](=[O:45])[C@@H:39]([C:41]([SH:44])([CH3:43])[CH3:42])[NH2:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:17]([NH:40][C@@H:39]([C:38]([O:37][CH3:36])=[O:45])[C:41]([SH:44])([CH3:43])[CH3:42])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)S
Temperature: 0 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of Nα -Boc-phenylalanine (10.0 in 50 mL of methylene chloride (CH2Cl2) was cooled to -78° C. under an argon atmosphere. To this magnetically-stirred solution was added N-methylmorpholine (NMM) (3.8 g, 37.7 mmol) and isobutylchloroformate (IBCF) (5.15 g, 37.7 mmol). The reaction was allowed to slowly warm to 0° C., and then was maintained at this temperature for 45 minutes. The mixture was then recooled to -78° C., and treated with 3.8 g (37.7 mmol) of NMM and 7.5 g (37.7 mmol) of D-penicillamine methylester hydrochloride. After the reaction had warmed to room temperature and was stirred for 18 hours, it was diluted with 600 mL of ethyl acetate (EtOAc) and washed with 3×175 mL of 0.5 N potassium bisulfate (KHSO4) and 150 mL of a saturated aqueous sodium chloride solution (brine). The organic solution was then dried over anhydrous sodium sulfate (Na2SO 4), filtered, and stripped of all solvent under reduced pressure. The white solid residue title product was obtained in 91% yield (14.07 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH3:2].[N+:14](=[CH2:16])=[N-:15]>C(Cl)Cl.CCOCC>[N+:14](=[CH:16][C:11](=[O:12])[CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])=[N-:15]
Reactant: CCc1ccccc1CCC(=O)Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1ccccc1CCC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A solution of 3-(2-ethylphenyl)propanoyl chloride (crude, 23.8 mmole) in methylene chloride was slowly added to a solution of diazomethane (generated from 15.6 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether (100 ml) cooled in an ice bath. The mixture was then warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (10→20% ethyl acetate/hexanes) to give 1-diazo-4-(2-ethylphenyl)butan-2-one (3.47 g, 72% over 2 steps). 1H NMR (CDCl3) δ 7.1-7.25 (4H, m, phenyl), 5.21 (1H, broad s, diazo), 2.97 (2H, m, CH2 of ethyl), 1.20 (3H, t, CH3). Step 3:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:15]1([CH2:21][O:22][C:23](=[O:41])[NH:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[Cl:40])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([O:22][C:23](=[O:41])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([NH2:14])[CH:3]=2)=[CH:27][C:26]=1[Cl:40])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)OC1(C)C
Product: Nc1cnc(OCC(F)(F)F)c(-c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example C) and N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-carbamic acid phenylmethyl ester (CAN 1218791-42-4) as starting materials; MS (EI) 452.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(=O)(OCC=C)O[CH2:14][CH:15]=[CH2:16]>Cl[Pd]Cl>[CH2:16]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH:15]=[CH2:14]
Reactant: C=CCOC(=O)OCC=C
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl[Pd]Cl
Product: C=CCN1C(C)(C)CC(O)CC1(C)C
Temperature: 110 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
2,2,6,6-tetramethyl-piperidin-4ol (0.5 g, 3.18 mmol), PdCl2 (20 mg, 0.11 mmol) and di-allyl carbonate (5 ml, 36 mmol) are charged, under inert atmosphere, into a 10 ml-flask equipped with a reflux condenser. The reaction mixture is then heated to 110° C. under stirring for about 6 hours. Gas-chromatographic analysis shows that the reaction afforded the desired 1-allyl-2,2,6,6-tetramethyl-piperidin-4ol in 85% yield (calculated on the starting piperidinol) and >98% selectivity.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].C1([O:35][C:36](=O)[NH:37][C:38]2[CH:42]=[C:41]([C:43]3([C:46](C)(C)[O:47][SiH2]C(C)(C)C)[CH2:45][CH2:44]3)[O:40][N:39]=2)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[C:23]([O:22][C:20]([N:18]1[CH2:19][C:12]2[C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:36](=[O:35])[NH:37][C:38]3[CH:42]=[C:41]([C:43]5([CH2:46][OH:47])[CH2:44][CH2:45]5)[O:40][N:39]=3)[CH:2]=[CH:3]4)=[N:16][CH:15]=[N:14][C:13]=2[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(c2cc(NC(=O)Oc3ccccc3)no2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(CO)CC5)on4)c3)c2C1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6 (7H)-carboxylate (2 g, 5.68 mmol) in DMF (50 mL), at 0° C., NaH (0.681 g, 17.0 mmol) and {5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-isoxazol-3-yl}-carbamic acid phenyl ester (3.09 g, 7.95 mmol) are added. After 1 h the reaction is complete. After quenching with water, the organics are extracted with EtOAc and the fractions combined, dried and evaporated. The crude product is dissolved in THF (10 mL) at 0° C. and TBAF (17.0 ml, 17.03 mmol) is added. After 2 h at it the reaction is complete and is quenched with NH4Cl and extracted with EtOAc. The product is separated with FCC eluting with 50:50 heptane:EtOAc to give 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester which is then dissolved in DCM (10 mL) and TFA (10 mL) is added. The reaction is stirred for 20 minutes, the organics are then evaporated and the crude product is taken up in EtOAc and NH4OH (37% in water) is added to free-base the amine. Then the flask is again subjected to vacuum to remove the excess EtOAc. The crude product is then loaded onto a silica gel column and eluted with DCM:MeOH:NH4OH 100:0:0 to 90:9.5:0.5 to give the title compound. MS (ESI) m/z 433.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.25 (s, 1H) 8.65 (d, J=2.02 Hz, 1H) 8.31 (d, J−8.84 Hz, 1H) 8.18 (d, J=3.79 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.18 (dd, J=9.09, 2.27 Hz, 1H) 6.80-6.82 (m, 2H) 4.99 (s, 1H) 4.58-4.67 (m, 4H) 3.66 (d, J=5.81 Hz, 2H) 1.10-1.11 (m, 2H) 1.03-1.04 (m, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.[CH3:17][C:18]1([CH3:34])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.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.C(OCC)(=O)C>[CH3:17][C:18]1([CH3:34])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:19]1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
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: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC1(C)C=C(c2ccccc2O)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a mixture of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol (3.5 g, 15.9 mmol), trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enyl ester (5 g, 17.4 mmol) produced in Example (4a) and 1,2-dimethoxyethane (20 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.79 mmol) and 2N aqueous solution of sodium carbonate (23.9 mL, 47.7 mmol), followed by stirring for 1 hour at an external temperature of 90° C. under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 3.7 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2[nH]c1=O
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (50.3 g, 134.5 mmol) in chloroform (905.2 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (36.65 g, 161.4 mmol). The reaction was poured into 500 mL sat (aq) NaHCO3 and stirred for 15 min. To the resulting slurry was added diatomaceous earth (CELITE®) and the mixture was filtered over CELITE®. The phases were separated and the subsequent CELITE® washes, chloroform (2×400 mL), were used to extract the aqueous layer. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford a brown/red solid. The solid was triturated in 2-propanol (700 mL) and filtered to furnish the title compound (31.4 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.91-11.57 (m, 1H), 7.77 (s, 1H), 7.55 (s, 2H), 7.43 (t, J=4.8 Hz, 3H), 6.87 (s, 2H), 5.17 (s, 2H), 4.06 (d, J=7.0 Hz, 2H), 3.48 (s, 2H), 1.17 (t, J=7.2 Hz, 3H). [M+H]=372.1.