Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].[CH:23]1(I)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(C=O)C>[CH:23]1([O:20][C:4]2[CH:5]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)[CH:18]=[CH:19][C:3]=2[C:1]#[N:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) and DMF (20 mL) was added NaH (47 mg, 95%, 1.87 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of cyclopentyl iodide (0.26 mL, 2.25 mmol). The reaction was stirred at room temperature for 24 hours. After the reaction, all volatile components were evaporated under vacuum. The residue was purified using silica gel column chromatography, eluting with 25% EtOAc/hexane, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.23 (s, 1H), 7.78 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.6 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=2.0, 8.2 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.56 (dd, J=1.9, 8.6 Hz, 1H), 4.96 (s, 2H), 4.95 (t, J=5.8 Hz, 1H), 1.95-1.55 (m, 8H); MS (ES) m/z: 336 (M+H)+; HPLC purity: 99.15% (220 nm), 99.62% (MaxPlot).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:14]=3[C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[O:16])[CH2:10]2)=[N:6][CH:7]=1.[OH-].[Na+]>C1OCCOC1.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[N:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:14]=3[C:15]([NH:17][C:18]3([C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=4)[CH2:19][CH2:20]3)=[O:16])[CH2:10]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a solution of methyl 4-(1-(2-(3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)cyclopropyl)benzoate (D182) (35 mg, 0.065 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml) 1M NaOH (0.098 ml, 0.098 mmol) was added. The mixture stirred 24 h at room temperature. After solvent evaporation, 1N HCl solution was added up to pH2. The solid precipitate was filtered off and washed with diethylether to afford the title compound (E48) (27 mg)
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[C:23]1([CH3:34])[CH:28]=[CH:27][C:26]([CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[NH2:20][C:19]1[C:14]([C:12]([NH:11][CH2:10][CH2:9][N+:6]([CH3:7])([CH3:8])[CH2:5][CH2:4][CH2:3][NH:2][S:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:34])=[CH:24][CH:25]=2)(=[O:32])=[O:31])=[O:13])=[N:15][C:16]([Cl:22])=[C:17]([NH2:21])[N:18]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: Cc1ccc(CS(=O)(=O)Cl)cc1
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(CS(=O)(=O)NCCC[N+](C)(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1

Procedure:
A solution of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (0.30 g, 0.756 mmol), p-tolyl-methanesulfonyl chloride (0.16 g, 0.76 mmol) and N-methylmorpholine (0.4 mL, 3.64 mmol) in DMF (5 mL) is shaken at RT for 16 h. The solvent is removed in vacuo and the residue is subjected to chromatography (basic alumina; 0-15% methanol in DCM) to yield the title compound. M+ 484.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1C=CC(S(O)(=O)=O)=C[CH:26]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:18][O:19][C:21]([CH3:26])([CH3:20])[O:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc(OCc3ccccc3)cc2)CO1
Temperature: 30 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a suspension of 2-(4-(benzyloxy)phenyl)propane-1,3-diol (2.0 gm, 0.00775 moles) in dry toluene (500 ml), dry acetone (20 ml) and PTSA (1.2 gm, 0.0062 mole) were added and the reaction mixture was stirred for 18 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was washed successively with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 1.47 gm product as white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[S:33][C:34]([CH:37]=[O:38])=[CH:35][N:36]=1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[S:33][C:34]([CH:37]=[O:38])=[CH:35][N:36]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:30])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: O=Cc1cnc(Br)s1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ncc(C=O)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (108 mg, 0.259 mmol), 2-bromo-1,3-thiazole-5-carbaldehyde (74.7 mg, 0.389 mmol), sodium bicarbonate (32.7 mg, 0.389 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol) were stirred at 100° C. in 1,2-dimethoxyethane (DME) (4 mL) under nitrogen for 16 h then cooled to room temperature. A saturated NaHCO3 aqueous solution (1 mL) was added and the resulting mixture was stirred at 100° C. for 4 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM and the organic phase was filtered through celite then concentrated in vacuo to give 1-methylethyl [(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (104 mg, 0.259 mmol, 100%) which was used in the next step without further purification. LCMS (method G): Retention time 0.91 min, [M+H]+=402.0
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>O1CCCC1>[CH:22]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]3[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:13]=[C:14]([CH3:15])[C:3]=23)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(NC3CC3)c12
Temperature: 100 °C

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.7 g, 2.37 mmol) and cyclopropylamine (0.7 g, 73.6 mmol) in tetrahydrofuran (20 mL) was heated under reflux at 100° C. overnight in a sealed stainless tube. The solution was cooled to room temperature, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=93:7) to give N-cyclopropyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine. To a solution of the compound above in ethanol (10 mL), a saturated hydrochloric acid/ethanol solution (10 mL) was added and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/ethyl acetate to give the title compound (0.52 g, 56% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH3:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][C:16]1[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:18]=[CH:19][CH:20]=1)[CH3:2].Cl.[O:29]([NH2:31])[CH3:30].C([O-])(=O)C.[Na+]>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[N:31][O:29][CH3:30])[CH3:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][C:16]1[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=O)ccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=NOC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole (23 mg), methoxylamine hydrochloride (15 mg, 3 eq.), and sodium acetate (15 mg, 3 eq.) in methanol (1 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and aqueous sodium bicarbonate added to pH 9, then extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-[1-(methoxyimino)ethyl]-1H-benzimidazole. 1H NMR (CDCl3): δ 7.94 (d, 1H); 7.73 (dd 1H); 7.73 (dd, 1H); 7.63 (d, 1H); 7.52 (m, 1H); 7.38-7.40 (m, 3H); 7.27 (m, 1H); 6.19 (d, 1H); 4.32 (s, 2H); 3.87-4.10 (m, 5H); 2.30 (s, 3H); 1.22 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([O:9][CH:10]([F:12])[F:11])[N:6]([CH3:13])[N:5]=1)(=[O:3])[NH2:2].S(Cl)([Cl:17])(=O)=O>C(#N)C>[C:1]([C:4]1[C:8]([Cl:17])=[C:7]([O:9][CH:10]([F:12])[F:11])[N:6]([CH3:13])[N:5]=1)(=[O:3])[NH2:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(C(N)=O)cc1OC(F)F
Solvent: CC#N
Product: Cn1nc(C(N)=O)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
23,6 g (0.12 mole) 3-Carbamoyl-5-difluoromethoxy-1-methylpyrazole in 720 ml acetonitrile was treated with 16.7 g (0.12 mole) sulfuryl chloride and the mixture stirred for 10 minutes at room temperature. It was then concentrated and recrystallised from diisopropyl ether/ethyl acetate.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH:1]=[CH2:2])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCN
Solvent: CC#N
Solvent: O
Product: C=CNCc1ccc(Cl)nc1

Procedure:
To a solution of aqueous ethylamine, an appropriate amount of acetonitrile is, added. Then 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise in ice bath. The reaction is monitored by TLC. After completion, the mixture is added large amount of water, extracted by DCM, dried, filtered and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)ethenamine as oil.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[NH:14][CH:15]=[CH:16][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.[H-].[Na+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCCC1.C(OC)(C)(C)C>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:14]2[N:13]3[C:3]4[C:2]5[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=5)[N:6]=[CH:5][C:4]=4[N:11]=[C:12]3[CH:16]=[CH:15]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: c1ccc2c(c1)ncc1nc3cc[nH]n3c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc4cnc5ccccc5c4n32)cc1
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline (1.00 g, 4.80 mmol) in tetrahydrofuran (24 mL), under a nitrogen atmosphere, was chilled in an ice-water bath. The solution was treated with NaH (0.29 g, 7.20 mmol, 60%) in small portions over 2 min. After 10 min, the mixture was treated with p-toluenesulfonyl chloride (1.01 g, 5.28 mmol), and allowed to come to ambient temperature. After 1.5 h the reaction was quenched with slow addition of water (5 mL). The reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was purified by prep. HPLC (100 g silica gel eluted with 1-10% CMA in chloroform) to give a tan foam. The foam was dissolved in methyl tert-butyl ether (25 mL) and filtered through filter paper. The filtrate was concentrated under reduced pressure to yield 0.49 g of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[C:29]([N+:30]([O-:32])=O)=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:29]3[N:30]([OH:32])[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1C(=C(OS(=O)(=O)C(F)(F)F)c1ccncc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of trifluoromethanesulfonic acid 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(pyridin-4-yl)vinyl ester (1.5 g, 3.20 mmol) in ethyl acetate (50 ml ) was added stannous chloride dihydrate (2.89 g, 12.8 mmol) and the reaction mixture was warmed to 50° C. After 1 h, the warm solution was treated with saturated sodium bicarbonate solution (10 ml) and filtered through Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (CH2Cl2-95% CH2Cl2/MeOH gradient) gave 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a tan solid (700 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[C:21]([O:25][C:26]([NH:28][CH:29](P(OC)(OC)=O)[C:30]([O:32][CH3:33])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=[C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:30]([O:32][CH3:33])=[O:31])=[CH:15][CH:14]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc(Br)nc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (480 uL, 3.2 mmol) was added to a mixture of 6-bromo-pyridine-3-carbaldehyde (Aldrich, Cat. #596280) (500 mg, 3 mmol) and methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (Fluka, Cat. #09659) (960 mg, 3.2 mmol) in methylene chloride (5 mL) at r.t. under N2. The reaction was stirred for 2 h. The reaction was partitioned between EtOAc and 1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude methyl 3-(6-bromopyridin-3-yl)-2-[(tert-butoxycarbonyl)amino]acrylate (0.9 g, 93%) as an off white solid. Analytical LCMS (M+H)+: m/z=356.8, 358.9.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:45]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 42 ml of DMF are silylated, under a protective gas, with 3.15 g (20.9 mmol) of tert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RT for 20 h. The reaction mixture is diluted with ethyl acetate, and this mixture is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are exitacted 2× with ethyl acetate, and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1 h. Subsequently, the reaction mixture is partially evaporated and the residue is diluted with ice-cold 10% citric acid solution; this mixture is then extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1) results in the pure title compound: TLC Rf (C)=0,13; tRet (II)=21.7 min.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:19]([C:26]#[N:27])=[N:20][CH:21]=[C:22]([CH2:24][OH:25])[CH:23]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:17][C:18]1[C:19]([C:26]#[N:27])=[N:20][CH:21]=[C:22]([CH2:24][O:25][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=1
Reactant: N#Cc1ncc(CO)cc1Cl
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ncc(COc2ccccc2)cc1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Di-tert-butyl azodicarboxylate (174 mg, 0.76 mmol) was added to a stirred solution of 3-chloro-5-hydroxymethyl-pyridine-2-carbonitrile (71 mg, 0.42 mmol), phenol (79 mg, 0.84 mmol) and triphenylphosphine (199 mg, 0.76 mmol) in anhydrous THF (3.3 mL) at 0° C. The mixture was stirred at 120° C. for 30 minutes under microwave irradiation. Then, the mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-5-phenoxymethyl-pyridine-2-carbonitrile (83 mg, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:44][C:43]2([CH2:47][O:46][CH2:45]2)[CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.Cl[Si](C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][C:43]5([CH2:47][O:46][CH2:45]5)[CH2:44]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CC2(COC2)C1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CC2(COC2)C1
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (222 mg, 0.46 mmol), 2-methyl-2-(6-oxa-2-azaspiro[3.3]heptan-2-yl)propanal (231.17 mg, 1.37 mmol) and pyrrolidine (0.23 mL, 2.73 mmol) in DCM (10 mL) at room temperature was added chloro(trimethyl)silane (0.17 mL, 1.37 mmol). After stirring 2 h, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography to obtain 133 mg of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-(6-oxa-2-azaspiro[3.3]heptan-2-yl)pent-2-enenitrile. MS (pos. ion) m/z: 623 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH2:11][CH2:12]OS(C)(=O)=O)=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][C:9]([CH2:11][CH2:12][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8]
Reactant: C=C(C)CCOS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccccc1
Temperature: 80 °C
Yield: 66.4 %

Procedure:
A mixture of 24.4 g (260 mmol) of phenol, 47.0 g (286 mmol) of 2-methyl-4-methylsulfonyloxy-1-butene, 107 g (780 mmol) of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred and heated at 80° C. for 6 hours, and then it was poured onto 500 ml of ice-water. The resulting mixture was extracted with hexane and the combined extracts were dried (MgSO4) and evaporated in vacuo to give the title compound as an oil (28.0 g, 66% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>CN(C=O)C>[F:16][CH2:17][CH2:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1
Reactant: NCCF
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FCCNc1ccn2c(n1)nc1ccccc12
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.081 mmol, 1.0 equiv), 2-fluoroethylamine hydrochloride (0.012 g, 0.121 mmol, 1.5 equiv) and triethylamine (0.034 ml, 0.242 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 10 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (81%) of T802 as an off-white solid. MS (ESI, Pos.) m/z 331.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Methyl bromoacetate (0.07 ml, 0.78 mmol) was added to 250 mg (0.78 mmol) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide in 4 ml of DMF, stirred at 60° C. for 0.5 hour, and then at room temperature for 20 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAC solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAc to give 196 mg (64%) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester melting at 188-193° C.