Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:13]=[N:14][C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(Cl)[CH3:16])([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([N:13]=[N:14][C:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:16])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)N=NC(C)(Cl)c1ccccc1
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N=NC(C)(OOC(C)(C)C)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of 2.0 grams (.025 moles) of 50% sodium hydroxide in 20 ml. of methanol, cooled to 15° C in a 50 ml. erlenmeyer flask was added 2.77 grams (.0277 moles) of 90% t-butylhydroperoxide slowly and with rapid stirring. After the addition was complete, the reaction was stirred for 10 minutes at 10° C. To the above solution was added 4.05 grams (.02 moles) of 1-t-butylazo-1-phenyl-1-chloroethane dropwise over a 15 minute period holding the temperature at 10° C. After the addition was complete, the reaction was stirred for 30 minutes at 0°-5° C, poured into 150 ml. of ice water and extracted with pentane. The pentane solution was washed with 10% potassium hydroxide solution, water, saturated NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 3.3 grams (65% yield) of crude 1-t-butylazo-1-phenyl-1-(t-butylperoxy)ethane. The infrared spectrum indicated the product was contaminated to a small extent by 1-t-butylazo -1-phenyl-1-methoxyethane which resulted from the chloro compound reacting to a small extent with the methanol solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[S:27])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[OH:26])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][C@@H:37]([CH3:40])[CH2:38]O)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][CH2:36][C@@H:37]([CH3:40])[CH2:38][O:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:16]1[C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:27])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: C[C@@H](CO)CNC(=O)OC(C)(C)C
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC[C@H](C)CNC(=O)OC(C)(C)C)c1
Yield: 81 %

Procedure:
Using a procedure analogous to Example 38-D, N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoyl-amino]pyridine-2-carboxamide and (2R)-3-(t-butoxycarbonyl-amino)-2-methylpropanol gave the desired product as a solid (850 mg, 81%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].CCO.[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(Br)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Yield: 76.3 %

Procedure:
A solution of 477 mg (1.55 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in toluene (13 mL) and EtOH (6.5 mL) was treated with 215 mg (1.71 mg) of cyclohex-1-enylboronic acid and 6.21 mL (12.4 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 179 mg (0.155 mmol) of Pd(PPh3)4, and heated to 80° C. for 17.5 h. The mixture was cooled to RT, diluted with EtOAc (50 mL), and washed with water (2×25 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 365 mg (76%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 6.90 (dd, 1H, J=8.4, 2.4 Hz), 6.84 (d, 1H, J=2.4 Hz), 6.62 (d, 1H, J=8.4 Hz), 5.70-5.66 (m, 1H), 4.03 (br s, 2H), 3.20-3.13 (m, 2H), 2.93-2.87 (m, 2H), 2.83 (s, 6H), 2.24-2.17 (m, 4H), 1.82-1.74 (m, 2H), 1.74-1.66 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C16H24N2O2S, 309.2 (M+H). found 309.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH2:27][CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH2:27][CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CCC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: CCC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)N1CC(C(=O)OC)C1

Procedure:
Reaction of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-one (0.200 g, 0.497 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.113 g, 0.745 mmol), according to reference R and the general procedure for reductive amination gave racemic methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate. Separation of enantiomers was accomplished by SFC chromatography (Column: Chiralpak AD-H (21×250 mm, 5 um); A: Liquid CO2; B: Isopropanol (0.2% DEA); Isocratic: 79:21 (A:B); Flow Rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate and (S)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 501.2; Observed: 502.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[CH:19]=[N:18][N:17](COCC[Si](C)(C)C)[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCCC1.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[NH:1][C:42](=[O:43])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3[nH]c(=O)[nH]c3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (80.0 mg, 0.156 mmol) in tetrahydrofuran (3.0 mL) was treated with N,N-carbonyldiimidazole (50.0 mg, 0.31 mmol) and stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the SEM-protected intermediate which was used without further purification. The crude intermediate was diluted with methylene chloride (4.0 mL) and trifluoroacetic acid (4.0 mL) and stirred at 40° C. for 2 h. The reaction mixture was concentrated, diluted with acetonitrile, adjusted to pH ˜7 with 1 M NaOH, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 13.96 (br s, 1H), 11.03 (br s, 1H), 10.91 (br s, 1H), 7.68 (br s, 1H), 7.22-7.05 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 6.70 (dd, J=8.6, 8.6 Hz, 1H), 6.53-6.39 (m, 1H), 3.46 (s, 3H); LCMS calculated for C20H14F2N5O3 (M+H)+: m/z=410.1. found: 410.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CCCCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperidine-1-carboxylate (0.0454 g, 0.0854 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperidin-4-yl)butyl]benzofuran-3(2H)-one (0.0243 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[N+]=[N-])[CH3:11]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:10]([O:12][C:13]([C@@H:14]1[CH2:6][C@H:5]1[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17])[CH3:11]
Reactant: C=Cc1cccc(F)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Around-bottomed flask was charged with 3-fluorostyrene (13.0 g, 0.107 mol) in anhydrous methylene chloride (130 mL). To this mixture was added rhodium acetate dimer (1.30 g, cat amount). A solution of ethyldiazoacetate (33.28 g, 0.291 mol) in anhydrous methylene chloride (130 mL) was added to the reaction via a syringe pump over 5 h and stirred at room temperature for 1 h in darkness. The reaction mixture was filtered through a plug of celite, which was washed with water followed by brine. The organic layer was dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc/petroleum ether 1:9) gave rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 59%) as a colorless liquid sufficiently pure for the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:8]1[C:3]([CH2:2][S:22][C:20]2[NH:21][C:17]3[CH:16]=[C:15]([C:14]([F:26])([F:25])[F:13])[CH:24]=[CH:23][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.4 g of 2-(chloromethyl)-3-methyl-4-nitropyridine and 10 g of 5-(trifluoromethyl)-2-benzimidazolethiol in 260 ml of abs. acetone was treated with 3 g of finely ground potassium carbonate and stirred at room temperature under argon for 18 hours. 180 ml of acetone were distilled off in a vacuum, whereupon the remaining portion of the reaction mixture was poured on to ice. The crystallized-out product was filtered off and dried at 35° in a drying oven By recrystallization from ethyl acetate/n-hexane there was obtained 2-[[(3-methyl-4-nitro 2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 192°-193°.
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:46]1=[O:63])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:46]1=[O:63])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: O=C(OC1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21)c1ccccc1
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CCc3ccccc3)c3ccc(Cl)cc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-2-oxo-1-phenethylindolin-3-yl benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][CH:14]([F:28])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:26][CH2:25][C:24](=[O:27])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10](=[O:11])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]([F:13])[F:28])[CH:16]=3)[C:22]3[CH2:26][CH2:25][C:24](=[O:27])[C:23]2=3)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (240 mg, 0.974 mmol) in dichloromethane (2 mL) is added dropwise to a solution of 3-(3-(difluoromethyl)phenyl-amino)cyclopent-2-enone (intermediate 5, 217 mg, 0.974 mmol) in dichloromethane (2 mL) and the reaction mixture is heated at reflux for 2 h. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 159 mg; ESI mass spectrum: [(79Br)-M+H]+=433, [(81Br)-M+H]+=435; Retention time HPLC: 0.56 min (X012_S01).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:36])=[C:4]([C:9]2[N:10]=[C:11]([CH:33]3[CH2:35][CH2:34]3)[N:12](COCC[Si](C)(C)C)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]#[N:24])[N:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>CCO>[NH2:1][C:2]1[C:3]([F:36])=[C:4]([C:9]2[N:10]=[C:11]([CH:33]3[CH2:35][CH2:34]3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]#[N:24])[N:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cc(Cl)cc(N)c2F)c1-c1ccnc(NCCC#N)n1
Agent: Cl
Solvent: CCO
Product: N#CCCNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(Cl)cc(N)c2F)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (0.58 g, 1.1 mmol) in EtOH (10 mL) was added concentrated HCl (1 mL). The resulting reaction was maintained at room temperature for 9 hours after which the reaction mixture was concentrated and partitioned between water (60 mL) and EtOAc (250 mL). The layers were separated and the aqueous portion was neutralized with solid NaHCO3, and then extracted with EtOAc (200, 100 mL). The combined organic portions were then extracted with 0.1 M aqueous HCl solution (2×100 mL). The combined acidic aqueous extracts were neutralized with solid NaHCO3 and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine, dried (Na2SO4), and then concentrated to furnish 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (328 mg) as an amber residue which was carried forward without further purification: LCMS (m/z) 398.1 (MH+), tR=0.55 minute.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:31][CH2:30]1>>[ClH:25].[ClH:25].[OH:43][C@H:40]1[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:34][CH2:33]2)[CH2:38][C@@H:39]1[CH3:44]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 14 analogously to the method described in example 1.
Reaction SMILES: F.[C:2]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22][CH2:21]2)=[O:19])=[N:15][CH:16]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[C:2]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]2)=[O:19])=[N:15][CH:16]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Agent: F
Solvent: CC#N
Product: O=C(Nc1ccc(OC(=O)N2CCC(O)CC2)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
hydrofluoric acid (min. 40% in water, 0.50 mL) was added to a stirred solution of 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (364 mg, 0.77 mmol) in acetonitrile. After stirring overnight at room temperature the solvent was evaporated in vacuo. The residue was redissolved in dichloromethane. After addition of triethylamine (1 mL) the solution was filtered over a short pad of silicagel and washed with ethyl acetate:acetone 50:50. Evaporation of the solvent yielded the title compound (180 mg, 68% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH2:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24][CH3:25])=[O:23])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccccc1-n1nc(C2CCCC2)cc1N
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Nc1cc(C2CCCC2)nn1-c1ccccc1C
Temperature: 110 °C
Yield: 58.5 %

Procedure:
A mixture of 3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate B, 400 mg, 1.66 mmol), methyl 2-bromobenzoate (297 mg, 1.38 mmol), cesium carbonate (630 mg, 1.93 mmol), BINAP (87 mg, 0.14 mmol), and Pd2(dba)3 (72 mg, 0.07 mmol) in anhydrous toluene (4 mL) was heated to 110° C. for 16 h under an argon atmosphere. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/Hex (1:8, v/v) as the eluent. The product was obtained as a light yellow oil (303 mg, 58%). ES-MS m/z 376.3 (MH+); HPLC RT (min) 3.94.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]2.C[Si](Cl)(C)C>C(O)CCC>[CH:24]1([NH:23][C:4]2[C:5]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]4)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Temperature: 135 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (145 mg, 0.374 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (60 mg, 0.370 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (50 mg). MS 360.3 (M+H); UV 202.2, 292.7 nm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CS(C)=O>[O:11]=[C:9]([CH3:10])[CH:8]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:12])[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)CC(=O)c1ccccn1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of 3.38 g (20.7 mmol) of 1-(pyridin-2-yl)butane-1,3-dione dissolved in dimethyl sulfoxide was slowly added dropwise to 0.911 g (22.78 mmol) of sodium hydride in 25 ml of dimethyl sulfoxide such that the temperature did not exceed 30° C. The mixture was stirred at 20° C. for another 30 minutes. 3.486 g (22.78 mmol) of methyl bromoacetate in a little dimethyl sulfoxide were then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for a further 4 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was washed repeatedly with water. Drying of the combined organic phases, removal of the solvent under reduced pressure and chromatography of the residue gave 3.48 g of product (71.4% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.CO.[Pd]>[C:1]([C:5]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (20 mg, 0.065 mmol) in 5% AcOH-MeOH (1 mL) was added 10% Pd—C (14 mg) under nitrogen atmosphere. The mixture was stirred under H2 (1 atm) at room temperature for 1 h. The catalyst was removed via filtration through Celite, and the filtrate was concentrated to give tert-butyl 2-tert-butyl-5-aminobenzylcarbamate (E-4), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 6.47 (dd, J=8.5, 2.6 Hz, 1H), 4.61 (br s, 1H), 4.40 (d, J=5.1 Hz, 2H), 4.15 (br s, 2H), 1.39 (s, 9H), 1.29 (s, 9H); HPLC ret. time 2.47 min, 10-100% CH3CN, 5 min gradient; ESI-MS 279.3 m/z (MH+).