Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1>Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Agent: Cl
Product: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alternative solvents for removal of the Boc group include, but are not limited to, MeOH and water, as demonstrated here with EXAMPLE 45: A suspension of tert-butyl 4-[4-(1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (670 mg, 1.55 mmol) in 4 N HCl (aq) (20 mL) was stirred at rt for 18 h. The precipitates were collected by filtration and washed with ether (3×10 mL) to afford (1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine as tri-HCl salt. 1H-NMR (DMSO-d6, 400 MHz): δ=2.63 (m, 2H), 3.30 (m, 2H), 3.79 (m, 2H), 6.52 (s, br, 1H), 7.44 (dd, J=2.0, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 8.18 (d, J=1.2 Hz, 1H), 8.26 (s, 1H), 9.59 (s, 1H). MS (ES+): m/z 332.12 [MH+]. HPLC: tR=0.44 and 1.37 min (ZQ2000, polar—5 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:15][C:16](O)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C(OCC)C>[C:19]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][OH:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCC(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
In 70 mL of ice-cooled diethyl ether was suspended 1.9 g of lithium aluminum hydride, followed by dropwise addition of a solution of 4,4-diphenylbutyric acid (6.0 g) in diethyl ether (50 mL). After completion of dropwise addition, the mixture was refluxed for 2 hours and, then, allowed to cool. To this reaction mixture, 1.9 mL of water, 1.9 mL of 15% aqueous sodium hydroxide, and 5.7 mL of water were added in the order mentioned and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered off and the filtrate was concentrated to provide 5.6 g of the title compound. Yield 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])[C@@H:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:35]=[C:34]([NH:36][CH2:37][CH2:38][CH3:39])[C:33]([CH:40]=O)=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:35]=[C:34]([NH:36][CH2:37][CH2:38][CH3:39])[C:33]([CH2:40][NH:1][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:21])[C@@H:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH3:11])[CH:5]=[CH:6][CH:7]=3)=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CNc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reaction time: 5 h
Yield: 68.4 %

Procedure:
To a solution of (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9, 28 mg) and 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carbaldehyde (E14, 24 mg) in methylene chloride (2 mL), sodium triacetoxyborohydride (28 mg) and acetic acid (50 μL) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 60 to 0% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-(((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methyl)amino)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E18, 33 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6](C(C1C=CC=CC=1)=O)[CH:7]2[C:12]#N.BrC[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[H-].[Na+].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: N#CC1c2cccc(Br)c2C=CN1C(=O)c1ccccc1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1nccc2c(Br)cccc12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
A solution of 5-bromo-2-(phenylcarbonyl)-1,2-dihydro-1-isoquinolinecarbonitrile (D10; 70 g, 206 mmol) and 1,1-dimethylethyl 3-bromopropanoate (Aldrich; 37.9 ml, 227 mmol) in dry, degassed DMF (250 ml) was added dropwise over 40 mins to a suspension of sodium hydride (60%; 24.76 g, 619 mmol) in dry, degassed DMF (750 ml) at −10° C. under nitrogen. The mixture was stirred at −10° C. for 10 mins, then allowed to warm to room temp over 3 h. Water (1500 ml) was cautiously added and the mixture extracted with ethyl acetate (3×500 ml). The combined organic extracts were washed with brine (5×500 ml) and dried (MgSO4). The solvent was evaporated to give a brown oil. The crude intermediate was dissolved in THF (700 ml) and lithium hydroxide (24.71 g, 1032 mmol) in water (100 ml) (note: not all soluble) was added. The mixture was vigorously stirred for 30 h, then stored in the fridge over the weekend. The mixture was partitioned between water (700 ml) and ethyl acetate (3×500 ml) and the combined organic extracts washed with brine (2×500 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica eluting with 5-15% ethyl acetate in isohexane gave the title compound (48.2 g)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=2)[C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=2)=[O:13])=[N:6][CH:7]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>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:21]([C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([O:8][C:5]3[C:4]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=4)=[CH:3][C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:7][N:6]=3)[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: C1CCNC1
Reactant: CNc1nccc(-c2cc(Cl)cnc2Oc2cc(C(=O)Nc3cccc(C(C)C)c3)ccc2C)n1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1nccc(-c2cc(N3CCCC3)cnc2Oc2cc(C(=O)Nc3cccc(C(C)C)c3)ccc2C)n1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared using the procedure of Harris et. al. [Organic Letters 2002, 4 (17), 2885-2888.]: In a N2-flushed sealing tube, 3-[5-Chloro-3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-N-(3-isopropyl-phenyl)-4-methyl-benzamide (100 mg, 0.21 mmol), pyrrolidine (0.022 mL, 0.26 mmol), Pd2(dba)3 (5.1 mg, 0.0055 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (5.2 mg, 0.13 mmol) were combined. The tube was flushed with argon, and 1 M Li(TMS)2 in THF (Aldrich, 0.67 ml) was added. The sealed tube was heated at 70° C. for 20 h. 1 N HCl was added, the mixture was stirred 5 minutes, then saturated aqueous NaHCO3 was added. After extraction, the organic layer was dried over Na2SO4. After concentration, the residue was purified by HPLC (Gilson, acidic mobile phase), desalted by aqueous NaHCO3/EtOAc extraction, and purified by flash chromatography (2:1 to 1:1 hexanes/EtOAc. The resulting solid was triturated with a small amount of t-BuOMe to provide the product. MS m/z=523 [M+H]+. Calc'd for C31H34N6O2: 522.65.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=1[Cl:12].[OH-].[Na+].Cl>C1COCC1>[Cl:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH2:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: C=Cc1ccc(C(=O)OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 70 °C

Procedure:
To solution of 2-chloro-4-vinyl-benzoic acid methyl ester (50 mg, 0.26 mmol) in THF (2 ml) was added 2M NaOH (1 ml). The solution was heated to 70° C. for 1 hour. The reaction was cooled back to room temperature and brought to a pH of ˜3 with 1M HCl. The aqueous solution was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated down under reduced pressure to give 2-chloro-4-vinyl benzoic acid as a white solid. Amount obtained: 40.3 mg (86%). LCMS (M/Z): 183 (M+H); 1H NMR (Chloroform-d) δ: 5.47 (d, J=10.9 Hz, 1 H) 5.93 (s, 1 H) 6.70 (dd, J=17.6, 10.9 Hz, 1 H) 7.38 (dd, J=8.2, 1.8 Hz, 1 H) 7.52 (s, 1 H) 8.02 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[NH:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCOc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of (E)-8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl)quinoline (0.101 g, 0.223 mmol) in DCM (1.0 mL) was added iodosobenzene diacetate (0.0719 g, 0.223 mmol). After stirring at ambient temperature for 5 hours the reaction mixture was partitioned between DCM and aqueous saturated Na2S2O3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 DCM/MeOH) to provide 70 mg (70%) of desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:24])[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h
Yield: 53.9 %

Procedure:
Benzyl 4-hydroxy-1-piperidinecarboxylate (1.0 g, 4.25 mmol), succinic anhydride (0.425 g, 4.25 mmol) and 4-DMAP (52 mg, 0.425 mmol) were dissolved in CHCl3 (10 mL) and stirred for 24 hours. The volatiles were removed in vacuo. Aqueous NaHCO3 (100 mL) was added and the mixture was washed with Et2O (2×50 mL). The aqueous layer was acidified to pH=6 to 7 with 2N HCl and extracted with CH2Cl2 (2×60 mL). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4 and concentrated in vacuo to afford compound 64 (768 mg, 54%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.62 (m, 2H), 1.85 (m, 2H), 2.60-2.70 (m, 4H), 3.38 (m, 2H), 3.74 (m, 2H), 4.97 (m, 1H), 5.12 (s, 2H), 7.35 (m, 5H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH2:44]([O:51][NH:52][C:25]([C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=1)=[O:26])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)O)cc1C2=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)NOCc3ccccc3)cc1C2=O
Temperature: -15 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4,5-diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid (6.14 g) in dry dimethylformamide (1.1 l) and nitrogen at -15° C. was added dropwise N-methylmorpholine (3.71 g) as a solution in dimethylformamide (20 ml) during 5 minutes. Stirring at -15° C. was continued for 40 minutes before the dropwise addition of isobutylchloroformate (2.51 g) as a solution in dimethylformamide (10 ml) over 10 minutes. The mixture was stirred at -15° C. for 45 minutes when a solution of O-benzylhydroxylamine hydrochloride (2.93 g) in dimethylformamide (20 ml) was added dropwise. Stirring was continued for 5 hours at -15° C. and the mixture was then allowed to warm to room temperature. After 16 hours at room temperature, the dark solution was concentrated in vacuo. The gummy residue was triturated with ethyl acetate to yield a bright yellow solid. This was triturated with tetrahydrofuran and the insoluble material then washed with 5% aqueous sodium bicarbonate solution. The insoluble yellow solid was washed with water and dried in vacuo yielding the title compound, m.p. 192°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C@H:9]3[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:5]=2[CH:4]=1.COC1C2[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3CCOC=2C=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: COc1cccc2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CCO2
Product: COc1ccc2c(c1)OCC[C@H]1CNC[C@H]21

Procedure:
The title compound was prepared as the hydrochloride salt as described in Example 272F substituting the product from Example 280E for the product obtained from Example 272E. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.69-1.86 (m, 1H) 1.86-2.03 (m, 1H) 2.03-2.14 (m, 1H) 2.84-3.03 (m, 1H) 3.12-3.27 (m, 1H) 3.35-3.47 (m, 1H) 3.47-3.63 (m, 2H) 3.64-3.76 (m, 4H) 4.31-4.47 (m, 1H) 6.53-6.73 (m, 2H) 7.00 (d, J=8.33 Hz, 1H) 9.26 (s, 2H); MS (DCI+) m/z 220.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=O)[O:9]CC.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([S:28]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[N+:36]([O-])[CH:35]=[CH:34]3)(=[O:30])=[O:29])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([S:28]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37]([O:9][CH3:8])=[N:36][CH:35]=[CH:34]3)(=[O:30])=[O:29])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c[n+]([O-])ccc3c2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nccc2cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 mL of triethylamine and 0.1 mL of ethyl chlorocarbonate were added dropwise with stirring at 0° C. to a methanol (5 mL) solution of 300 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide, and the mixture was then stirred at room temperature for 3 hours. After the completion of reaction, the reaction solvent was distilled off under reduced pressure. To the obtained residue, 20 mL of ethyl acetate was added, and the deposited insoluble matter was removed by filtration. The filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 110 mg of the compound of interest as a white crystal (36%).
Reaction SMILES: [CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[CH3:28]C1C=CC(C(OCC)=O)=C(NC2C(C)=CC3C(C)=CCC(C)(C)C=3C=2)C=1.C(O)C.[OH-].[K+]>O>[CH2:1]([N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]=2[CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C)cc1Nc1cc2c(cc1C)C(C)=CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Temperature: 60 °C
Yield: 92 %

Procedure:
Following previously described General Procedure E, to a solution of ethyl 4-[methyl-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 40, 0.05 g, 0.14 mmol) and 2 mL of absolute ethyl alcohol was added aqueous 5 M KOH (0.3 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2 N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as a dark green solid. PNMR (300 MHz, CDCl3) δ—1.24 (s, 6 H), 2.12 (s, 3 H), 2.14 (s, 3 H), 2.22 (d, 2 H, J=2.4 Hz), 3.32 (s, 3 H), 5.81 (s, 1 H), 6.52 (d, 2 H, J=7.5 Hz), 7.08 (s, 1 H), 7.19 (s, 1 H), 7.92 (d, 2 H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:68]=[CH:67][N:66]([CH2:69][C:70]([CH3:73])([OH:72])[CH3:71])[N:65]=1>>[OH:72][C:70]([CH3:73])([CH3:71])[CH2:69][N:66]1[CH:67]=[CH:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (WO2009127544) (0.11 g, 0.67 mmol) at room temperature and purified by Prep-HPLC to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a trifluoroacetic acid salt: white solid (Yield 62 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:36][Si](C)(C)C)(C)C.[Li+]>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].O1CCCC1>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[CH:11]([N:7]1[C:8]3[C:4](=[CH:3][C:2]([NH2:36])=[CH:10][CH:9]=3)[CH:5]=[CH:6]1)[CH2:12]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Brc1ccc2c(ccn2C2CN3CCC2CC3)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2C2CN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
Compound 69 (95 mg, 0.311 mmol), Tris(dibenzylideneacetone)dipalladium (0) (28.5 mg, 0.031 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 125.9 mg, 0.062 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of Lithium bis(trimethylsilyl)amide (0.993 ml, 0.993 mmol) and mixture refluxed for a period of 45 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 15 minutes. The solution was diluted with ethyl acetate and conc. NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to yield a yellow residue 70 (60 mg, 79.9%). 1H NMR (DMSO-d6) δ 1.22-1.47 (m, 2H), 1.57-1.70 (m, 1H), 1.73-1.90 (2×m, 2H), 2.66-2.84 (2×m, 3H), 2.97-3.04 (m, 1H), 3.09-3.20 (m, 2H), 4.41-4.54 (2×m, 3H), 6.17 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.8, 2.0 Hz), 6.68 (d, 1H, J=2.0 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.50 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 242 (MH+, 100%).
Reaction SMILES: Cl[C:2]1C(=O)N[C:5]([C:9](OCC)=O)=[CH:4][CH:3]=1.C(OC([N:21]([C:29]1[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH:4]1(/[CH:3]=[CH:2]/[C:33]2[N:32]=[CH:31][N:30]=[C:29]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:34]=2)[CH2:5][CH2:9]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ncn1
Reactant: CCOC(=O)c1ccc(Cl)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ncn1

Procedure:
A mixture of [(E)-2-cyclopropylvinyl]boronic acid (1, 1.0 g, 8.93 mmol), tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2, 3.24 g, 9.83 mmol), sodium carbonate (2.84 g, 26.8 mmol), 1,4-dioxane (10 mL) and water (3 mL) in a microwave vial was degassed with argon for 10 minutes. To this mixture 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.73 g, 0.89 mmol) was added and purged with argon for 5 minutes. After sealing, the vial was irradiated in a microwave reactor at 130° C. for 45 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The organics were washed with water (2×10 mL) and saturated brine solution (1×10 mL). The organics were then separated, dried with sodium sulfate, and filtered before concentration to dryness. The crude residue was purified by column chromatography (silica, ethyl acetate/hexanes=25%) to obtain tert-butyl N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3) as a light brown solid. Yield: 370 mg, 16%; MS (ESI) m/z 262.22 [M+1-Boc]+; 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.60 (s, 1H), 7.63 (s, 1H), 6.50 (m, 2H), 1.48 (s, 9H), 0.91 (m, 2H), 0.64 (m, 2H)