Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC2C=CC=CC=2)[CH:17]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2cccc(OCc3ccccc3)c2)[nH]c2cc(Cl)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1c(C(=O)c2cccc(O)c2)[nH]c2cc(Cl)ccc12
Reaction time: 2.5 h
Yield: 24 %

Procedure:
A mixture of methyl[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example 177, 0.37 g, 0.85 mmol) and 10% palladium-charcoal (80 mg) in ethyl acetate-methanol (5:1, 30 ml) was stirred under hydrogen atmosphere for 2.5 h. The mixture was filtered thorough a pad of Celite and the filtrate was concentrated. The solids were washed with dichloromethane (10 ml) to afford 70mg (24%) of the title compound as white solids.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1.[OH-].[Na+]>O1CCCC1>[Br:24][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol)[prepared in Example 116] and n-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (4.54 ml, 27.2 mmol) which stirred at 70° C. in a sealed tube for 4 h. The solution was partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (369 mg, 1.29 mmol, 48% yield) as an orange oil: LCMS (ES) m/e 285, 287 (M, M+2)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A suspended mixture of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.00 g, 3.3 mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (2.00 g, 11.4 mmol) and cesium carbonate (4.00 g, 12.3 mmol) in butanone (50 mL) was refluxed for 5 h under nitrogen. The reaction mixture was cooled to ambient temperature and filtered. The solid was washed with acetone (50 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 30% to 70% gradient of ethyl acetate in hexanes to afford methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (0.88 g, 61%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.27-6.91 (m, 4H), 6.53 (s, 1H), 6.38 (s, 1H), 5.12 (ABq, 2H), 4.81 (ABq 2H), 4.51 (t, J=8.7 Hz, 2H), 3.89 (s, 3H), 3.04-2.91 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.6, 161.9, 161.2, 161.2, 159.2, 145.0, 141.0, 133.6, 132.5, 129.0, 124.1, 120.1, 119.9, 199.1, 108.8, 93.2, 80.5, 72.4, 57.7, 52.3, 37.2, 29.0; MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:42])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC2CCCC2)c2c(=O)[nH]cnc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [9] in Example 15, 7-acetoxy-5-cyclopentyloxy-3,4-dihydroquinazolin-4-one (5 g) was reacted with carbon tetrachloride and triphenylphosphine to give 7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline (5.3 g); NMR Spectrum: (CDCl3) 1.65-1.8 (m, 2H), 1.8-2.05 (m, 4H), 2.1 (m, 2H), 2.4 (s, 3H), 4.95 (m, 1H), 6.78 (d, 1H), 7.35 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 307 and 309.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[O:11][CH3:18])[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(C)ccc(O)c2n1C
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(OC)c2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of 3.50 g (15.5 mmol) of ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate, 4.14 g (30.0 mmol) of potassium carbonate, 4.26 g (30.0 mmol) of potassium iodide and dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice water followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3.21 g of ethyl 1,4-dimethyl-7-methoxy-2-indolecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](I)[CH:3]=1.[CH3:12][C:13]1([CH3:47])[C:37]2[C:17]([CH:18]=[C:19]3[CH:36]=[C:35]4[C:22]([C:23]5[C:28]([C:29]6[C:34]4=[CH:33][CH:32]=[CH:31][CH:30]=6)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:21][C:20]3=2)=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:15]2[CH:16]=[C:17]3[C:37]([C:13]([CH3:47])([CH3:12])[CH:14]=2)=[C:20]2[C:19]([CH:36]=[C:35]4[C:22](=[CH:21]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]4=2)=[CH:18]3)[CH:3]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: O=[N+]([O-])c1ccc(Br)cc1I
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: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2cc(Br)ccc2[N+](=O)[O-])C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 100 °C
Yield: 56.4 %

Procedure:
A mixture of 7.5 g (22.8 mmol) of 4-bromo-2-iodo-1-nitrobenzene, 10.7 g (22.8 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.29 g (0.25 mmol) of tetrakis(triphenylphosphine)palladium, 17 ml of 2M Na2CO3, 40 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 7 g (yield 57%) of yellow product which was recrystallized from toluene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=[C:13]3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=[C:13]3[N:12]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-2-(methoxymethyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (35 mg, 114 μmol) was stirred in abs. dichloromethane (30 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (65 mg, 343 μmol, 3 eq.), anhydrous copper(II) acetate (62.3 mg, 343 μmol, 3 eq.), abs. pyridine (25 μl) and triethylamine (35 mg, 343 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (22 mg, 114 μmol, 1 eq.), anhydrous copper(II) acetate (21 mg, 114 μmol, 1 eq.) and abs. pyridine (829 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (4.4 mg, 9% of theory).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[CH2:10][CH2:9][N:8](C(O)=O)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylic acid tent-butyl ester (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Diethyl ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with diethyl ether, and dried under vacuum. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].C(OC([N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=O)(C)(C)C.[BrH:22]>C(O)(=O)C>[BrH:22].[CH:1]([NH2:3])=[S:2].[C:16]1([NH:11][CH2:12][C:13]([OH:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: Br
Agent: NC=S
Solvent: CC(=O)O
Product: O=C(O)CNc1ccccc1

Procedure:
A solution of 364 mg of t-butoxycarbonyl phenylglycine thiocarboxamide in 4 mL 30% HBr in acetic acid was stirred for 1 hour. The volitile materials were removed under reduced pressure and the crude phenylglycine thiocarboxamide hydrobromide was obtained as a pale solid. The material was utilized without further purification.
Reaction SMILES: [F:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:25]3[S:26][CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:29]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[F:1][CH:2]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:25]3[S:26][CH:27]=[C:28]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:29]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)Cc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(F)Cc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A mixture of ethyl 2-fluoro-3-{4-[(4-{[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}-propanoate (740 mg, 1.31 mmol), tetrahydrofuran (15 mL), methanol (10 mL), water (10 mL) and lithium hydroxide monohydrate (165 mg, 3.92 mmol) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-diisopropyl ether to give the title compound (505 mg, yield 68%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:7]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]([S:15][C:16](C)([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrC(C)C(OCC)=O>>[CH:23]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]([S:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1)C(=O)O
Agent: CCOC(=O)C(C)Br
Product: CC(Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1)C(=O)O

Procedure:
The title compound was prepared in a similar manner to 2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-2-methyl-propionic acid using ethyl 2-bromoproprionate as the alkylating agent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[CH3:80][C@H:81]1[CH2:83][O:82]1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:80][C@@H:81]([OH:82])[CH3:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 82.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (100 mg, 0.164 mmol) was alkylated using (S)-2-methyloxirane (18 mg, 0.329 mmol) DIPEA (86 mg, 0.494 mmol) and ethanol (5 mL) to get 90 mg (81.8%) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=666.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]>C(O)CCC>[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:6]2[C:5]([CH2:9][NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1
Reactant: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCc1ccc(NCc2cnc(Cl)nc2N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,4-Dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine (200 mg, 0.71 mmol) (from Example 38c supra) was dissolved in hot n-butanol (2 mL) (Aldrich). After cooling to room temperature, triethylamine (0.20 mL, 0.92 mmol) (Allied Signal) and (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (198 mg, 0.91 mmol) (from Example 9c supra) were successively added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (20% ethyl acetate in hexanes) to give (±)-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-{2-chloro-5-[(4-ethyl-phenylamino)-methyl]-pyrimidin-4-yl}-amine as a viscous oil. (Yield 272 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9](=[O:27])[CH:10]([O:24][CH2:25][CH3:26])[N:11]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[N:12]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][C:38]([NH2:40])=[O:39]>CN(C=O)C.CCOC(C)=O.O>[C:38]([CH2:37][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[C:14]([CH3:16])=[CH:15][N:11]([CH:10]([O:24][CH2:25][CH3:26])[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=2)=[O:27])[N:12]=1)(=[O:39])[NH2:40]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2O)n1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2OCC(N)=O)n1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide (200 mg) at r.t. in DMF (4 ml) under an argon atmosphere were added cesium carbonate (200 mg) followed by iodoacetamide (114 mg). The mixture was then stirred for 2 h. The mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organics were washed with water. A solid started to precipitate out of the organic phase in the separating funnel. This solid was collected by filtration and washed with cyclohexane to give (RS)-2-[3-(2-carbamoylmethoxy-phenyl)-4-methyl-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (153 mg) as white powder. The organic layer of the filtrate was separated and washed with brine, dried (MgSO4), filtered and concentrated to leave a yellow solid. This was taken in Et2O (5 ml) and 5 drops of methanol were added. The suspension was stirred for 30 min at r.t. and this second crop of product was collected by filtration, washed with Et2O and dried to give more (RS)-2-[3-(2-carbamoylmethoxy-phenyl)-4-methyl-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (31 mg) of an off-white powder. MS 448.5 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O>C(#N)C.[Pt]>[NH2:15][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:1])[CH3:18])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2ccccc12)NS(C)(=O)=O
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2ccccc12)NS(C)(=O)=O
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of N-{1,1-dimethyl-2-[(3-nitroquinolin-4-yl)amino]ethyl}methanesulfonamide (4.0 g, 12 mmol) in acetonitrile (200 mL) was added to a Parr vessel charged with 5% platinum on carbon (0.5 g) and purged with nitrogen. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) and shaken overnight. The reaction was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile and dichloromethane until the filtrate was colorless. The filtrate was concentrated under reduced pressure to provide 3.51 g of N-{2-[(3-aminoquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide as a yellow powder.
Reaction SMILES: [C:1]1([N:7]([C:22](=[O:28])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[N:8]([C:16]2C=CC=C[CH:17]=2)[C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])C=C[CH:4]=[CH:3][CH:2]=1.C1(NNC2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([N:7]([C:22](=[O:28])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[N:8]([CH2:16][CH3:17])[C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)SCC(=O)N(c1ccccc1)N(C(=O)CSC(C)=O)c1ccccc1
Agent: c1ccc(NNc2ccccc2)cc1
Product: CCCCN(C(=O)CSC(C)=O)N(CC)C(=O)CSC(C)=O

Procedure:
Following the procedure for the preparation of Compound 3, the title compound is prepared by substituting N,N-butylamino ethylamine (Lancaster, Windham, N.H.) for N,N'-diphenylhydrazine.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[C:7](NN)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH3:3][C:2](=[N:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)NN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)=NNC(=O)OC(C)(C)C

Procedure:
Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[C:28]2=[O:36])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.54 g, 2.14 mmol) in dichloromethane (20 mL) under nitrogen was added the product from Example 58D (0.71 g, 2.14 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.82 g, 4.29 mmol) and N,N-dimethylpyridin-4-amine (0.013 g, 0.11 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.41 (m, 4H), 7.25-7.33 (m, 8H), 7.16-7.23 (m, 2H), 6.94-7.01 (m, 4H), 4.19 (s, 1H), 4.14 (s, 2H), 3.58 (t, J=4.7 Hz, 2H), 3.49 (t, J=6.5 Hz, 2H), 3.38-3.42 (m, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.36 (t, J=4.8 Hz, 2H), 2.29 (t, J=4.6 Hz, 2H).