Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:28]4[CH2:30][CH2:29]4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(C4CC4)c23)C1
Temperature: 80 °C
Yield: 29 %

Procedure:
A suspension of Intermediate 1 (200 mg) obtained in Example 1, Step A, cyclopropylboronic acid (57 mg, Aldrich), anhydrous potassium phosphate (372 mg, Aldrich), and tricyclohexylphosphonium tetrafluoroborate (33 mg, Aldrich) in toluene (2 ml) is added with palladium acetate (10 mg, Wako Pure Chemical Industries), and the mixture is stirred at 80° C. with heating for 14 hours under a nitrogen gas atmosphere. The reaction mixture is cooled to room temperature, and then added with ethyl acetate (5 ml), and the insoluble matters are removed by filtration through Celite. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (53 mg (predictive yield)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[CH:6][N:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: OCc1cc2cc(Cl)ncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2cc(Cl)ncc2[nH]1
Reaction time: 96 h
Yield: 70.2 %

Procedure:
(5-Chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (225 mg, 1.23 mmol) was dissolved in methylene chloride (25 mL). Manganese dioxide (1.07 g, 12.3 mmol) was added and the reaction mixture was stirred for 4 days. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with hot ethyl acetate. The filtrate was concentrated to give 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (156 mg, 70%) as a tan solid: 1H NMR (300 MHz, Acetone-d6) δ7.43 (1H, s), 7.80 (1H, s), 8.77 (1H, s), 10.08 (1H, s), 11.49 (1H, br s).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc(C2=CCOCC2)n1
Yield: 30.6 %

Procedure:
Under an atmosphere of nitrogen, a solution of 6-bromo-pyridine-2-carboxylic acid (CAN: 21190-87-4, 1 g, 4.9 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 9-d, 1.1 g, 5.4 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 0.08 g, 0.1 mmol) and potassium carbonate (1.37 g, 10 mmol) in water (50 mL) was stirred for 24 h at 100° C. The reaction mixture was extracted with ethyl acetate (50 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (6×50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by prep-HPLC to yield the title compound (0.3 g, 1.5 mmol, 29.5%) as white solid; MS (EI): m/e=206.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)CCCCC1.[C:14]([O:17]CC)(=[O:16])[CH3:15]>[Ru]>[C:14]([O:17][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])[CH3:15]
Reactant: c1ccccc1
Reactant: CCOC(C)=O
Agent: [Ru]
Solvent: OC1CCCCC1
Product: CC(=O)OC1CCCCC1
Reaction time: 28 h

Procedure:
When a benzene solution containing 15 mmols of cyclohexanol, 5 mmols of ethyl acetate and 0.05 mmols of complex 1 was refluxed under argon atmosphere, GC analysis after 28 hrs showed that all of the ethyl acetate disappeared and cyclohexyl acetate was formed as a single product (Table 8, entry 1). 1H NMR and GC-MS of the isolated product were identical to cyclohexyl acetate prepared by refluxing neat acetic anhydride with cyclohexanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:36][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33]
Reactant: CN(CCOCCN)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCOCCNc1c([N+](=O)[O-])cnc2ccccc12)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]=[O:14].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:8]=[C:7]2[CH:13]=[O:14]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL) was added a solution of 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151 mmol, 1.00 eq) in DMF (50 mL) dropwise at 0° C. over a period of 30 min. The mixture was stirred at room temperature for 2 h, then SEM-Cl (26.4 g, 159 mmol, 1.08 eq) was added dropwise and the mixture was stirred at room temperature for another 3 h. Then the mixture was poured into an ice-water mixture (1000 mL) and extracted with EtOAc (300 mL×3), the organic phases were combined, dried over Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc=20:1→10:1) to afford 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (XIX) as a mixture of regioisomers (53.0 g, 151 mmol, 100% yield) as a yellow oil. ESIMS found for C1-4H19BrN2O2Si m/z 355 (M+H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:50])[N:25]([C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1)[C:26]#[C:27][Si](C(C)C)(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:50])[N:25]([C:26]#[CH:27])[C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:42][CH:43]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
TBAF (954 mg, 3.02 mmol) was added to a solution of (4-morpholin-4-yl-phenyl)-[(triisopropylsilanyl)-ethynyl]-carbamic acid tert-butyl ester (600 mg, 1.31 mmol) in THF (10 ml) at 0° C. The mixture was stirred for 1 hour at this temperature and was then warmed up to RT. H2O (15 ml) was added and the organic phase was extracted with Et2O (3×15 ml) and dried over Na2SO4. The solvent was removed under reduced pressure and the desired compound was obtained after purification by column chromatography (PE/AcOEt:80/20 to 75/25). The title compound was obtained as yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:3][CH2:2]1.[O:14]1[CH2:16][C@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:17][C@@H:15]2[CH2:16][O:14]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C(NC1CC1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of N-cyclopropyl-2-hydroxybenzamide (270 mg, 1.52 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (378 mg, 1.68 mmol) and cesium carbonate (645 mg, 1.98 mmol) in DMF (4 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (40% heptane in ethyl acetate) to give the subtitled compound (354 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>C(OCCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:15])[C:12]([Cl:14])=[O:13]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCOCCCC
Product: O=C(Cl)C(=O)c1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 5-chloroindole (20 g, 0.13 mole) and dibutyl ether (230 mL) and cool to 5° C. and slowly add the oxalyl chloride (20.08 g, 0.16 mole) over 15 min while maintaining the temperature between 5° C. and 10° C. Warm to room temperature and stir for 1 hour to give a solid. Cool to 5° C. and stir for 15 minutes, collect the solid by filtration, wash with dibutyl ether, and dry under vacuum to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C(#N)C>[C:37]([O:39][CH2:40][CH2:41][N:13]1[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:12]1[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:38])[CH3:36]
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCn1c(CCCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
In 50 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of the imidazole (101e), followed by addition of 3.2 g (23.2 mmol) of potassium carbonate and 2.9 g (17.4 mmol) of ethyl bromoacetate, and the mixture was heated at 60° C. for 11 hours. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to provide 5.75 g (yield 96%) of (2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-yl)-ethyl acetate (136d) as oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=1.C1C=CC=CC=1>O.CCOCC>[Cl:1][C:15]1[CH:16]=[C:11]([O:10][CH3:9])[CH:12]=[CH:13][C:14]=1[NH:17][C@H:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20]
Reactant: COc1ccc(N[C@H](C(=O)O)C(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(N[C@H](C(=O)O)C(C)C)c(Cl)c1

Procedure:
A mixture of N-chlorosuccinimide (1.17 mmole), m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine (1.23 mmole) and benzene (20 ml) is refluxed under nitrogen for about 60 hours. The reaction is worked up in water/ether. The ether layer is washed with water and brine and dried over sodium sulfate. The crude product is purified by preparatory TLC eluting with 15% ether/hexane to give the m-phenoxybenzyl ester of N-(2-chloro-4-methoxyphenyl)valine, MS m/e 439 (M+, 7.4), 212 (100).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][CH:3]1[CH2:17][CH3:18].[Br:19]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][C:3]1([CH2:17][CH3:18])[Br:19]
Reactant: CCC1Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of (1-oxo-2-ethyl-7-bromo-5-indanyloxy)acetic acid in acetic acid is treated over a 10-minute period with a solution of bromine in acetic acid. The reaction mixture is stirred at ambient temperature for 0.5 hour and poured into water containing sodium bisulfite (1 g.). The (1oxo-2-ethyl-2,7-dibromo-5-indanyloxy)-acetic acid is extracted from the reaction mixture with ether, and the ether solution washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent yields the products as an oil.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:14]([O:6][CH2:7][C@@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@H](CO)N1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 115.1 %

Procedure:
Imidazole (5.24 g, 77 mmols) was added to a CH2Cl2 (85 ml) solution of (5R)-5-(hydroxymethyl)-2-pyrrolidinone (4.03 g, 35 mmols). Then, during cooling with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (7.92 g, 98.7%):
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27][C:23]=3[NH:24][C:25]=2[CH:26]=1.[ClH:39]>CO>[ClH:39].[CH2:31]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([N:3]4[CH:4]=[CH:5][C:6]([C:8]5[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=5)=[CH:7][C:2]4=[O:1])=[CH:26][C:25]=3[NH:24][C:23]=2[CH2:27][CH2:28][CH2:29][NH:30]1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)ccc3c2C1
Agent: Cl
Solvent: CO
Product: O=c1cc(-c2ccc(C(F)(F)F)cn2)ccn1-c1ccc2c3c([nH]c2c1)CCCNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
tert-Butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (30 mg, 0.057 mmol) was treated with 1.25 M HCl in MeOH (5.5 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was partially concentrated and diluted with Et2O. The resulting solids were collected by filtration, washed with Et2O and dried to yield the title compound (13 mg, 51%) as a yellow powder: mp 310-320° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.81 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.08-7.04 (m, 2H), 4.44 (s, 2H), 3.49-3.47 (m, 2H), 3.06-3.04 (m, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 425 [M+H]+; HPLC (Method A) 96.9% (AUC), tR=13.7 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.65 g), 1-phenylpiperazine (1.3 ml) and potassium carbonate (1.2 g) in dimethylformamide (50 ml) was stirred at 60° C. for 1 hr. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (4.4 g). The obtained solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=10:1) to give a pale-brown solid (3.45 g). The obtained solid was crystallized from ethyl acetate and the crystals were recrystallized from a mixture of ethyl acetate, ethanol and hexane to give the title compound (1.4 g) as white crystals, m.p.=135-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([F:1])[CH:7]=1)[CH3:21]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromobiphenyl 13-1 (7.5 gm, 31.8 mmol), ethyl acrylate (4.3 mL), Pd(OAc)2 (0.714 gm, 3.2 mmol), tri-o-tolylphosphine (1.94 gm, 1.5 mmol) and triethylamine (12 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (40 mL). The organic solution was washed with 10% aq. citric acid (20 mL), satd. aq. NaHCO3, and brine (20 mL). The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (95:5 to 90:10 hexanes/EtOAc) to give the acrylate ester 13-2 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1>[Pd].CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CC#Cc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Yield: 88.1 %

Procedure:
A warm solution of 2-(4′-fluorophenyl)-4-[4′-(1-dimethylamino-2-propyn-3-yl)phenyl]thiazole (0.2 g, 0.6 mmol) in abs. EtOH (20 mL) containing a catalytic amount of palladium on activated carbon (5%, 20 mg) is shaked under hydrogen atmosphere (30 psi) for 2 h. After removal of the catalyst by filtration, the filtrate is concentrated to give 2-(4′-fluorophenyl)-4-[4′-(3-N,N-dimethylaminopropyl)phenyl]thiazole as desired product (0.18 g, 89%)
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.II>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: II
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (I2 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 2H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21]
Reactant: O=[N+]([O-])c1cc(Oc2ccnc3ccccc23)ccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Oc2ccnc3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Nitro-4-(quinolin-4-yloxy)-phenol (prepared as described in Example 40, 3.1 g, 11 mmol, 1.0 eq.) was suspended into MeOH (100 mL) and the atmosphere was replaced by argon. The catalyst, 10% Pd/C, was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at balloon pressure at RT until TLC showed reaction done. The Pd/C was filtered, the MeOH removed and the crude was purified by column chromatography (10-100% EtOAc/Hexane to 2% MeOH/EtOAc) to yield 2-amino-4-(quinolin-4-yloxy)-phenol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:33]=[CH:32][N:31](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:33]=[CH:32][NH:31][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(N5CCN(C)CC5)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Yield: 46.4 %

Procedure:
To a solution of N4-(1H-indazol-6-yl)-N2-(4-(4-methylpiperazin-1-yl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (29 mg, 0.049 mmol) in methanol (MeOH) (2 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was then heated at 60° C. for 4 h. before it was concentrated in vacuo. The residue was then acidified with acetic acid (HOAc) (2.0 mL) and purified by HPLC to give the title compound (10 mg). MS 440.2 (M+H) (Compound 13-1).