Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>CC(O)(C)C.CC1CCCO1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13]3([C:14]2=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=1
Reactant: BrCCOCCBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CC(C)(C)O
Product: O=C1c2cc(Br)ccc2CC12CCOCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.2 %

Procedure:
A solution of potassium tert-butoxide (3.94 g, 35.1 mmol) in t-BuOH (35 mL) was added dropwise over 15 min to a solution of 6-bromo-1-indanone (3.53 g, 16.73 mmol) in 2-methyl-tetrahydrofuran (350 mL) at r.t. under a nitrogen atmosphere. After 15 min bis(2-bromoethyl)ether (2.102 mL, 16.73 mmol) was added and the resulting mixture was stirred at r.t. for 5 h. Potassium tert-butoxide (0.938 g, 8.36 mmol) was added and the mixture was stirred at r.t. overnight. The mixture was quenched with saturated aq. NH4Cl (150 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL) and Et2O (50 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue was taken up in DCM, concentrated onto silica gel and purified on a silica gel column eluted with 0-40% EtOAc in heptane to give 1.14 g (24% yield) of the title compound; MS (ES+) m/z 281 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][N:11]([C:23]([C:22]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=4[F:20])=[O:24])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: Clc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)c1
Reaction time: 6 h

Procedure:
7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 μL, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone. ESI-MS m/z calc. 426.1. found 427.5 (M+1)+. Retention time: 2.12 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m, 2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:14]=1
Reactant: CSc1nccc(I)n1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CSc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (35.7 g, 142 mmol) and 1-ethynyl-4-fluorobenzene (17.0 g, 142 mmol) were added to triethylamine (200 mL) at room temperature. To the resulting solution were added dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol) and copper iodide (1.0 g, 5.2 mmol). Then the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remove excess triethylamine. The residue was partitioned between water (400 mL) and dichloromethane (400 mL). The organic layer was washed with water (2×400 mL) and dried (MgSO4), and the solvent was evaporated under reduced pressure to give an oil. Flash chromatographic purification on silica gel with 0 to 50% ethyl acetate/hexanes as eluant gave 18.3 g of the title compound as a light brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=O>CC(O)=O>[N+:23]([C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[N:10]=2)[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccn3c(n2)nc2ccccc23)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask equipped with a magnetic stir bar, containing AcOH (20 mL) was placed 1H-benzoimidazol-2-amine (1 g, 7.5 mmol, 1.0 equiv). To this solution was added (E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one (1.7 g, 7.5 mmol, 1 equiv) and the reaction was allowed to stir at 120° C. for 24 h. After the reaction was complete by LCMS, the solvent was completely evaporated and the reaction mixture was neutralized with NaHCO3 solution. Yellow solid was filtered and washed with DCM to give the nitro compound DHK-7-16 0.83 g (39%). MS (ESI, Pos.) m/z: 291.1 M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[CH3:2].Cl.[NH2:17]O>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:8][N:17]=1)=[O:15])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccco2)on1
Temperature: 85 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
After a suspension of 10.0 g of 4-furan-2-yl-2,4-dioxo-butyric ethyl ester prepared above and hydroxylamine hydrochloride was stirred at 85° C. for 2 hrs, the solvent was removed under reduced pressure. The concentrate was dissolved in a mixture of methylene chloride and distilled water, followed by separating the organic layer. The organic layer was dried over anhydrous sodium sulfate, filtered through a silica gel layer, and concentrated in vacuo to produce a yield of 8.01 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (Yield 77%). The concentrate was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:33]=[CH:32][C:22]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]1=2>C(O)(C(F)(F)F)=O>[NH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=3[N:9]=2)=[CH:33][CH:32]=1
Reactant: CN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2nc(-c3ccc(CN)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 112.6 %

Procedure:
tert-Butyl 4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (40 mg, 0.090 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as a white solid (35 mg, 85% yield). 1H-NMR (500 MHz, MeOD) δ 7.54 (1H, s), 7.36 (2H, d), 7.31 (2H, d), 7.25-7.29 (3H, m), 7.18-7.23 (2H, m), 4.95 (2H, s), 4.07 (2H, s), 3.41 (3H, s). LCMS (Method D): RT=0.69 min, M+H+=346.20.
Reaction SMILES: OCCN=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH2:25])[CH3:21].C(O)(=O)C>C(O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24](=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[NH2:25])[CH3:21]
Reactant: CCOC(CN)OCC
Reactant: Nc1cnccc1C(=NCCO)c1ccccc1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)C(N)=C(c1ccncc1N)c1ccccc1Cl
Yield: 54.1 %

Procedure:
A solution of 2-hydroxy-N-[α-(3-amino-4-pyridyl)-2-chlorobenzylidene]-ethylamine (6.28 g, 22 mmol), aminoacetaldehyde diethyl acetal (10 g, 75.1 mmol) and acetic acid (3 ml) in ethanol (150 ml) was refluxed for 30 hours. The mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methanol: chloroform=1:9) to give the title compound (4.27 g, 11.9 mmol) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(O)CCCCCl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: C=CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
This compound was prepared as described in Example 1 starting with 7-Allyl-3-ethyl-xanthine and 1-chloro-5-hydroxy-5-methylhexane and recrystallizing the final product from diisopropyl ether with addition of some ethyl acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: COCc1cocn1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(COC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methoxymethyl-oxazole (110 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (68 mg), giving the product (107 mg) as a yellow gum.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[O:22][CH2:23][O:24][CH3:25])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:8]=3[N:9]=2)=[C:13]([O:22][CH2:23][O:24][CH3:25])[CH:14]=1
Reactant: NCc1ccccn1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
A mixture of 6 (612 mg, 1.5 mmol), 2-(aminomethyl)pyridine (1.08 g, 10 mmol), and Na2CO3 (excess) in CH3CN (30 mL) was stirred overnight at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Water (20 mL) was added to the residue, which was extracted with ethyl acetate (20 mL) three times. The combined organic layer was washed with brine and water, dried over MgSO4, and evaporated. The resulting oily material was purified by silica gel column chromatography (CHCl3-ethyl acetate) to afford 7 as pale yellow oil (112 mg, 17%): 1H-NMR (500 MHz, CDCl3) δ53.56 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 4.30 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.15 (dd, 1H, J=7.5, 5.0 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.55 (d, 1H, J=5.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Li+].[CH3:21][Si:22]([CH3:46])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:23]1[CH2:28][CH:27]2[C:25]([CH2:29][OH:30])([O:26]2)[CH:24]1[CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]2[C:25]([OH:26])([CH2:29][OH:30])[CH:24]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:23]([Si:22]([CH3:46])([CH3:21])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28]2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: C[Si](C)(c1ccccc1)C1CC2OC2(CO)C1COCc1ccccc1
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(c1ccccc1)C1CC(n2cnc3c(OCc4ccccc4)nc(N)nc32)C(O)(CO)C1COCc1ccccc1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
To a 1-L 3-necked round bottomed flask equipped with a mechanical stirrer and a thermometer, was charged 2-amino-6-benzyloxypurine (24 g, 0.1 moles), lithium hydride (0.48 g, 0.06 moles) and DMF (40 mL). The mixture was heated at 60° C. for about 1 hour under an atmosphere of argon. 77 (60 g, 0.1 moles) in 20 mL DMF was added. The reaction temperature was heated at 105° C. for 5 hours, cooled to room temperature and diluted with EtOAc (600 mL). The organic layer was washed with brine (300 mL), 1 M citric acid (150 mL), and NaHCO3 solution (100 mL). The organic layer was concentrated in vacuo to furnish crude title product (60 g) as an oil. It was crystallized from EtOAc and hexane to give 23 g of the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1cccs1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 9.1 g (30 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 87, part B) and 50 mL (50 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 7.7 g (65% of yield) of 4-(5-methoxy-1-thiophen-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[C:5]1[CH:10]2[C:11]([CH3:13])([CH3:12])[C:7]([CH3:14])([CH2:8][CH2:9]2)[C:6]1=[O:15].[OH:20][S:21](O)(=[O:23])=[O:22].O=S(=O)=O>>[CH3:1][C:2]1[C:3]([CH:4]=[C:5]2[CH:10]3[C:11]([CH3:12])([CH3:13])[C:7]([CH3:14])([CH2:8][CH2:9]3)[C:6]2=[O:15])=[CH:16][C:17]([S:21]([OH:23])(=[O:22])=[O:20])=[CH:18][CH:19]=1
Reactant: Cc1ccccc1C=C1C(=O)C2(C)CCC1C2(C)C
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1ccc(S(=O)(=O)O)cc1C=C1C(=O)C2(C)CCC1C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25.4 g of 3-o-methylbenzylidene camphor are dissolved with stirring in 84 ml of oleum containing 20% by weight SO3 with cooling so as to maintain the temperature below 25° C. Stirring of the resulting reaction mixture is continued for an additional 30 minutes at ambient temperature at which time it is poured into 200 ml of crushed ice. The precipitate which forms is filtered and crystallized in 100 ml of acetone to produce white crystals melting at 130° C. and corresponding to the dihydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1
Reactant: COc1cccc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
143.6 g (one mole) of 2-chloro-6-methoxy-pyridine were added dropwise with stirring over one hour to a mixture of 1600 ml of concentrated sulfuric acid and 800 ml of fuming nitric acid cooled to 0° C. and the temperature was allowed to rise to 20° C. over three hours. The mixture was then stirred at 20° C. for three hours and was poured into 5000 g of crushed ice. The mixture was vacuum filtered and the product was washed with a large volume of water until acid free and dried to obtain 151-156 g (80-83% yield) of 2-chloro-3nitro-6-methoxy-pyridine in the form of yellow crystals melting at 67° to 69° C. with a purity of 84 to 85%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(Br)cn2)c(F)c1
Yield: 91.1 %

Procedure:
2,5-Dibromopyridine (3.0 g; 12.66 mmol), 2,4-difluorophenol (4.11 g; 31.65 mmol) and K2CO3 (5.25 g; 38 mmol) in DMF (40 ml) are stirred at 150° C. for 3 hours. The reaction mixture is poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified via chromatography (SiO2, heptane/TBME 97:3) to yield the title compound as white crystals (3.3 g; 85%). MS (m/z) ES+: 286, 288 (MH+). Retention time: 3.05 minutes (LC-MS method 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ncc(Br)cc1N
Temperature: 95 °C
Yield: 94.5 %

Procedure:
In a 500 mL, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-2-methoxy-3-nitropyridine (15) (20.0 g, 0.086 mol), Fe (20.0 g, 0.36 mol), and NH4Cl (20.0 g, 0.36 mol) in EtOH/H2O (150 mL, 1:1). After heating at 95° C. for 1 h, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give 16.5 g (95%) of 5-bromo-2-methoxypyridin-3-amine (16) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C)C=O.CI>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1-c1ccccc1Cl
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1-c1ccccc1Cl
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1.21 g (3.57 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester in 35 ml N,N-dimethylformamide 0.18 g (3.7 mmol) sodium hydride (55% dispersion in mineral oil) were added at room temperature. After 30 min 0.25 ml (3.9 mmol) methyl iodide were added and the reaction mixture was stirred for 1 h. Quenching was followed by extraction with tert-butyl methyl ether. The organic layer was washed with two portions of water, and the combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried with sodium sulfate and concentrated to give 1.26 g (100%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.CO.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: Nc1nc(Br)cs1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)cs1
Temperature: 70 °C

Procedure:
4-Bromo-thiazol-2-ylamine (100 mg, 0.34 mmol) was combined with 57 mg (0.51 mmol) of 2-furan boronic acid. To this mixture was added 5 mL of MeOH, 1 mL of sat. NaHCO3 (aq), and 0.8 mL of DMF. Reaction mixture was degassed and Pd[P(Ph)3]4 (25 mg) was added. Reaction mixture was heated at 70° C. for 7 hours. The reaction mixture was brought to room temperature and filtered. The filtrate was evaporated and purified using reverse phase HPLC.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.[N:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:36][CH2:35][CH2:34][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Reactant: OCCN1CCNCC1
Product: NC(=O)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.143 mmol) was used in general procedure 3 with 2-(piperazin-1-yl)ethanol (0.71 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(4-(2-hydroxyethyl)piperazin-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]2[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=2[CH:29]=1>>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[N:7][C:2]([NH:27][C:28]2[CH:41]=[CH:40][C:31]3[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2-n2cccn2)n1
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4-n4cccn4)n3)cc21

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-2-pyrazol-1-yl-phenyl)-amine was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-bezo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-morpholin-4-yl-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (7%); 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.39 (s, 1H), 9.31 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.98 (bd, 1H), 7.82 (s, 1H), 7.59 (d, J=8.08 Hz, 1H), 7.41 (s, 1H), 7.12 (s, 1H), 6.98 (d, J=11.11 Hz, 1H), 6.79 (d, J=8.59 Hz, 1H), 6.54 (s, 1H), 3.78 (m, 4H), 3.21 (m, 4H), 2.15 (m, 2H), 1.95 (m, 2H), 1.27 (s, 6H); MS (m/e) 559.54 (M+H).