Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][CH:7]1[S:11](=[O:13])(=[O:12])[O:10][CH2:9][CH2:8]1>O1CCCC1>[C:1]([NH:5][CH2:9][CH2:8][CH:7]([S:11]([OH:13])(=[O:12])=[O:10])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC1CCOS1(=O)=O
Solvent: C1CCOC1
Product: CC(CCNC(C)(C)C)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-butylamine (1.0 mL, 9.5 mmol) in tetrahydrofuran (15 mL) was added 2,4-butane sultone (1.33 g, 10.0 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with THF (2×20 mL), and dried in vacuo; affording compound ES: 1H NMR (DMSO, 500 MHz) δ ppm 2.97 (t, 2H, J=6.6 Hz), 2.62 (m, 1H), 1.95 (m, 0.5H), 1.750 (m, 0.5H), 1.22 (s, 9H), 1.12 (d, 3H, J=6.8 Hz). 13C NMR (DMSO, 125 MHz) δ ppm 56.17, 53.15, 29.87, 25.87, 17.05. ES-MS 207 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[N:43]([CH:45]=[O:46])C>CCOC(C)=O>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([N:43]=[C:45]=[O:46])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(Cl)c2)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N=C=O)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 358 (187 mg, 0.4997 mmol) in DMF (1.5 mL) at RT under nitrogen was added TEA (167.1 μL, 1.199 mmol) neat via syringe followed by DPPA (129.6 μL, 0.5996 mmol) neat by syringe. The solution was stirred for 2 h at RT then warmed to 60° C. After 3 h at 60° C., the reaction was cooled to RT and diluted to 30 mL with EtOAc. The organic extract was washed with H2O (3×30 mL) and brine (1×30 mL). The organics were dried (MgSO4), filtered and concentrated to afford 170 mg (91%) of tert-butyl 4-(3,4-dichlorophenyl)-4-isocyanatopiperidine-1-carboxylate (360) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1

Procedure:
A mixture of 5.5 g (36 mmol) of methyl 3-methylbenzoate, 7.1 g (39.5 mmol) of N-Bromosuccinimide and 0.44 g (1.8 mmol) of benzoyl peroxide in 75 ml of Cl4C is refluxed for 5 h. The solid is filtered and washed with Cl4C. The mother liquors are concentrated and a yellow solid is obtained which is, essentially, monobromated product. This is used in the next step without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:32])[N:16]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:17](=[O:24])[C:18]3[C:23]=2[C:22]=1[CH:21]=[CH:20][CH:19]=3>CN(C)C=O>[Cl:1][C:12]1[C:11]([NH:10][CH3:9])=[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]2=[C:14]([CH:13]=1)[C:15](=[O:32])[N:16]([CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:17]3=[O:24]
Reactant: CNc1ccc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CNc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A slurry of N-chlorosuccinimide (0.255 g; 1.90 mmol) and 2,3-dihydro-6-methylamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.65 g; 1.80 mmol), prepared as in Example 5, in N,N-dimethylformamide (12 mL) was stirred approximately 72 hours. The solvent was removed and acetone (approximately 25 mL) was added to the residue. The acetone mixture was heated to boiling and then stirred for 1 hour at room temperature. The solid was collected from the mixture, stirred again in acetone, and recollected. Drying under vacuum gave 5-chloro-2,3-dihydro-6-methylamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.65 g; 1.65 mmol), m.p. 298°-302° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=O.[OH-].[Na+].[NH4+].[Cl-]>CO.CC(O)=O>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[CH:13]=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])([OH:19])=[O:18]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1C(=O)O)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.3 %

Procedure:
To a solution of 6-methoxy-1-indanone (15 g, 93 mmol) and 2-formylbenzoic acid (14 g, 93 mmol) in MeOH (1 L) was added NaOH (47 ml, 5N). The mixture was stirred at r.t. for 20 hrs. NH4Cl solution was added and the resulting mixture was buffered to pH 6 with HOAc. The yellow solid was filtered, washed with H2O, and dried in air to give 25 g (92%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:28]=[CH:27]2.C(Cl)CCl.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]([CH3:38])[C:35]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:21])=[O:36])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc([C@@H](C)C(=O)O)ccc2c1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O[C@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (50 g, 152 mmol), (R)-2-(6-methoxynaphthalen-2-yl)propanoic acid (38.6 g, 168 mmol), DMAP (20.5 g, 168 mmol), and EDC (43.8 g, 229 mmol) were dissolved in DMF (300 ml), and the reaction mixture was stirred at RT for 2 hours. Thereafter, water (500 ml) was added, and the solution stirred till complete precipitation occurs. The solid was filtered and dissolved in DCM (500 ml). The organic solution was washed with aqueous HCl 1N (2×500 ml), saturated aqueous NaHCO3 solution (500 ml) and dried over Na2SO4. The solvent was evaporated under vacuum and the solid residue sonicated in EtOH (300 ml) and triturated for 1 hour. The resulting precipitate was collected by filtration and dried under vacuum at 40° C. for 4 h to give 79 g (99% yield) of the title compound, as diastereoisomeric mixture.
Reaction SMILES: O.O.Cl[Sn]Cl.[N+:6]([C:9]1[CH:10]=[C:11]([Cl:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:6][C:9]1[CH:10]=[C:11]([Cl:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2scnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Cl)c2scnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of SnCl2.2H2O (0.5 g, 2.2 mmol) in 5 mL of HCl was added 5-nitro-7-chlorobenzothiazole (0.12 mg, 0.56 mmol) in a portion and the resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aq. NaOH and extracted with EtOAc. Organic extracts were dried over Na2SO4 and concentrated in vacuo to yield 110 mg (0.54 mmol, >95%) of the desired product.
Reaction SMILES: [F:1][CH:2]([F:19])[CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:19][CH:2]([F:1])[CH:3]([N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[CH2:4][C:5](=[CH2:7])[CH2:6][Br:20]
Reactant: C=C(C)CC(C(F)F)N1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)CC(C(F)F)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,1-difluoro-2-phthalimido-4-methyl-4-pentene (17.8 g, 67.2 mmoles) prepared as in Step B above, N-bromosuccinimide (14.4 g, 80.6 mmoles), carbon tetrachloride (200 mL) and benzoyl peroxide (4 times one end of spatula during the heating period) is heated under strong reflux (325 W lamp) during 6.5 hours. After cooling, the solution is extracted 3 times with water, dried over magnesium sulfate, and concentrated. The oily residue obtained is used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:10]/[C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:8]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Product: CN(C)/C=C/C(=O)c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
1-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a microwave to 120° C. for 15 minutes, the reaction was allowed to cool and was concentrated to remove the residual DMF acetal, to give (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one, 0.32 gm, as a red oil, LC/MS (M+H)+: 244.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:29]([O:28][C:26]([CH:25]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])=[O:27])[CH3:30]
Reactant: CCOC(=O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)SC[C@H](N)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CS[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
By following the same procedure as described in Example 4, a condensation reaction was carried out between 336 mg of t-butyl rel-α-[6(R)-amino-5-oxo-2(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate and 552 mg of ethyl 2-bromo-6-phthalimidohexanoate in the presence of 318 mg of sodium carbonate to give two diastereoisomers. These isomers were separated by column chromatography through silica gel using a mixture of cyclohexane and ethyl acetate in the ratio 5:1 by volume as the eluent.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[Na+].OO>O1CCCC1.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>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 169.7 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 1-(4-trifluoromethylphenyl)-2-(4-bromophenyl)acetylene (3.9 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), sodium hydroxide (2.4 g, 60 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-heptenylcatecholborane (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 10% aqueous solution of sodium hydroxide (5 ml) and 30% aqueous hydrogen peroxide (2 ml) were added to the mixture, followed by stirring for 1 hour. The mixture was extracted with ethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride (20 ml each) twice and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography to obtain 1-(4-trifluoromethylphenyl)-2-[4-(1-trans-pentenyl)phenyl]acetylene (3.2 g). Yield: 84%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=CC(F)=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.[C:38](O)([C:40]([F:43])(F)F)=O>C(Cl)Cl>[F:43][C:40]1[CH:38]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=4)[C:34]#[N:35])[CH2:25][C:24](=[O:36])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K98) (307 mg, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a eggshell solid (146 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[O:16][CH2:17][CH3:18])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Br)cc1OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (1.038 mL) was added to a mixture of 4-bromo-2-ethoxyphenol (1.694 g) and potassium carbonate (1.618 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford ethyl(4-bromo-2-ethoxyphenoxy)acetate (2.26 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](Br)=[CH:15][N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].P(=O)(O)(O)[OH:31]>>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][C:15](=[O:31])[N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(O)(O)O
Reactant: CN(CCOc1cccc2c1c(Br)cn2Cc1ccccc1)C(=O)OC(C)(C)C
Product: CN(CCOc1cccc2c1CC(=O)N2Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
[2-(1-Benzyl-3-bromo-1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was treated with phosphoric acid using the procedure of step 4 of Example 6 to provide [2-(1-benzyl-2-oxo-2,3-dihydro-1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].P(=O)(O)(O)O>>[CH2:1]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1(O)CCCCC1
Agent: O=P(O)(O)O
Product: CC(C)CC1=CCCCC1
Temperature: 145 °C
Yield: 253.2 %

Procedure:
In a flask equipped with a Vigreux-distillation apparatus, crude 1-isobutylcyclohexanol (200 g, 1.28 mol) was treated with phosphoric acid (100 g) and heated at 145° C. under vacuum (170 mbar). While 1-isobutylcyclohex-1-ene and water distilled (boiling point 60° C.), a second fraction of 1-isobutylcyclohexanol (492 g, 3.15 mol) was added dropwise in the reaction flask. At the end of the addition, the thick reaction mixture was diluted with paraffin oil (100 ml) and additional phosphoric acid (50 g) and heated further (vacuum from 170 to 40 mbar). The distillate was decanted and the water phase extracted with pentane (100 ml). The combined org. phases were dried (MgSO4) and the solvent evaporated to give 1-isobutylcyclohex-1-ene (448 g, 78%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].O>C(O)C>[CH2:26]([NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and butylamine (170 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (358 mg, 99.1% yield).
Reaction SMILES: N#N.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>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.O.C1(C)C=CC=CC=1.CCO>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:12]3[CH:11]=[C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]4)[CH:15]=[CH:14][N:13]=3)[CH:17]=2)=[CH:33][CH:32]=1
Reactant: CN1CCN(c2ccnc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccnc(-c3cccc(-c4ccc(F)cc4)c3)c2)CC1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a N2 flushed vial was sequentially added trifluoromethanesulfonic acid 3-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-phenyl ester (20 mg, 0.05 mmol), Pd(PPh3)4 (10 mg), and toluene/EtOH (4:1, 1 mL). After 5 min, 4-fluorophenylboronic acid (10 mg, 0.07 mmol) and 2 M aqueous K2CO3 (0.2 mL) were added. The resulting mixture was heated at 90° C. for 16 h, then was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated, and the resulting residue was purified by preparative TLC (MeOH/CH2Cl2) to yield the title compound as a solid.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C(OC([NH:47][C@H:48]([C:50](O)=[O:51])[CH3:49])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:50](=[O:51])[C@H:48]([CH3:49])[NH2:47])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](N)C(=O)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (251 mg, 0.46 mmol) and N-(tert-butoxycarbonyl)-L-alanine (97 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (0.24 mL, 1.38 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (116 mg, 0.61 mmol) and the mixture was stirred at room temperature for 15 hours. The reaction was worked-up as described above to give the crude amide as a mixture of diastereomers. Purification and separation of the diastereomers was accomplished by column chromatography on silica gel (EtOAc) to afford a low polarity diastereomer (78 mg, 24%) and a high polarity diastereomer (48 mg, 15%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][NH:6][C:5]1=[O:9].[Br:10][C:11]1[C:16]2[S:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[Br:10][C:11]1[C:16]2[S:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:1][CH2:2][CH2:3][N:4]4[CH2:8][CH2:7][NH:6][C:5]4=[O:9])[N:21]=3)=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cnc(Cl)nc1-c1cc2cccc(Br)c2s1
Reactant: NCCn1cc[nH]c1=O
Solvent: C1COCCO1
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(Br)c3s2)n1
Reaction time: 3 h
Yield: 51.8 %

Procedure:
Combine 1-(2-aminoethyl)-2-imidazolone (100 g, 774 mmol) with 4-(7-bromo-benzo[b]thiophen-2-yl)-2-chloro-5-fluoro-pyrimidine (90 g, 262 mmol) in 1,4-dioxane (650 mL) and heat to 90° C. with stirring under nitrogen for 3 hours. Cool the reaction to room temperature. Filter and wash the solid with water (3×500 mL) and diethyl ether (500 mL). Vacuum-dry at 50° C. to give the title compound (59.2 g, 52%) as a yellow solid. MS (ES) m/z 436 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14]
Reactant: ClCc1ccccc1Cl
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCCN(Cc1ccccc1Cl)c1ccccn1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Sodium hydride (1.32 g) was disolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.5 g) added at room temperature. 2-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After standing overnight water (200 ml) was added and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and after partitioning into ether and chloroform at pH 3.5 and 14, an oil was obtained which was further purified by HPLC (silica gel, dichloromethane then 2% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-(2-chlorobenzyl) amino]pyridine (3.44 g) as an oil.