Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzyloxyaniline (0.999 g, 5.01 mmol) in DCM (10 mL) was added pyridine (1.22 ml, 15.03 mmol) and phenyl chloroformate (0.68 ml, 5.51 mmol) dropwise (Exotherm!). The reaction was then allowed to stir at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and 1M HCl, extracted twice, combined organics passed through phase separating cartridge and filtrate evaporated to dryness to give an orange solid. This was then triturated in 10% ethyl acetate/hexanes, filtered and dried to give the product, phenyl [3-(benzyloxy)phenyl]carbamate, as beige solid (1.209 g, 3.78 mmol, 75% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].[CH3:14][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1)([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH:29]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:24][CH:23]=1)([CH3:14])[CH3:16]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccc(OCCNC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccc(C(=O)C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of 2.55 g of indole-4-carboxaldehyde and 4 ml of 50% sodium hydroxide solution was added with stirring under an inert atmosphere to a solution of 3.5 g of the product of Step B in 40 ml of ethanol and after stirring for 24 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and the wash water was reextracted with an 8-2 chloroform-methanol mixture. The extract was washed with water and aqueous sodium chloride solution and the combined organic phases were dried over a deshydrant and were evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 4.3 g of 1-[4-{-2-(1,1-dimethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E) melting at ≃162° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:18]1([CH2:17][O:9][C:5]2[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1

Procedure:
4-bromo-2,6-difluorophenol (2 g, 9.57 mmol) was dissolved in DMF (19 mL) and to this was added Cs2CO3 (4.37 g, 13.34 mmol) and the solution was stirred for 15 minutes before benzyl bromide (1.64 g, 9.57 mmol) was added. After 2 hours at room temperature the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the layers were separated and the aqueous extracted with ethyl acetate (100 mL). The combined organics were washed with brine (2×50 mL) and water (2×50 mL) and dried over MgSO4. The crude material (2.67 g) was filtered through a pad of silica and eluted with hexane to afford 4-bromo-2,6-difluorophenyl phenylmethyl ether after evaporation of the solvent (2.38 g, 83%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1>[C:15]1([CH2:14][NH:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][NH:7][C:8]3=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccc2c1CCNC2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCc2c(NCc3ccccc3)cccc21
Temperature: 0 °C
Yield: 19.3 %

Procedure:
To a solution of 2.0 g (12.3 mmol) of 5-amino-3,4-dihydro-1(2H)-isoquinolinone, monohydrochloride in 10 ml of THF was added 2.6 g (14.76 mmol) of benzylbromide and 2 ml of triethylamine. The mixture was heated under reflux for six hours and then poured into ice water and extracted with ether. The ether extracts were washed with water, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2, ether to 10:1 ether/methanol) to provide 0.6 g of the dibenzylated product and 0.95 g (31%) of the desired monobenzylated product after crystallization from ethanol; mp. 142°-144°.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH2:14]([N:21]([CH3:43])[C:22]([C:24]1[CH:37]=[N:36][C:35]2[C:26](=[CH:27][C:28]([F:42])=[C:29]3[C:34]=2[N:33]=[CH:32][C:31]([C:38](=O)[NH2:39])=[C:30]3Cl)[CH:25]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[CH2:14]([N:21]([CH3:43])[C:22]([C:24]1[CH:37]=[N:36][C:35]2[C:26](=[CH:27][C:28]([F:42])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]([C:38]#[N:39])[C:30]3=[O:4])[CH:25]=1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(Cc1ccccc1)C(=O)c1cnc2c(c1)cc(F)c1c(Cl)c(C(N)=O)cnc12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CN(Cc1ccccc1)C(=O)c1cnc2c3c(c(F)cc2c1)C(=O)C(C#N)C=N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Trifluoroacetic anhydride (0.5 ml) was added dropwise to a stirred, ice-cooled mixture of 8-(N-benzyl-N-methylcarbamoyl)-3-carbamoyl-4-chloro-5-fluoro-1,10-phenanthroline (0.3 g) in pyridine (3 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was acidified with 3M hydrochloric acid and stirred at ambient temperature for 18 hours. The mixture was filtered and the solid so obtained recrystallised from a mixture of methanol and ethyl acetate to give 8-(N-benzyl-N-methylcarbamoyl)-3-cyano-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 24% yield, mp 267-269° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:65])[C:32]([C:40]3[N:41]=[C:42]([NH:45][C:46]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:43][CH:44]=3)=[N:33][O:34]C(C)(OC)C)[C:28](=[O:66])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].Cl>CC(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:65])[C:32]([C:40]3[N:41]=[C:42]([NH:45][C:46]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[S:43][CH:44]=3)=[N:33][OH:34])[C:28](=[O:66])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.775 g of the product of Step A, 14 ml of acetone and 4.5 ml of N hydrochloric acid was stirred for 2 hours at room temperature and the acetone was evaporated under reduced pressure. 20 ml of ethyl acetate were added thereto and the mixture was stirred and decanted. The organic phase was washed 4 times with 10 ml of slightly salted water and the wash waters were extracted with 5 ml of ethyl acetate. The combined organic phases were dried and vacuum filtered and the filter was rinsed with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in ether and was crystallized. Efflorescence occurred and the mixture was vacuum filtered. The product was rinsed with ether and was dried to obtain 1.88 g of the syn isomer of diphenylmethyl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate with a Rf=0.5 (eluant-ether containing 20% acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCC(c2cccc3ccc(N)cc23)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCC(c2cccc3ccc(NC(=O)c4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 7-amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene (0.139 g, 0.615 mmol, product of Example 68) and triethylamine (0.103 mL, 0.738 mmol) in tetrahydrofuran (5 mL) was chilled to 0° C. and benzoyl chloride (0.086 mL, 0.738 mmol) was added. The reaction was warmed to room temperature and stirred overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic layer was washed with 0.5N, sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2 inches). Elution proceeded as follows: 50% to 75% ethyl acetate/hexane (375 mL), nil; ethyl acetate (200 mL), nil; 2% triethylamine/2% methanol/ethyl acetate (200 mL), 0.14 g of brown oil which partially crystallized. Recrystallization from ethyl acetate gave 0.058 g, (28%) of the title compound as white crystals. mp 137°-145° C.; 1H NMR δ 8.57 (d, J=2 Hz, 1 H), 8.06 (br s, 1 H), 7.95 (dd, J=1.5, 8 Hz, 2 H), 7.86 (d, J=9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.59-7.49 (m, 4 H), 7.40 (t, J=7.5 Hz, 1 H), 4.15 (sym m, 1 H), 3.04 (t, J=9 Hz, 1 H), 2.93-2.81 (m, 2 H), 2.80-2.68 (m, 1 H), 2.66-2.50 (m, 1 H), 2.47 (s, 3H), 2.08-1.96 (m, 1 H). Analysis calculated for C22H22N20: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.36; H, 6.72; N, 7.94.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[CH:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:8]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH2:22]([O:20][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=2)[CH:6]=1)[CH3:23]
Reactant: CCI
Reactant: OCc1cc(O)cc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(CO)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
3-(Hydroxymethyl)-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenol from Step 1 (460 mg, 1.61 mmol), in acetone (10 mL), was treated with 1-iodoethane (0.143 mL, 1.77 mmol), potassium carbonate (279 mg, 2.02 mmol) and 18-crown-6 (85 mg, 0.323 mmol). The mixture was heated to reflux for 16 h, cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30%, EtOAc:heptane) to afford the title compound (357 mg, 70% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1)(=[O:18])[CH3:17]
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1

Procedure:
30 g of 2-amino-4-(4'-nitrophenyl)-1,3-thiazole (prepared in accordance with J. Chem. Soc. 1959, (2365) and 100 ml of acetic anhydride are heated for 3 hours at 140° C. Excess acetic anhydride is removed by vacuum distillation and the residue is treated with 500 ml of warm water, filtered, washed, and dried to constant weight, affording 34 g of 2-acetamido-4-(4'-nitrophenyl)-1,3-thiazole.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].[Br:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C1C=CC=CC=1>[CH2:13]1[CH2:12][O:15][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:18][CH2:17][Br:16])[O:14]1
Reactant: O=C(CCBr)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: BrCCC1(c2ccccc2)OCCO1
Yield: 49.9 %

Procedure:
p-Toluenesulfonic acid in a catalytic amount and ethylene glycol (2.9 g) were added to a solution of 3-bromo-1-phenyl-1-propanone (10 g) in benzene (100 ml), and the mixture was stirred at refluxing temperature for 70 hr. The reaction mixture was washed successively with 10% aqueous potassium carbonate solution and brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 6.0 g of 3,3-ethylenedioxy-3-phenylpropyl bromide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[Na+]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol), N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate (0.7 g, 8.3 mmol) in acetronitrile (160 ml) was warmed to reflux for 24 hours. Upon cooling to room temperature, the reaction mixture was filtered through a pad of celite and the solids were washed with DCM. The combined filtrates were concentrated to give the N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was used without further purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][OH:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C>ClCCl>[CH2:12]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC/C=C\COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C/C=C\COCc1ccccc1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
11.1 g of pyridinium chlorochromate and 12 g of celite were suspended in 100 ml of dry dichloromethane, and 6 g of (Z)-4-benzyloxy-2-buten-1-ol was added thereto under stirring at 0° C. The mixture was stirred at room temperature for three hours, and then diethyl ether was added thereto. The insolubles were removed by filtration. The filtrate was subjected to distillation under reduced pressure for removal of the solvent, and the residue was purified by silica gel column chromatography (diethyl ether) to obtain 3.9 g of (Z)-4-benzyloxy-butenal as slightly yellow oily substance.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[N+:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl)([O-:23])=[O:22]>CCO>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[N+:21]([O-:23])=[O:22])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 79.5 %

Procedure:
To a solution of valine tert-butyl ester hydrochloride (1.5 g, 7.15 mmol) in EtOH (10 mL) was added triethylamine (2.09 mL, 15 mmol), followed after 10 minutes by 2-nitrobenzyl chloride (1.227 g, 7.15 mmol). The mixture was then stirred for 20 h under reflux before it was evaporated. The residue was purified by flash chromatograhy (petrol/ethyl acetate, 85/15) to afford the sub-title compound as a colorless oil (1.753 g, 80%). 1H NMR (400 MHz CDCl3) δ 0.93 (6H, m), 1.48 (9H, s), 1.83-1.96 (2H, m), 2.82 (1H, d), 3.92 (1H, d), 4.11 (1H, d), 7.39 (1H, t), 7.57 (1H, t), 7.65 (1H, d), 7.89 (1H, d).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=4)=[N:10][NH:11][CH:12]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=Cc1c[nH]nc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]nc3-c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 471 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH2:34]>C1COCC1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:34][CH3:33])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Solvent: C1CCOC1
Product: CNc1nc(C)c2cc(-c3cnn(CCO)c3)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 70 %

Procedure:
8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) was dissolved into 3 ml methylamine in THF (1.0 M). The reaction mixture was then heated to 100° C. in microwave for 30 minutes. The solvent was removed via rot vap and the residue was re-dissolved in 5 ml methanol. A few drop of concentrated HCl was added the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (45 mg, 70% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:23](O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O>[NH2:13][C@H:14]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Yield 175 mg, [α]D21 -17.4° (c=0.5, H2O); amino acid analysis (acid hydrolysis): Arg 1.00(1), Tyr 0.94(1); average recovery 86.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:23])[N:13]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH:15]([C:16](O)=[O:17])[C:5]2=1.[CH3:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:23])[N:13]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH:15]([C:16]([N:25]([CH3:26])[CH3:24])=[O:17])[C:5]2=1
Reactant: CNC
Reactant: COCCN1CC(C(=O)O)c2c(n(C)c3ccc(Cl)cc23)C1=O
Product: COCCN1CC(C(=O)N(C)C)c2c(n(C)c3ccc(Cl)cc23)C1=O

Procedure:
The preparation is carried out as in Example 1.5, from 8.3 g (26 mmol) of (±)-6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and from dimethylamine. 8.6 g of product are isolated, which product is recrystallized from propan-2-ol. 6.9 g (19 mmol) of product are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([NH:20][CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1.[CH3:22][N:23](C=O)C>O.[C-]#N.[Zn+2].[C-]#N>[C:22]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([NH:20][CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(Cl)nc(C)n2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(C#N)nc(C)n2)cc1
Temperature: 150 °C

Procedure:
Bubble nitrogen gas through a solution of 1-[4-(6-chloro-2-methyl-pyrimidin-4-yl)oxyphenyl]-N-methyl-methanesulfonamide (26.6, 81.1 mmol) in DMF (266.0 mL) for 15 minutes. Thereafter add zinc cyanide (14.59 g, 121.2 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (6.76 g, 8.1 mmol). Heat the suspension to 150° C. for 6 hr while maintaining it under a nitrogen atmosphere. Cool the mixture to room temperature. Dilute the mixture with water (600 mL) and extract the mixture with EtOAc (3×500 mL). Combine the EtOAc extracts. Sequentially wash the combined extracts with water (500 mL) then brine (500 mL); dry over sodium sulfate; filter and concentrate the filtrate under reduced pressure. Isolate the title compound using silica gel chromatography eluting with hexane/EtOAc (1:1) to give the title compound (18 g, 70%). MS (m/z): 319 (M+1).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N:1]1([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: OC(CCCn1cnc2cnc3ccccc3c21)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
By the general method described in Step 6 of Example 1, 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol) (7.2 g, 22.7 mmol) was oxidized with DMSO (2.70 g, 34.0 mmol), oxalyl chloride (3.20 g, 25.0 mmol), and triethylamine (6.90 g, 68.1 mmol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.08 g) as a light yellow solid after chromatography on silica gel (elution with 10% methanol in dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1.C(O)(=[O:13])C>>[NH2:1][C:2]1[NH:7][C:6](=[O:13])[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1
Reactant: Nc1nc(F)cc(CF)n1
Reactant: CC(=O)O
Product: Nc1nc(CF)cc(=O)[nH]1

Procedure:
12.1 Parts of 2-amino-4-fluoro-6-fluoromethylpyrimidine was dissolved in 200 parts of 20% aqueous acetic acid at reflux, with stirring. The mixture was heated under reflux for 1 hour then cooled. The precipitated solid was filtered, washed with 50% aqueous acetic acid and then with acetone. The solid was dried in vacuo at 140° C. to give 2-amino-6-fluoromethylpyrimidine-4-one, m.p. 237°-238° C. (decomposition).