Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])=[CH:24][CH:23]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCc2ccc(Br)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-(4-bromo-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C20H22BrNO5 [M+H]+: 437.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([N+:18]([O-])=O)[C:5]=1[CH:21]=[CH:22][C:23]([O:25]C)=O)(=[O:3])[CH3:2]>[Ni].C(O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]2[C:5]=1[CH2:21][CH2:22][C:23](=[O:25])[NH:18]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2

Procedure:
5.0 g (14.07 mmol) methyl 3-(2-acetyl-4-benzyloxy-6-nitro-phenyl)-acrylate are combined with 100 mL ethanol and hydrogenated at 4 bar with Raney nickel as catalyst. The catalyst is separated off and the filtrate is acidified with 15 mL 2 N hydrochloric acid. The product that crystallises out is suction filtered and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]=[O:10])=[CH:3][CH:2]=1
Reactant: OCCCc1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCc1ccncc1
Reaction time: 1 h

Procedure:
4-pyridinepropanol (0.60 mL, 4.65 mmol) was added to a solution of the Dess-Martin reagent (2.37 g, 5.58 mol) in dichloromethane (30 mL). After 60 min at RT, the solution was quenched with 10% aq. Na2S2O3, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded the title compound. MS 136 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[CH:5]=1)(=O)[CH3:2].[H-].[Na+].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C>C1COCC1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4](/[C:1](/[CH3:2])=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:12]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2cc(C)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccc2cc(C)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.3 %

Procedure:
2-Acetyl-6-methylnaphthalene (5.08 g) was added to a cooled (0° C.) mixture of NaH (60% oil dispersion, 2.34 g) in THF (150 ml) and ethyl diethylphosphonoacetate (14.12 g) and the mixture was stirred at room temperature for 14 hours. The reaction was quenched by the addition of water. The organic layer was washed with water and brine, dried and concentrated. Recrystallization of the residue from hexane gave the titled compound (3.25 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[C:4]([F:23])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:48]([C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)(=[O:50])=[O:49])[CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH:9]=2)=[C:4]([F:23])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2ccc(Cl)cc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Product: CN(Cc1cc(-c2ccc(Cl)cc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 44 and using tert-butyl {[5-(4-chloro-2-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (127 mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0.22 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (120 mg), the title compound was obtained as a colorless oil (yield 103 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:61][C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([NH2:69])[CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:68][C:65]1[CH:66]=[CH:67][C:62]([F:61])=[CH:63][C:64]=1[NH2:69])=[O:28])=[O:17]
Reactant: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(F)ccc1NC(=O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid (424 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (436 mg, 82% yield) as a brown solid. LC-MS (m/z) 533 (M+1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH:37]([NH:44][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 1 supra) by following the method in Example 61.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[B:30]1(B2OCC(C)(C)CO2)[O:35]CC(C)(C)C[O:31]1.C([O-])(=O)C.[K+].[NH4+].[Cl-]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([B:30]([OH:35])[OH:31])=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 88.6 %

Procedure:
To a stirred solution of [2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]trifluoromethanesulfonate (25 g, 56.1 mmol) in DMSO (250 mL) at rt was added bis(neopentylglycolato) diboron (25.20 g, 112.10 mmol) and potassium acetate (16.5 g, 168.2 mmol). The resulting reaction mixture was de-gassed by purging N2 for 15-20 min followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM adduct (6.8 g, 8.4 mmol). The reaction mixture was again purged with N2for 15-20 min then heated to 80° C. for 90 min. After the completion of reaction (by TLC), the reaction mixture was poured onto saturated NH4Cl solution (1 L). The resulting precipitate was filtered and dried under vacuum. The solid cake was taken up in 2N NaOH (200 mL) and stirred for 45 min at rt. The solution was filtered and the filtrate acidified up to pH 5-6. The solid thus obtained was filtered and dried to obtain the desired product (17 g, 88%). 1H-NMR (DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.84 (br s, 1H), 7.41 (m, 1H), 8.01 (m, 1H), 8.12 (s, 1H), 8.25 (m, 3H), 8.40 (s, 1H), 8.79 (d, J=4.0 Hz, 1H) and 10.57 (br s, 1H). MS: 343.25 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[C:14]([S:16][C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[C:13]([F:23])=[CH:12][C:11]=2[N+:24]([O-])=O)=[N:6][CH:7]=1.[NH4+].[Cl-]>[Fe].C(O)(C)C>[NH2:24][C:11]1[CH:12]=[C:13]([F:23])[C:14]([S:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:27]
Reactant: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c(N)cc1F
Yield: 52.2 %

Procedure:
A mixture of N-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-2-nitro-benzamide (1.42 g, 3.14 mmol). 325 mesh iron dust (7.1 g, 127 mmol), 6 mL of 4 M aqueous NH4Cl and 60 mL of isopropanol were mechanically stirred at 85° C. for 4 h, then slurried hot with Celite and filtered. The filtrate was diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated. The residue obtained was triturated in boiling methanol. After cooling, the resulting solid was collected by filtration and dried under high vacuum to provide 692 mg (52%) of the title compound as a light-green solid. 1H NMR (500 MHz, DMSO-d6): δ 3.67 (s, 3H), 6.58 (d, 1H, J=12 Hz), 6.89 (s, 1H), 6.95 (br s, 2H), 7.26 (s, 1H). 7.99 (d, 1H, J=8 Hz), 8.03 (d, 1H, J=8 Hz), 8.04 (d, 1H, J=8 Hz), 8.50 (s, 1H). 10.86 (s, 1H); LCMS (m/z): 422/424 [C16H13BrFN5OS+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(C)ccc1F
Yield: 82.1 %

Procedure:
Heat a mixture of 2-fluoro-5-methyl-benzoic acid (1.0 g, 6.48 mmol), iodomethane (1.38 g, 9.73 mmol), and potassium carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) at reflux overnight. Cool the reaction and filter through Celite®. Concentrate the filtrate under reduced pressure to provide the title compound as a colorless gum (0.895 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 2.32 (s, 3H), 3.89 (s, 3H), 6.95-7.10 (m, 1H), 7.20-7.30 (m 1H), 7.75-7.80 (m, 1H); TLC Rf=0.45 (2:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+]=[N-].[Na+].[NH4+].[Cl-].[OH-].[NH4+].CP(C)C>CCOC(C)=O.C1COCC1.O.[Cu]I.CCO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH2:27])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CP(C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a mixture of tert-butyl((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16h-B, 1.47 g, 3.38 mmol), copper(I) iodide (0.139 g, 0.730 mmol), (+)-sodium 1-ascorbate (0.131 g, 0.661 mmol), and sodium azide (0.688 g, 10.6 mmol) were added EtOH (4.6 mL) and water (2.3 mL). The reaction mixture was purged with Nitrogen for 10 min, followed by the addition of (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.110 mL, 0.698 mmol). The reaction mixture was heated to 70° C. for 1.5 h and cooled to RT. The reaction mixture was poured into 10:1 saturated NH4Cl/ammonium hydroxide, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure to give a solid, which was dissolved in THF (12 mL) and water (4 mL). A solution of trimethyl phosphine (1.0 M in THF, 3.40 mL, 3.40 mmol) was added and the reaction mixture was stirred at RT for 15 min. The reaction mixture was diluted with EtOAc and water, the aqueous phase was separated and extracted with EtOAc. The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in heptane) to give the title compound (1.03 g, 2.77 mmol, 82% yield) as a white solid. MS m/z=372.0 [M+H]+. Calculated for C17H20F3N3O3 371.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2ccc(N)cc2)n1

Procedure:
The 6-methyl-N-(4-nitrophenyl)pyrid-2-amine (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([C:13]([OH:15])=O)[CH:6]=[N:7]2.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:13]([C:5]2[CH:6]=[N:7][C:8]3[C:3]([C:4]=2[OH:16])=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[F:12])=[O:15])=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2c(F)ccc(F)c2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)ccc(F)c2c1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.25 g of 5,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 mL of dimethyformamide is added 0.20 g of carbonyldiimidazole. The mixture is stirred 18 h at 50° C. and then it is cooled to 25° C. The mixture is treated with 0.10 mL of distilled water and stirred for 5 min. To the resulting solution is added 0. 15 mL of 4-chlorobenzylamine. After stirring for 18 hours the solvent is evaporated at reduced pressure and the residue is dissolved in 10 mL of refluxing glacial acetic acid. Hot (100° C.) water is added dropwise until the solution becomes cloudy, and the mixture is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with two successive 5 mL portions of 50% aqueous acetic acid. It is dried for 18 h at 20 torr and 90° C. This procedure yields the title compound as 173 mg of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(CCc2ccc(Cl)cc2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3ccc(Cl)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as an off-white solid; MS: m/e=342 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[C:13]1(=O)[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]1=O>CC(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[C:24]1[C:25](=[N:10]2)[C:26]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: Clc1cc(Cl)c2nc3c4ccccc4c4ccccc4c3nc2c1
Yield: 81 %

Procedure:
When 0.12 mole each of 2,4-dichloro-6-nitroaniline and phenanthrenequinone were reacted by the method of Example 1, 24 g. (81 percent yield) of 10,12-dichlorodibenzo[a,c]phenazine, mp = 221°-222° C. (acetone), were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) was reacted with phenyl isocyanate to provide 123 mg of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a light brown solid, m.p. 171.5-172.5° C. Analysis: Calculated for C22H24N6O.0.60 H2O: %C 66.18; %H, 6.36; %N, 21.05; Found: %C, 66.05; %H, 6.43; %N, 20.61.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([F:42])=[CH:35][N:34]=1)(C(C)(C)C)(C)C>ClCCl>[F:42][C:36]1[C:37]([O:40][CH3:41])=[C:38]([CH3:39])[C:33]([CH2:32][OH:31])=[N:34][CH:35]=1
Reactant: COc1c(F)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(F)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Tetrabutylammonium fluoride (1 M solution, 1.49 ml) was added to a tetrahydrofuran (10 ml) solution of the above 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-fluoro-4-methoxy-3-methylpyridine (353 mg) under cooling in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, and was then washed with water. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (150 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH:6]([CH3:10])[C:7](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].O1CCOCC1.P(Cl)(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH:6]([C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:10]
Reactant: NNC(N)=S
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 9.4 grams (0.040 mole) of 2-(3,4-dichlorophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane and heated to 90° C. The addition funnel was charged with phosphorous oxychloride (POCl3), (6.7 grams, 0.044 mole) which was slowly added (for 15 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for approximately 100 minutes, and then topped with a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off and partially air dried, and was recrystallized from the minimum amount of H2O/ethanol mixture, filtered and then dried in a vacuum oven at 80° C. to 8.0 grams of fluffy white crystals of 5-[1-(3,4-dichlorophenoxy)ethyl]-2amino-1,3,4-thiadiazole. (Melting point 136°-138° C.).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:20][C@@H:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:18]2[C:13](=[CH:14][C:15](Cl)=[CH:16][C:17]=2Cl)[NH:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH2:24]([O:23][C:21]([C@H:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:20]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 17.7 %

Procedure:
Cis-2,4-dibenzyloxycarbonyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.23 g) was dissolved in 50% aqueous methanol (30 ml) and 1N sodium hydroxide (0.54 ml, 1.1 molar equivalents) was added and the reaction mixture was stirred for 14 h at room temperature. The solvents were removed in vacuo to give a residue which was dissolved in water (30 ml) and washed with diethyl ether (2×30 ml). The aqueous layer was acidified to pH 1 with dilute hydrochloric acid and extracted into diethyl ether (2×30 ml) then dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on silica gel with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane as eluent. The solid obtained on evaporation was recrystallised from diethyl ether/hexane to give, as a colourless solid, cis-4-benzyloxycarbonyl-2-carboxy-1,2,3,4-tetrahydroquinoline (0.027 g, m.p. 144° C. dec). δ (360 MHz, CDCl3) 2.35 (1H, m, CHACHBHCCHD), 2.81 (1H, dm, J=13.9 Hz, CHACHBHCCHD), 4.03 (2H, m, CHACHBHCCHD), 5.07 (2H, s, PhCH2), 6.57 (1H, d, J=1.5 Hz, 6-H or 8-H), 6.77 (1H, d, J=1.5 Hz, 6-H or 8-H), 7.32 (5H, m, Ph); m/e 379 (M+), 198 (100%); Found: C, 56.53; H, 4.00; N, 3.65 . C18H15Cl2NO4 requires C, 56.86; H, 3.98; N, 3.68%.