Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([NH:27][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: NN1CCCC1
Agent: Cl
Product: O=C(NN1CCCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 23 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (100 mg, 0.29 mmol) was converted, using 1-aminopyrrolidine hydrochloride instead of S-(+)-1-amino-2-propanol, to the title compound (31 mg, 23%), which was obtained as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1>>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1

Procedure:
Prepared analogously to XVI.1 from 2.3 g trans-(3-Hydroxy-cyclobutyl)-carbamic acid tert-butyl ester, 1.6 g 5-fluoro-2-nitrophenol and 2.423 mIDIAD.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:20](OCC)=[O:21])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH2:20][OH:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C3=C(CO)CCCC3)ccc21

Procedure:
Ethyl 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexene-1-carboxylate, described in Example 1, is stirred with excess lithium aluminum hydride in diethyl ether at reflux temperature for 3 hours. The mixture is cooled and water is added dropwise. The organic layer is dried over sodium sulfate and evaporated to give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexenylmethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])[C:18]([Cl:36])=[CH:17][N:16]=1>>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOCC4)n3)cc2N1

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (80 mg, 60%). HPLC purity 99%, LCMS 498.21 (M+H), 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.47 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.15 (s, 1H), 7.33-7.30 (m, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93-6.89 (m, 2H), 6.82 (d, J=8.3 Hz, 1H), 4.61-4.59 (m, 1H), 3.603.56 (m, 2H), 3.37-3.33 (m, 2H), 2.55-2.52 (m, 2H), 2.07-2.03 (m, 4H), 1.78-1.74 (m, 2H), 1.48-1.45 (m, 2H).
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH2:3]1.Cl[O-:15].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C>[O:15]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH2:3]1
Reactant: NC1CCC(N2CCNC2=O)CC1
Reactant: [O-]Cl
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1CCC(N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18.3 g of 1-(4-aminocyclohexyl)-2-imidazolidinone as a mixture of cis and trans isomers, 2.0 g of benzyltributylammonium chloride, 250 ml of ethyl acetate and 360 ml of an aqueous 10% potassium hypochlorite solution [according to methodology as described by C. A. Meyers, J. Org. Chem. 26, 1046 (1961)] is stirred at room temperature for 11/2 hours. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The pooled organic phases are washed with water, sodium bicarbonate solution and dilute hydrochloric acid, then dried and evaporated to dryness to yield 1-(4-oxocyclohexyl)-2-imidazolidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])=[CH:4][C:3]=1[O:16][CH3:17].N1C=CC=CC=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>ClCCCl.CN(C=O)C>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])=[CH:4][C:3]=1[O:16][CH3:17])=[O:28]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1cc(C(=O)Nc2nccs2)ccc1N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COc1cc(C(=O)Nc2nccs2)ccc1NC(=O)CC(C)(C)C
Reaction time: 2 h

Procedure:
To 200 μL of a 0.2 M stock solution of 4-amino-3-methoxy-N-thiazol-2-yl-benzamide in 1,2-dichloroethane/DMF, containing 1.2 mmol pyridine per mmol 4-amino-3-methoxy-N-thiazol-2-yl-benzamide, was added 0.05 mmol of 3,3-dimethyl-butyric acid chloride. The reaction mixture was incubated at ambient temperature for 2 h. Purification was performed by preparative HPLC-MS.
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[C@H:9]3[C@H:14]([NH:15][C:31](=[O:33])[CH3:32])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.4 g (1.05 mmol) (−)-(cis)-7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine in a mixture of CH2Cl2 (10 mL) and triethylamine (0.44 mL, 3.15 mmol), acetyl chloride (0.187 mL, 2.62 mmol) in CH2Cl2 (5 mL) was added and it was stirred at ambient temperature for 1 h. Saturated (aq) NaHCO3 was added and the organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude compound which was used without further purification (0.44 g, 100%).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:33]C(=O)OC(C)(C)C)[C@H:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH3:11])=[O:8])[CH2:3]1.[ClH:41]>O1CCOCC1>[Cl-:41].[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:8])[C@@H:9]([NH3+:33])[C@H:10]([CH:12]2[CH2:13][CH2:14][CH:15]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[CH2:16][CH2:17]2)[CH3:11])[CH2:3]1
Reactant: Cl
Reactant: C[C@@H](C1CCC(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: C1COCCO1
Product: C[C@@H](C1CCC(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H]([NH3+])C(=O)N1CC[C@H](F)C1
Product: [Cl-]

Procedure:
To the solid material prepared in Step A (0.028 g, 0.047 mmol) was added a 4 M solution of hydrogen chloride in dioxane (2 mL). After 2 h at ambient temperature the reaction was concentrated in vacuo, affording the title compound as a white solid. 1H NMR (CD3OD): δ 7.99 (d, J=5.5 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 5.42 (s, 0.5H as a single rotamer), 5.36 (t, J=3.0 Hz, 0.5H as a single rotamer), 5.31 (s, 0.5H as a single rotamer), 5.26 (t, J=3.0 Hz, 0.5H as a single rotamer), 4.01 (d, J=9.0 Hz, 1H), 3.96 (d, J=9.0 Hz, 1H), 3.76 (m, 6H), 3.68 (s, 3H), 3.49 (m, 2H), 3.03 (m, 2H), 2.20 (m, 3H), 1.94 (m, 1H), 1.83 (m, 2H), 1.55 (m, 2H), 1.32 (m, 2H), 1.15 (m, 2H), 0.89 (dd, J=2.0 Hz, J=7.0 Hz, 3H); LC/MS 496.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[N:33]=[C:34]([CH3:37])[S:35][CH:36]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 10 minutes. 4-Chloromethyl-2-methylthiazole hydrochloride (310 mg, 1.68 mmol) was added and the mixture was heated at 70° C. for 3.5 hours. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride/acetonitrile/methanol (50/45/5 followed by 50/40/10). The resulting purified solid was dissolved in methylene chloride/methanol and a solution of 5M hydrogen chloride in isopropanol (1 ml) was added. Partial evaporation led to the precipitation of a white solid. This solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (240 mg, 35%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1F.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH2:30][CH2:31][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH2:30][CH2:31][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Reactant: CN1CCNCC1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 180 °C
Yield: 42.9 %

Procedure:
A microwave vial charged with 1-methylpiperazine (2.74 ml, 24.69 mmol) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.000 g, 8.23 mmol) was heated to 180° C. in a microwave reactor for 90 minutes. The reaction mixture was concentrated then transferred to a vial charged with Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.291 g, 0.412 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.96 g, 8.23 mmol), and potassium phosphate (8.74 g, 41.2 mmol). 8 mL dioxane and 4 mL water were added, and the reaction mixture was heated to 120° C. for 2 hours. After cooling to rt, the reaction mixture was poured into water and extracted with DCM. The organics were concentrated then purified by reverse phase column chromatography [RediSep Gold C18 150 g, 15 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding tert-butyl 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.68 g, 3.53 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:8][C:7]1[C:2]([Br:1])=[N:3][C:4]([I:9])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1nc(I)ccc1OCc1ccccc1

Procedure:
2-Bromo-6-iodopyridin-3-ol was reacted with potassium carbonate and benzyl bromide to obtain 3-(benzyloxy)-2-bromo-6-iodopyridine, which was then reacted in a similar manner to Reference Example 11, Example 22 and Example 4, successively. Further, the resulting product was subjected to catalytic reduction using palladium/carbon to obtain an objective compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([C:22]([F:25])([F:24])[F:23])[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([C:22]([F:25])([F:23])[F:24])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(CN)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 149.8 %

Procedure:
(4-Methanesulfonylamino-3-trifluoromethyl-5-vinylbenzyl)carbamic acid tert-butyl ester (89.3 mg, 0.23 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hr. The reaction mixture was purified according to step 6 of Example 8 to give a title product (101.4 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].C([O-])(=O)C.[NH4+]>CC(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc(C#N)c1)C(C)=O

Procedure:
3-cyanobenzaldehyde (2,62 g) was condenced with 2,4-pentanedione (3,0 g) in 2-propanol (10 ml) in the presence of ammonium acetate. Mp 63°-64° C., yield 1,27 g (30%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.[OH-].[Na+].C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(Br)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2sc(Br)c(-c3cccc(Br)c3)c2c(N)c1C(=O)O
Temperature: 150 °C
Yield: 77.1 %

Procedure:
To a solution of ethyl 4-amino-2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 47) (2.566 g, 5.46 mmol) in DMSO (25 mL) was added aqueous NaOH (2M) (13.64 mL, 27.3 mmol). The mixture was then heated at 150° C. for 1 h. After cooling to RT, the solution was diluted with water (40 mL) and acidified (ca. pH 4-5) with formic acid. The aqueous layer was then extracted with ethyl acetate (50 mL×3), and the combined organic layers were dried and concentrated. Water (excess) was then added to the residue, and a white precipitate crashed-out. The solution was filtered and the precipitate was collected and left to dry overnight in the vacuum oven, to give the title compound (1.861 g). LCMS (A) m/z: 443 [M+1]+, Rt 1.10 min (acidic).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[SH:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:23]1.[CH2:41]([C:43](C)=O)[CH3:42]>>[CH2:42]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:23]1)[CH2:41][CH3:43]
Reactant: CCC(C)=O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Reactant: BrCCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1ccccc1OCCCCCSCC1COC(CCC(=O)OCC)(CCC(=O)OCC)S1
Yield: 80 %

Procedure:
Potassium carbonate (2.5 g) was mixed with a solution of 5-phenoxy-1-bromopentane (1.7 g, 0.006 mol) and the product of Example 1 (2.0 g, 0.006 mol) in methyl ethyl ketone (20 ml). The reaction mixture was stirred and refluxed under a nitrogen atmosphere for 4 hrs and then worked up according to the procedure described in Example 2. The residue was chromatographed on silica gel using 4% acetone/benzene as eluent to give 1.8 g (80%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([CH2:7][C:8]([O-])=[O:9])[C:3]([O:5][CH3:6])=[O:4].CO>ClCCl.O1CCCC1>[F:1][C:2]([F:11])([CH2:7][CH2:8][OH:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)CC(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(F)(F)CCO
Temperature: 80 °C

Procedure:
In a 4 L flask equipped with a reflux condenser and 1 L dropping funnel, a solution of BH3.Me2S complex (10M, 88 mL) in dry dichloromethane (1 L) is slowly added over a 2 hour period to a stirred solution of the methyl 2,2-difluorosuccinate (120 g, 0.714 moles) in dry tetrahydrofuran at 20° C. After refluxing (bath temperature 80° C.) for about 15 hours, the mixture is allowed to cool to room temperature and methanol (1 L) is slowly added. Evaporation yields methyl 2,2-difluoro-4-hydroxybutyrate as an oil which is stripped with methanol (1 L) and finally with CCl4 to yield a yellow oil: 100 g (92%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([N+:15]([O-])=O)=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1CC2CC(C1)c1cc(N)ccc12
Yield: 98.5 %

Procedure:
10-ethyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (280 mg, 1.20 mmol) in 10 ml EtOH in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (239 mg, 98%).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.P(Cl)(Cl)([Cl:24])=O.Cl>C(#N)C.C(O)C.CCOCC>[ClH:24].[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:1]=[N:3][CH2:4][CH:5]2[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCC(CNC=O)c1cccc(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CCCC1CN=Cc2ccc(OC)cc21
Temperature: 60 °C

Procedure:
The formaldehyde obtained in Step C (6.8 g; 23 mmol) is dissolved in 100 ml of acetonitrile, then the reaction mixture is heated to approximately 60° C. Phosphorus oxychloride (7 ml) is added to the solution, which is heated at reflux for 6 hours with stirring and then evaporated under reduced pressure. The residue obtained is taken up twice in ethanol and evaporated under reduced pressure, and is then taken up in water. The aqueous phase is washed with dichloromethane and then rendered alkaline with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is taken un in ether saturated with HCl(g) and then evaporated under reduced pressure. The residue is taken up in toluene in the heated state and is stirred until precipitation occurs. The precipitate obtained is then suction-filtered off and the title product is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].[O:43]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:31]([NH:48][C:45]4[CH:46]=[CH:47][O:43][N:44]=4)=[O:32])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1
Reactant: Nc1ccon1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccon4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
3-((4-(4-Aminobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.152 mmol, 60 mg) was dissolved in dichloromethane (12 mL) and a solution of 4-nitrophenyl chloroformate (0.152 mmol, 30.7 mg) in dichloromethane (20 mL) was added dropwise. The reaction was stirred for 2 hours at room temperature. Isoxazol-3-amine (1.521 mmol, 128 mg) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue dissolved in dichloromethane. This solution was loaded onto a strong cation exchange column and washed with dichloromethane (20 mL) then methanol (20 mL). The column was then eluted with 2M ammonia in methanol (20 mL) and the eluent was concentrated under vacuum. The residue was purified by acidic reverse phase HPLC and lyophilised to give the title compound (46 mg).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].COCCOC.Cl.[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]2[O:33][CH2:3][CH2:4][N:5]=2)=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCBr
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1,2-dimethoxyethane are added simultaneously solutions of 31 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water. The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.