Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[O:4].[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[NH:29][C:30]2[S:31][CH2:32][C:33](=[O:35])[N:34]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH3:19])[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:32]1/[C:33](=[O:35])[N:34]=[C:30]([NH:29][C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:31]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Reactant: COc1c(C(=O)N(C)C)cnc2ccc(C=O)cc12
Product: COc1c(C(=O)N(C)C)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid dimethylamide (example 9c) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f) to give 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid dimethylamide. LC-MS m/e 473 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[NH:28]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH2:14][CH2:13]2)=[CH:37][CH:36]=1
Reactant: Cc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)CC2)cnn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)CC2)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
tert-Butyl {2-[(4-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}benzoyl)amino]phenyl}carbamate (prepared as described in Method 7; 308 mg, 0.61 mmol) was taken up in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) added. The reaction mixture was stirred at ambient temperature for 1 hour before being poured onto an SCX-3 cartridge (5 g). The cartridge was washed with dichloromethane (50 ml) and methanol (50 ml), before eluting the product with a 2M solution of ammonia in methanol (50 ml). The ammoniacal fraction was evaporated to afford a white solid (182 mg) that was purified by reverse phase preparative HPLC to afford the title compound (134 mg, 55%); NMR Spectrum: (DMSO d6) δ 1.70 (m, 4H), 2.01 (m, 2H), 2.22 (s, 3H), 2.57 (m, 1H), 2.95 (m, 2H), 3.28 (s, 2H), 3.71 (s, 3H), 4.86 (s, 2H), 6.60 (m, 1H), 6.78 (m, 1H), 6.97 (m, 1H), 7.17 (m, 1H), 7.23 (s, 1H), 7.37 (d, 2H), 7.90 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+404.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[N+]1([O-])CCOCC1.C(Cl)Cl.C(#N)C>C(OCC)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1

Procedure:
A mixture of the resultant alcohol from Example 16D (1.0 equivalent), N-methylmorpholine-N-oxide (1.5 equivalents), molecular sieves, and a catalytic amount of TPAP is stirred in a CH2Cl2/acetonitrile mixture until the reaction is judged complete by TLC analysis. The mixture is diluted with ethyl ether and filtered through SiO2. The product is purified by chromatography on silica gel.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]2=O>CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[Cl:3]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(Br)cc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(F)c(Br)cc2c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
Thionyl chloride (150 mL, 2.08 mol) was added to a solution of ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (25 g, 79.59 mmol) in DMF (50 mL) and the solution stirred at 80° C. for 4 h. The mixture was concentrated under vacuum and quenched by the addition of ice/water. The reaction mixture was extracted with DCM (8×100 mL), the organic extracts combined and the mixture adjusted to pH=7 by the addition of 1.5M ammonium hydrogen carbonate. The resulting mixture was washed with water (3×100 mL), the organics dried over Na2SO4 and concentrated in vacuo to afford the desired material (20 g, 76%) as a light yellow solid which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.49-1.42 (3H, m), 4.54-4.82 (2H, q), 7.86 (1H, d), 8.69 (1H, d), 9.23 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=334.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16](/[C:19](/[CH3:39])=[CH:20]/[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C@H:30]([O:36][CH2:37][CH3:38])[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](/[C:19](/[CH3:39])=[CH:20]/[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C@H:30]([O:36][CH2:37][CH3:38])[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)C(=O)O
Yield: 89.7 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (Example 101) (625 mg, 1.08 mmol) and sodium hydroxide (1M, 4.3 ml, 4.3 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (535 mg, 90%) as a colourless gum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:13]([OH:15])=O)([O-:9])=[O:8].[CH2:21]([CH2:23][NH2:24])[OH:22].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CCOC(C)=O.CCOCC.CN(C=O)C>[OH:22][CH2:21][CH2:23][NH:24][C:13](=[O:15])[C:12]1[CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCO)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Oxalyl chloride (6.4 g; 50.7 mmol; 5 eq) is added to a suspension of 3-nitro-5-methoxy benzoic acid (2 g; 10 mmol; 1 eq) and DMF (cat.) in DCM (50 mL) and the resulting mixture is stirred at room temperature for 1 h then evaporated to dryness. The residue is taken up in THF (20 mL) and added to a solution of ethanolamine (3.1 g; 50.7 mmol; 5 eq) and DIEA (6.6 g; 50.7 mmol; 5 eq) in THF (40 mL). The resulting mixture is stirred at room temperature for 2 h. The solution is evaporated to dryness and the residue partitioned between EtOAc and 0.5 M HCl. The aqueous phase is extracted with EtOAc (3×) and the combined organic layer is washed successively with 0.5 M HCl (2×) then brine (2×). After drying over MgSO4, the solution is concentrated in vacuo to afford a yellow solid. Trituration in a mixture of EtOAc and Et2O followed by filtration afforded 1.35 g (55%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 8.84 (t, J=5.6 Hz, 1H), 8.29 (t, J=1.7 Hz, 1H), 7.86 (d, J=1.7 Hz, 2H), 4.77 (t, J=5.6 Hz, 1H), 3.93 (s, 3H), 3.54 (q, J=5.8 Hz, 2H), 3.35 (q, J=5.6 Hz, 2H), HPLC (max plot) 99%; Rt 1.73 mm.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(C)=O
Reaction time: 8 h

Procedure:
812 mg of triphenylphosphine and 3 g of poly-Hunig base are added to a solution of 833 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 50 ml of dioxan and the mixture is stirred overnight at 50°. The poly-Hunig base is removed by filtration and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the title comcound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21]C)=[O:11])=[C:8]([CH3:23])[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]=1)[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[OH:21])=[O:11])=[C:8]([CH3:23])[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1O
Reaction time: 3 h
Yield: 40 %

Procedure:
To a cooled solution of 209 mg (0.5 mmol) 2-Ethylsulfanyl-N-[(4-fluoro-2-methoxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 17) in DCM (7 ml) were added dropwise 5 ml (5.0 mmol, 1M in DCM) BBr3 at −50° C. The RM was then allowed to reach 0° C. and stirring was continued at this temperature for 3 h. Then a 1M aq. NaHCO3 sol. (15 ml) was added at 0° C. and the mixture was diluted with MeOH (10 ml) and DCM (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 81 mg (0.2 mmol, 40%) 2-Ethylsulfanyl-N-[(4-fluoro-2-hydroxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 18). [M+H]+ 406.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: NC(=O)C1CC1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C2CC2)c1
Temperature: 90 °C
Yield: 84.5 %

Procedure:
A mixture of Example A3 (0.50 g, 1.882 mmol), cyclopropanecarboxamide (0.641 g, 7.53 mmol), Cs2CO3 (0.920 g, 2.82 mmol), and X-phos (0.045 g, 0.094 mmol) in dioxane (10 mL) was sparged with Ar, treated with Pd2(dba)3 (0.086 g, 0.094 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration. The filtrate was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (500 mg, 85%). MS (ESI) m/z: 315.1 (M+H+).
Reaction SMILES: CN(C)[N:3]=[CH:4][CH:5]=[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:9]1([C:7]2[NH:3][CH:4]=[CH:5][C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)N=CC=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 3.1 g (0.011 mole) of 4-dimethylhydrazono-1,2-diphenyl-2-buten-1-one, 11.2 g (0.064 mole) sodium hydrosulfite in 75 ml ethanol and 37.5 ml water was heated at reflux for three hours. The mixture was cooled and poured into 300 ml ice water. The white crystalline produce was collected, washed with water and air dried to give 1.9 g (79%), m.p. 130°-1°, identical to produce obtained via the decarboxylation, Method A.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].Cl>C1COCC1.CO.CCOCC.CCOC(C)=O>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
110 mg (0.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in a mixture of THF and methanol was refluxed with 1 ml (1 mmol) of LiOH (1M aqueous solution). Thereafter the mixture was diluted with Et2O:EtOAc (1:1), and acidified with aqueous HCl to pH5. The organic phase was separated, washed (water and brine), dried (MgSO4) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](O)([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.OC1(CC(OCC)=O)C2C=CC=CC=2CC2C=C(OC)C=CC=2C1>>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2cc(F)ccc21
Agent: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2ccccc21
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2cc(F)ccc21

Procedure:
According to the procedure of Preparation 10(f), except substituting ethyl (±)-10,11-dihydro-7-fluoro-10-hydroxy-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a colorless oil following silica gel, chromatography (10% EtOAc/hexanes): MS (ES) m/e 329.2 (M+H)+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1ccccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccccc1F
Yield: 89.8 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 2-fluoro-aniline (1.6 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.08 g of the crude title compound.
Reaction SMILES: [C:1]1(=[O:13])[C:5]2[CH:6]=[C:7]3[N:12]([C:4]=2[CH2:3][NH:2]1)[CH2:11][CH2:10][CH2:9][CH2:8]3.Br[C:15]1[N:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[O:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:23][C:19]1[C:16]([CH:17]=[O:18])=[C:15]([N:2]2[CH2:3][C:4]3[N:12]4[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]4)=[CH:6][C:5]=3[C:1]2=[O:13])[N:22]=[CH:21][CH:20]=1
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: O=C1NCc2c1cc1n2CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1Cc2c(cc3n2CCCC3)C1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 238d (400 mg, 2.27 mmol), 2-bromo-4-chloronicotinaldehyde (1.50 g, 6.90 mmol, 3.0 eq.), Pd2(dba)3 (208 mg, 0.227 mmol, 0.1 eq.), xantphos (131 mg, 0.227 mmol, 0.1 eq.), Cs2CO3 (1.50 g, 4.54 mmol, 2.0 eq.), and dioxane (30 mL). After bubbling nitrogen through the resulting mixture for 30 minutes, the reaction mixture was stirred at 90° C. for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residual was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 238e (300 mg, 42%) as a light yellow solid. MS-ESI: [M+H]+ 316.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.COC(=O)CC(=O)C(Br)C.COC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:28][C:29]=2[CH3:35])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: COc1ccc(-c2nc(CCO)c(C)s2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: COC(=O)CC(=O)C(C)Br
Agent: COc1ccc(C(N)=S)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-methoxy-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:3]([C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[N:20][O:21][CH3:22])[CH2:15][CH2:14]3)=[C:8](Br)[CH:9]=1)=[O:4].[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:3]([C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[N:20][O:21][CH3:22])[CH2:15][CH2:14]3)=[C:8]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)[CH:9]=1)=[O:4]
Reactant: CON=C1CCc2cc(-c3sc(C(=O)N(C)C4CCN(C)CC4)cc3Br)ccc21
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CON=C1CCc2cc(-c3sc(C(=O)N(C)C4CCN(C)CC4)cc3-c3ccncc3)ccc21
Yield: 71.6 %

Procedure:
The product of Step 2 (670 mg, 1.4 mmol), 4-pyridyl boronic acid (M. Lamothe et al J. Med. Chem., 1997, 40, 3542) (189 mg, 1.5 mmol), potassium carbonate (1.17 g, 8.5 mmol), triphenylphosphine (37 mg, 0.14 mmol), and palladium acetate (16 mg, 0.07 mmol) were dissolved in ethylene glycol dimethyl ether (15 ml) and water (5 ml). The biphasic solution was heated at reflux for 16 hours, with vigorous stirring, cooled, then filtered through a pad of celite, which was thoroughly washed with ethyl acetate. The two phase filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (×3) and brine. The solution was dried over magnesium sulfate and evaporated in vacuo to a crude solid (691 mg), which was purified by silica gel chromatography (1:9:90 0.880 ammonia:ethanol:dichloromethane), to afford the title product, (476 mg, 72%); MS (AP+) m/e 475 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2C(=O)C3=CC=CC=C3C2=O)C=CC=1.[ClH:19].[CH3:20][O:21][NH2:22].C(=O)([O-])[O-].[Na+].[Na+].O.NN.Cl>C(O)C.O>[ClH:19].[ClH:19].[NH2:8][CH2:4][CH2:3][CH2:2][NH:22][O:21][CH3:20]
Reactant: CON
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(Br)c1
Agent: Cl
Agent: NN
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CONCCCN
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10 g (0.037 mol) of N-(3-bromophenyl)-phthalimide, 6.2 g (0.075 mol) of methoxyamine hydrochloride and 15.0 g of sodium carbonate are suspended in 150 ml of ethanol and refluxed for 12 hours. After cooling, the salts are separated off by filtration and the solvent is removed. The oil which remains is treated with ethyl acetate, the insoluble residue is separated off and the solvent is removed. The oil which remains is taken up in 25 ml of ethanol and 1.15 g (0.023 mol) of hydrazine hydrate is added. The solution is stirred for 30 minutes at 80° C. After the addition of 3 ml of concentrated hydrochloric acid the mixture is stirred for a further 30 minutes at 80° C. 10 ml of water is then added and the whole filtered. Concentration and recrystallization from ethanol give the desired product as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH2:14](Br)[CH:15]=[CH2:16]>>[CH2:16]([N:4]1[C:5](=[O:12])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3]1=[O:13])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2ccccc21
Product: C=CCn1c(=O)c2ccccc2n(C)c1=O
Yield: 58 %

Procedure:
Starting from 1-methylquinazoline-2,4(1H,3H)-dione and allyl bromide and using Procedure E, the title intermediate was obtained as a colourless solid (0.125 g; 58% yield).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].OC1C(=O)[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:20])(=[O:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:19])(=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.3 %

Procedure:
Oxalyl chloride (0.185 g, 1.46 mmol) was added dropwise to a solution of 4-hydroxy-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.250 g, 0.88 mmol) in DCM (15 mL). The mixture was refluxed for 2 days and then evaporated. The residue was dissolved in water and extracted 3 times with dichloromethane. The combined organic layers were washed 2 times with water, dried through a phase separator and evaporated to give the title compound (0.245 g, 92%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.94-7.97 (m, 2H), 7.58-7.67 (m, 3H), 3.94 (t, 2H), 3.70 (t, 2H), 3.38 (s, 3H).