Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].II.[Cl:13][CH2:14][C:15]([CH2:17][Cl:18])=[O:16].Cl>O1CCCC1>[Cl:13][CH2:14][C:15]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1)([OH:16])[CH2:17][Cl:18]
Reactant: O=C(CCl)CCl
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCl)(CCl)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
A mixture of 1-bromo-3,5-difluorobenzene (5.0 g, 25.9 mmol), magnesium turnings (0.82 g, 31.1 mmol) and a small piece of iodine in dry tetrahydrofuran (50 mL) under nitrogen was stirred for 1 h at ambient temperature after which a solution of 1,3-dichloroacetone (3.46 g, 25.9 mmol) in dry tetrahydrofuran (20 mL) was added dropwise. The resulting mixture was stirred at ambient temperature for 1 h. Aqueous hydrochloric acid (50 ml, 5%) was added and the phases were separated and the aqueous phase was extracted with ethylacetate (2×50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (2.78 g, 45%). MS m/z (rel. intensity, 70 eV) 241 (M+, 1), 193 (32), 191 (bp), 127 (68), 77 (39).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH3:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(O)c1cccc(F)c1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound from Example 16 (55.5 g, 0.28 mol) in light petrol (100 cm3) was added dropwise to a stirred mixture of phosphorus pentoxide (127 g, 0.9 mol) in light petrol (300 cm3). The mixture was stirred overnight at room temperature (GLC analysis revealed reaction to be complete) and then filtered. 5% Palladium-on-charcoal (7 g) was added to the filtrate and the mixture was stirred under an atmosphere of hydrogen (12 h) at room temperature and pressure (GLC analysis revealed reaction to be complete). The palladium-on-charcoal was filtered off and the solvent was removed in vacuo to give the product as a colourless oil which was purified by distillation under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1cccc(C(F)(F)F)c1
Yield: 13.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with 3-trifluoromethylphenylboronic acid (47 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8 mg, 14%). MS m/e 473.16 (M+H+)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:8][C:7]1[CH:2]=[C:3]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sulfur trioxide pyridine complex (480 mg, 4.0 mmol) was added to a solution of 3-[3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (460 mg, 1.3 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.5 mL, 3.9 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (420 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.86 (s, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.63 (s, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 4.20 (t, J=6.1 Hz, 2H), 2.87 (t, J=6.1 Hz, 2H), 2.26 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:12]=[N:11]1)[CH3:18]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#Cc1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and ethyl azidoacetate (1.08 ml, 1.92 mmol) were combined in t-BuOH (4.0 mL) and water (2.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (1.0 mL). The reaction was stirred at room temperature for 5 h, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-30% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:59]1[CH:64]=[C:63]([O:65][CH2:66][CH3:67])[N:62]=[C:61]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:60]=1>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]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:59]2[CH:64]=[C:63]([O:65][CH2:66][CH3:67])[N:62]=[C:61]([S:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=3[F:77])[N:60]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
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: CCOc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-(aminosulfonyl)-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (67 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (35 mg), cesium carbonate (0.36 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-ethoxy-pyrimidine (the product from example 14, step i) (0.23 g) in dioxane (5 mL). Purification was by column chromatography on silica using EtOAc/isohexane (1:9 to 1:3 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.25 g
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][N:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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]>[F:8][C:3]1[C:2]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: Cc1cc(B(O)O)ccn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2cccnc2F)ccn1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 3-bromo-2-fluoropyridine (1.0376 g, 5.9 mmol), 2-methylpyridin-4-ylboronic acid (1.6154 g, 12 mmol), tris(dibenzylideneacetone)dipalladium(o) (0.5501 g, 0.59 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.4846 g, 1.2 mmol), and sodium carbonate (0.74 mL, 18 mmol) in acetonitrile:water (5:1 ratio) at 85° C. to stir overnight. The reaction was monitored by LCMS. Upon completion, the solvents were evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40S), eluting with a gradient of 0.5% to 5% methanol in DCM, to provide 4-(2-fluoropyridin-3-yl)-2-methylpyridine. [M+1]=189.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[C:8]([CH3:13])[N:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2nc(C)c(I)cc2c1O
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1I
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of ethyl 4-hydroxy-6-iodo-7-methyl[1,8]naphthyridine-3-carboxylate Prep 4(0.41 g) and 4-chlorobenzylamine (2.50 mL) is heated at 180° C. for 1 h. The reaction is cooled to room temperature. Ethyl acetate (10 mL) and then hexanes (20 mL) are added and the solid is filtered, washed thoroughly with hexanes, and dried. The crude solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (3L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (2L)) affords the desired product as a white solid (0.30 g, 0.66 mmol, 58%). Physical characteristics are as follows: m.p. 276-277° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.17, 10.10, 8.83, 8.66, 7.40, 7.35, 4.54, 2.77; IR (drift) 3063, 3022, 2957, 2895, 1650, 1596, 1552, 1521, 1493, 1405, 1352, 1323, 1241, 1095, 807 cm−1; MS (ESI) m/z 453.6 (M+H)+, 451.7 (M−H)−; Anal. Calcd for C17H13ClIN3O2: C, 45.01; H, 2.89; N, 9.26; Found: C, 44.92; H, 2.78; N, 9.17.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]#[C:15][C:16]1[C:24]2[S:23][C:22]([N:25]3CN(C)C[N:27]([CH2:32][CH3:33])[C:26]3=[O:34])=[N:21][C:20]=2[CH:19]=[C:18]([C:35]2[CH:36]=[N:37][C:38]([N:41]3[CH2:46][CH2:45][C:44]([CH2:52][CH3:53])([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]3)=[N:39][CH:40]=2)[CH:17]=1.[OH-].[Na+].C(Cl)Cl>CCO.O.CO>[O:12]1[CH2:13][CH2:14][C:15]([C:16]2[C:24]3[S:23][C:22]([NH:25][C:26](=[O:34])[NH:27][CH2:32][CH3:33])=[N:21][C:20]=3[CH:19]=[C:18]([C:35]3[CH:40]=[N:39][C:38]([N:41]4[CH2:42][CH2:43][C:44]([CH2:52][CH3:53])([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]4)=[N:37][CH:36]=3)[CH:17]=2)=[N:3]1
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCON4C(=O)c5ccccc5C4=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C3=NOCC3)c2s1
Temperature: 100 °C

Procedure:
Ethyl 1-[5-[7-[3-(1,3-dioxoisoindolin-2-yl)oxyprop-1-ynyl]-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (233 mg, 0.32 mmol) was suspended in EtOH (20 mL) and sodium hydroxide solution (10 mL, 1 M, aq) was added to give a light yellow solution. The solution was heated at 100° C. then cooled to rt after 48 h. The mixture was concentrated to dryness under reduced pressure and remaining water azeotroped with MeCN. The resulting yellow residue was suspended in MeOH with sonication and warming then filtered through a PTFE filter cup. A white (salt-like) solid was obtained (discarded) and a yellow filtrate. The yellow filtrate was concentrated to dryness under reduced pressure to give a yellow solid which was suspended in water, sonicated, DCM added and the mixture filtered through a PTFE filter cup leaving a pale yellow solid. This solid was dissolved in MeOH, passed through the filter cup and the solution concentrated to dryness under reduced pressure to give a pale yellow solid which was purified by chromatography, Biotage SP4, 40 g Si cartridge, 0-5% MeOH in DCM. The relevant fractions were combined to afford Compound 197 as a pale yellow solid, 9 mg. 1H NMR (MeOD): δ 8.67 (2H, s), 7.85 (1H, d, J=1.6 Hz), 7.51 (1H, d, J=1.6 Hz), 4.57 (2H, t, J=10.2 Hz), 4.57 (2H, m), 3.60 (2H, t, J=10.2 Hz), 3.36 (2H, q, J=7.2 Hz), 3.24 (2H, m), 2.22 (2H, dm, J=13.4 Hz), 1.64 (2H, J=7.5 Hz), 1.45 (2H, m), 1.24 (3H, t, J=7.2 Hz), 0.93 (3H, t, J=7.5 Hz). MS: 524.14 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[C:17]([CH3:19])=[CH2:18]>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18]
Reactant: C=C(C)c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Solvent: CO
Product: COC(=O)c1cc(-c2c(C(C)C)cnn2C)c(C)s1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (171 mg, 0.62 mmol) in methanol (3 ml) was added PdOH2 (34.8 mg, 0.25 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N2, filtered through Celite and concentrated affording methyl 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (173 mg, 0.62 mmol, 100% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.CN(C)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=1>[Cl-].[Zn+2].[Cl-].ClC1C=CC=CC=1>[CH2:8]([O:9][C:18]1[CH:19]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:22][C:23]=1[C:8]([C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([OH:10])=[O:12])=[O:9])[CH:7]([CH3:6])[CH3:2]
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)COc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
In a manner similar to that of part A of Example 3 condensation of tetrachlorophthalic anhydride (1.92 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) in contact with zinc chloride (1.35 g.) and with chlorobenzene (40-45 ml.) as diluent afforded 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (II: Y'2 = Y'4 = (CH3)2N, Z4 = Z'5 = Z'6 = Z7 = Cl) (m.p. 199°-201° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:25](O)=[O:26]>>[OH:11][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([CH:25]=[O:26])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc2c(c1O)CCC2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1cc(C=O)c2c(c1O)CCC2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5-Methylindan-4-ol (4.50 g) and hexamethylenetetramine (4.26 g) were dissolved in trifluoroacetic acid (100 mL), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture. After stirring for 30 min, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.76 g).
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:4])[C:6]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7]1)[CH3:2]
Reactant: CCI
Reactant: CS(=O)(=O)Cc1cnc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 8 h

Procedure:
Ethyl iodide (2.93 g.) was added to a stirred mixture of 4-hydroxy-3-methylsulphonylmethylquinoline (1.93 g.), anhydrous potassium carbonate (2.3 g.) and 2-butanone (80 ml.) The mixture was boiled under reflux for 24 hours and the solvent was evaporated. The mixture was diluted with water (200 ml.) and left overnight. The mixture was filtered and the filtrate evaporated to dryness to give a white solid. This was purified by high pressure liquid chromatography over silica gel using ethyl acetate:isopropanol 9:1 as the eluant at a flow rate of 200 ml. per minute. There was obtained the novel compound 1-ethyl-3-methylsulphonylmethyl-4-quinolone, m.p. 162°-164°.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Br:7][C:8]1[S:12][C:11]([C:13](=[O:19])[CH2:14][CH2:15]C(O)=O)=[CH:10][CH:9]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[Br:7][C:8]1[S:12][C:11]([C:13](=[O:19])[CH2:14][CH2:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#CCC(=O)CCC(=O)c1ccc(Br)s1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 2-cyanoacetic acid (13 g, 50 mmol) in THF (100 mL) was added dropwise i-PrMgC1 (16 g, 250 mmol) at −78° C. for 1 h. A solution of 4-(5-bromothiophen-2-yl)-4-oxobutanoic acid (8A) and CDI (12 g, 74 mmol) in THF was added dropwise at −78° C. and the resultant mixture was stirred at −78° C. for 1 h and at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (200 mL). The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford 8B as a black oil (9.7 g, 69%).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:35](=[O:36])[O:37][CH:38]([CH3:40])[CH3:39])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)OC(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
80.0 mg (0.217 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 75.9 mg (0.750 mmol) of triethylamine was added to the obtained solution. Then a solution of 31.9 mg (0.260 mmol) of isopropyl chloroformate in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=93:7 to 3:1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>ClCCl>[CH2:18]([O:25][C:26](=[O:27])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-bis(aminomethyl)benzene (10.0 g, 74 mmol) and triethylamine (9.8 ml, 74 mmol) in dichloromethane (480 ml) was cooled to 0° C. and treated with a solution of benzylchloroformate (10.5 ml, 74 mmol) in dichloromethane (250 ml). The resulting mixture was allowed to warm gradually to room temperature of a period of 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (450 ml) and 1M aqueous sodium hydroxide (300 ml). The resulting biphasic mixture was filtered and the organic phase separated, dried (magnesium sulfate) and reduced in vacuo to give a waxy solid. Trituration with hot ethyl acetate followed by concentration of the liquors gave the title compound as a waxy solid (7.4 g).
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=1[CH2:26][O:27][CH3:28]>C(#N)C>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)=[CH:19][C:18]=1[CH2:26][O:27][CH3:28]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1Br
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1Br

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (0.50 g; 2.36 mmol) and Intermediate 37 (0.64 g; 2.59 mmol). Title compound was isolated after trituration with ACN as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.23 (d, J=2 Hz, 1H), 8.14-8.09 (m, 1H), 8.06-8.02 (m, 1H), 8-7.92 (m, 3H), 4.57 (s, 2H), 3.90 (s, 3H), 3.46 (s, 3H). LC/MS (Method B): 423.1 (M+H)+. HPLC (Method A) Rt 5.91 min (purity: 98.5%).
Reaction SMILES: C([C:3]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)=O.C1C=CC=CC=1.C[C:27](C)=[O:28]>>[CH:27]([C:4]1[C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[C:16]([Cl:19])=[C:17]([Cl:18])[CH:3]=1)=[O:28]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1COc2cc(C=O)c(Cl)c(Cl)c2O1
Solvent: c1ccccc1
Product: CCOC(=O)C1COc2c(C=O)cc(Cl)c(Cl)c2O1
Yield: 49 %

Procedure:
This is passed through Lober column B (made by Merck) with benzene/acetone (30/1) as an eluent. The product in the earliest fraction is recrystallized from acetone/ether/petroleum ether to give 1.031 g (yield 47%) of the objective ethyl 6-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-51), m.p. 101°-102° C. And the product in the later fractions are also recrystallized in the same manner as above to give 1.057 g (yield 49%) of ethyl 5-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-50), m.p. 110°-113° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:3][CH:4]([O:7]C1CCCCO1)[C:5]#[CH:6].C(BC(C(C)C)C)(C(C)C)C.C[N+]([O-])(C)C.[OH-].[Na+].[I:36]I.O1CCCC1CC(O)=O.O>COCCOCCOC>[CH3:1][C:2]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:3][CH:4]([OH:7])/[CH:5]=[CH:6]/[I:36]
Reactant: II
Reactant: C#CC(CC(C)(C)CCC)OC1CCCCO1
Agent: CC(C)C(C)BC(C)C(C)C
Agent: C[N+](C)(C)[O-]
Agent: O=C(O)CC1CCCO1
Solvent: O
Solvent: COCCOCCOC
Product: CCCC(C)(C)CC(O)/C=C/I

Procedure:
Treatment of 23.8 g. (0.100 mole) of 5,5-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 999) successively with 233 ml. of 0.43 M disiamylborane in diglyme, 22.5 g. of trimethylamine oxide, 150 ml. of 1 N sodium hydroxide, 25.4 g. of iodine, and 900 ml. of 3:1:1 tetrahydrofuranacetic acid-water as described in Example 996 gives the title compound.