Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.O1CCOCC1>[CH2:22]([S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nncc2cc(SCc3ccccc3)ccc12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A two-neck round-bottom flask was charged with 6-bromo-1-chlorophthalazine (Pharmablock, Nanjing Hi-Tech Zone, China, 4.44 g, 18.24 mmol), Xantphos (0.528 g, 0.912 mmol), and Pd2(dba)3 (0.417 g, 0.456 mmol). 1,4-dioxane (36.5 ml) and N,N-diisopropylethylamine (6.37 ml, 36.5 mmol) were added. The flask was fitted with a reflux condenser and placed in an 80° C. heating bath. After 5 min, benzyl mercaptan (2.265 ml, 19.15 mmol) was added drop wise. After 20 min. the mixture was cooled, then concentrated under a vacuum. EtOAc (about 25 mL) was added to the residue, and the flask was rotated on the rotovap in a 40° C. bath for 1.5 h. This removed most of the solid from the sides of the flask. The flask was sonicated for 30 s, then the mixture was concentrated under a vacuum. The residue was taken up in EtOAc to form a thick slurry. The flask was sonicated for 30 s, then the mixture was filtered. The collected solid was washed with several large volumes of EtOAc (until the filtrates were essentially colorless). The filtrate was concentrated, and the residue was purified by chromatography on silica gel (80-g column with a 25-g silica gel loading column, 0 to 50% EtOAc/Heptane, then 50 to 100% EtOAc/Heptane). The resulting solid was taken up in heptane, sonicated for 30 s, then filtered. The collected solid was washed with heptane (3×, which removed some of the yellow color), and dried under a stream of N2 (g) for 20 min to give 6-(benzylthio)-1-chlorophthalazine (3.975 g, 13.86 mmol, 76% yield) as a light-orange powder: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=9.28 (d, J=0.7 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.82 (dd, J=1.9, 8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.45-7.28 (m, 5H), 4.35 (s, 2H); m/z (ESI) 287.2 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:18]([O:17][C:15]([C:12]1([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 118.6 %

Procedure:
To a solution of 7.84 g (30.0 mmoles) ethyl 1-benzoyl-4-piperidinecarboxylate (G. R. Clemo and E. Hoggarth, J. Chem. Soc., 41, (1941) in 60 ml dry tetrahydrofuran at -78° C. under argon was added dropwise over 10 minutes 33.0 ml (33.0 mmoles) lithium bis(trimethylsilyl)amide in tetrahydrofuran and the resulting solution was stirred 30 minutes. To this solution was added dropwise over 2 minutes 5.64 g (33.0 mmoles) benzyl bromide in 10 ml dry tetrahydrofuran and the resulting solution was stirred overnight while warming from -78° C. to room temperature. The reaction was quenched with 20 ml saturated ammonium chloride solution and extracted with 2×100 ml ethyl acetate. The combined extracts were washed with 20 ml water and brine, dried, and the solvent removed in vacuo to give an oil. The oil was stirred under 25 ml hexane at -15° C., the hexane was decanted and the oil was dried in vacuo to give 12.5 g crude product as a viscous oil;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: CC1=C(C(=O)OCc2ccc(Cl)c(Cl)c2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CC(C)O
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)c(Cl)c1
Yield: 75 %

Procedure:
Analogously to Example 1 eating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3,4-dichlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3, 4-dichlorobenzyl ester of melting point 155° C (from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([CH2:18][CH2:19][OH:20])[N:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O-:23][C:24]#[N:25].[Na+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:24]([O:20][CH2:19][CH2:18][N:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[CH:14][CH:15]=[N:16]1)(=[O:23])[NH2:25]
Reactant: OCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NC(=O)OCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A solution of 2-[5-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl]ethanol (118 mg, 0.40 mmol) in 1 mL of toluene was treated with solid sodium cyanate (2 eq.; 53 mg, 0.82 mmol) added in one portion. The resulting mixture was cooled in an ice-water bath and neat trifluoroacetic acid (60 μL, 89 mg, 0.78 mmol) was added dropwise via syringe. The reaction was stirred at room temperature. After 2 hours, the reaction had completely solidified and an additional 1 mL of toluene was added. After stirring overnight, the reaction was recooled to 0° C. and diluted with 3 mL of a saturated aqueous NaHCO3 solution. The aqueous layer was separated and extracted with EtOAc (3×5 mL). The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography (13 cm of flash silica in a 2 cm diameter column eluted with 600 mL of 3:2 CH2Cl2/EtOAc) afforded 21 mg (15%) of the carbamate as a solid, mp 120-125° C. 1H NMR (CDCl3): δ7.57 (d, 1H, J=2 Hz), 7.35 (d, 2H, J=9 Hz), 7.10-7.05 (m, 4H), 7.02 (d, 2H, J=9 Hz), 6.26 (d, 1H, J=2 Hz), 4.60 (br s, 2H), 4.43 (t, 2H), 4.35 (t, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl>[Br:25][C:5]1[CH:4]=[C:3]([F:2])[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc2c1OC(C1CCNCC1)C2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(Br)cc2c1OC(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidine hydrochloride (1.18 g, 4.58 mmol) in MeOH (36.6 mL) at 0° C. was added NBS (0.815 g, 4.58 mmol) in one portion. Upon completion of addition, the reaction mixture was immediately warmed to room temperature, where it stirred for 3 hours. At the conclusion of this period, the reaction mixture was quenched with aqueous Na2H2S2O5 (5%, 5 mL). The solvent was removed under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 (5 mL), washed with NaHCO3 (aq, sat, 3 mL) and brine (3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to afford Compound 3E as a colorless oil (1.3 g, 95% yield). LC/MS (m/z)=301 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[CH2:16][CH2:15]1
Reactant: OCC(O)CN1CCNCC1
Reactant: NC(=O)c1cccnc1Cl
Solvent: CCO
Product: NC(=O)c1cccnc1N1CCN(CC(O)CO)CC1
Yield: 34.9 %

Procedure:
Operation was carried out in a manner similar to the one described in Example 2, using 1.6 g of 2-chloronicotinamide, 3.2 g of 1-(2,3-dihydroxypropyl)piperazine and 30 ml ethanol and refluxing overnight. Column purification of the residue gave 1 g of 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]nicotinamide, which, recrystallized from acetone, melted at 140°-142° C.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1)=[CH2:2]
Reactant: Nc1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1ccc(N)nc1
Yield: 74 %

Procedure:
Vinyltributyltin (13 mL, 44.6 mmol), palladium(II) acetate (0.45 g, 2.1 mmol), triethylamine (12.4 mL, 89.1 mmol) and tri-(o-tolyl)phosphine (3.69 g, 12.15 mmol) were added to a solution of 5-bromopyridin-2-amine (7.0 g, 40.5 mmol) in acetonitrile (70 mL) and the reaction mixture refluxed for 18 hours. The reaction mixture was washed with 2M sodium carbonate solution (80 mL), the organics separated, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using methanol:dichloromethane 3:97 to yield 3.6 g of product. This residue was dissolved in dichloromethane and washed with aqueous solutions of potassium fluoride and then sodium hydrogencarbonate. The organic solution was dried over magnesium sulphate, filtered and concentrated in vacuo to yield 1.9 g of final product.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[N:8][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:25]
Reactant: CN1CCCC1=N
Reactant: Cc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(NC(=O)N=C2CCCN2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 6.73 g. (0.05 mole) of 1 -methyl-2 -iminopyrrolidine hydrochloride in 100 ml. of benzene is added 2 ml. of water followed by 5 ml. of 50 % NaOH. After stirring for 5 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice with 75 ml. portions of fresh benzene. The combined extracts are filtered from drying agent (dicalite pad and suction). To the filtrate is added in one portion with stirring 6.66 g. (0.05 mole) of p-tolylisocyanate. After stirring for 5 hours, the solution is taken to dryness in vacuo and the resulting solid is recrystallized from ethyl acetate to give 1 -(1 -methyl-2 -pyrrolidylidene)-3 -p-tolylurea, m.p. = 136°-137° C. A final recrystallization from acetone shows the product melting at 149°-150° C. Thin layer chromatography (TLC) indicates both samples to be identical in purity. Apparently the two melting points represent polymorphic forms.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][C:4]2[NH:3][C:2](=[O:1])[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 7.00 g (33.9 mmol) of ethyl 2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (IV) and 3.02 ml (37.3 mmol) of sulfuryl chloride in acetic acid (90 ml) was stirred at 90° C. for 1 h. The cooled reaction mixture was poured into ice-water. The precipitated solid was filtered off, washed with water, dried in vacuo and recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(C)C=CC=C[CH:12]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:11]([O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)=[O:10])[CH3:12]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(Br)c1

Procedure:
To a suspension of 2-bromo4-pyridine carboxylic acid (prepared according to the method of Ashimori, Chem. Pharm. Bull. 38 (9) 2446-2458 (1990)) in 2:1 toluene: absolute ethanol (45 mL) was added sulfuric acid (0.75 mL). The mixture was heated at reflux for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with chloroform (3 times). The combined chloroform extracts were dried over magnesium sulfate, filtered and concentrated afforded the crude product as a yellow oil. Purification by silica gel chromatography eluting with 9:1 hexane:ethyl acetate to afford the title compound (900 mg) as a clear, colorless oil.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([OH:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].C=O.S(=O)(=O)(O)O.[O:24]1[CH2:29]COC[CH2:25]1>>[CH:2]1[C:3]2[C:8]3[C:9]([C:11](=[O:12])[O:13][C:14](=[O:15])[C:7]=3[CH:6]=[C:5]3[C:4]=2[O:16][CH2:29][O:24][CH2:25]3)=[CH:10][CH:1]=1
Reactant: O=C1OC(=O)c2ccc(O)c3cccc1c23
Reactant: C1COCCO1
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc3c(c4cccc1c24)OCOC3

Procedure:
To a suspension of 620 mg (2.9 mmol) of 4-hydroxy-1,8-naphthalic anhydride (from Example S3) and 1.60 g (53.0 mmol) of paraformaldehyde in 20 mL dioxane was added 5.2 mL of concentrated sulfuric acid. The reaction mixture was refluxed for 1 hour and quenched with 100 mL water. The precipitate was isolated, dried, recrystallized from DMSO, washed with acetone, and dried again to yield 0.50 g of the title compound.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:14])=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23]C)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(B(O)O)c1C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc(O)c2C)cc1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.3 g (16.7 mmol) of 3-methoxymethoxy-2-methylbenzene-1-boronic acid (described in Example 11(c)) with 3 g (13.9 mmol) of ethyl 4-iodobenzoate, 16.7 mL of 2.0M potassium carbonate solution and 800 mg (0.69 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a colourless oil (m=3.07 g; Y=77%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (76 mg, 86%), MS (ISP) m/z=353.5 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-isopropyl-phenylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:28])([F:27])[F:26])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-5-{3-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromophenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.46 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light brown solid (0.46 g), which was subsequently deprotected.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O:33]CC)=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C.C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O-:33])=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40]
Reactant: CCOC(=O)COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (7.8 g) in a mixture of ethanol (50 ml) and THF (50 ml) was added 1N-NaOH solution (15.3 ml) at room temperature. After being stirred for 4 hours at the same temperature, the mixture was evaporated. The residue was washed with diethyl ether to afford sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}-phenoxy}acetate(6.7 g).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH2:42][NH2:43]>>[CH3:48][O:47][C:45]1[CH:44]=[C:41]([CH:40]=[C:39]([O:38][CH3:37])[CH:46]=1)[CH2:42][NH:43][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc(OC)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3,5-dimethoxybenzylamine, m.p. 183-184° C. MS [(+)ESI, m/z]: 584 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.CC1C=CC(N=[CH:27][C:28]2[C:29]([NH2:37])=[CH:30][C:31]3[O:35][CH2:34][O:33][C:32]=3[CH:36]=2)=CC=1>>[CH3:17][O:16][C:10]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[C:3]([O:2][CH3:1])[C:4]2[CH2:5][C:6]3[C:7]([C:8]=2[CH:9]=1)=[N:37][C:29]1[CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]2=[CH:36][C:28]=1[CH:27]=3
Reactant: COCOc1c(OC)cc2c(c1OC)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COCOc1c(OC)cc2c(c1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 78.7 %

Procedure:
Using the procedure of Example 1, 4,6-dimethoxy-5-methoxymethoxyindan-1-one (100 mg, 0.4 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (101 mg, 0.4 mmol) to yields 7,9-dimethoxy-8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (120 mg, 79% of theory). This material was used directly in part (B).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([NH2:18])[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[S:33][C:32]([S:34]([NH:18][CH:4]([C:5]2[N:9]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:36])=[O:35])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ccnn1-c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(OC)cc1
Yield: 54 %

Procedure:
To a stirred solution of the {2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}amine (0.77 g, 2.8 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.59 mL, 4.2 mmol) and 5-chlorothiophene-2-sulfonylchloride (0.73 g, 3.4 mmol). The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed twice with 1N HCl, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a tan solid in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[C:6]([CH3:9])=[C:5]([Cl:10])[N:4]=[N:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)nnc(Cl)c1CBr

Procedure:
To a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (500 mg, 2.82 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (503 mg, 2.82 mmol), and AIBN (2.3 mg, 0.014 mmol) in a round bottom flask equipped with condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 5 h. The formed succimide was filtered and the filtrate was concentrated to afford 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine as a brown solid. To a solution of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (400 mg, 1.56 mmol) in DMF was added with benzyl amine (188 μL, 1.72 mmol) and TEA (326 μL, 2.34 mmol). The reaction mixture was heated at 90° C. for 2 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford a brown oil. The crude material was purified by flash chromatography on silica gel, eluting with 30-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a the title compound as a greasy solid (430 mg, yield: 54% (two steps)).