Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
22.2 g(0.2 mol) of 4-aminomethyl piperidine was dissolved in 250 ml of toluene and 21.2 g(0.2 mol) of benzaldehyde was added thereto. The reaction mixture was heated to reflux for 3 hours with Dean-stack and then cooled down to 0° C. 34.2 g(0.2 mol) of benzyl chloroformate was added dropwise while stirring. The reactants were stirred for 3 hours and 220 ml of 1N KHSO4 was added at room temperature. The reaction solution was extracted with 200 ml of diethylether 3 times and the aqueous layer was basified with sodium hydroxide. After the aqueous solution was treated with saturated sodium chloride solution, it was extracted with 100 ml of dichloromethane 3 times. and the organic layer was dried over magnesium sulfate. Removal of dichloromethane under reduced pressure provided 38 g of the title compound(Yield 91%, MW 248).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH:7]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1c(CC(=O)O)sc2ccccc12
Reactant: BrCCCc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(CCCc2ccccc2)C(=O)O)sc2ccccc12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 3-methylbenzo[b]thiophene-2-acetic acid (1.00 g) in THF at −78° C. under nitrogen was added a solution of n-butyllithium in hexanes (2.5M; 3.98 ml). Stirring was continued for 15 mins at this temperature before 1-bromo-3-phenylpropane (965 mg) was added. The mixture was stirred for 30 mins before allowing to warm up to RT and then stirred at RT for a further 1 h. The reaction mixture was poured on to a mixture of water (50 ml) and 1 N sodium hydroxide solution (10 ml). The organic layer was separated and washed with water (2×10 ml), brine (10 ml) and dried (MgSO4). Filtration and evaporation of solvents under reduced pressure gaven the crude product, which was purificatied by silica gel column chromatography, eluting with 2:1 hexane/ethyl acetate, to give the title compound (579 mg, 37%) as a pale green oil. Rf 0.45 (2:1 hexane/ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](O)[CH3:8])=[CH:3][CH:2]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH3:8])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccncc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 48.4 %

Procedure:
A tetrahydrofuran solution (10 mL) of 1-(pyridin-4-yl)ethanol (283 mg, 2.32 mmol), phthalimide (375 mg, 2.55 mmol) and triphenylphosphine (686 mg, 2.55 mmol) was mixed with diisopropyl azodicarboxylate (40% in toluene, 1.34 mL, 2.55 mmol) and stirred at room temperature for 29 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give the desired product (283 mg, 48% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].C([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3C=O)[C:27]3[C:26](=[O:37])[N:25]([CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C:24](=[O:46])[N:23]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=O)(C)(C)C.O1CC[CH2:57][CH2:56]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:2]([O:4][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:56]=[CH2:57])[C:27]3[C:26](=[O:37])[N:25]([CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:43])([CH3:42])[CH3:44])[C:24](=[O:46])[N:23]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:52])([CH3:53])[CH3:51])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:11])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(=O)n(COC(=O)C(C)(C)C)c(=O)n3COC(=O)C(C)(C)C)n2-c2ccccc2C=O)CC1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (3.52 g) was dissolved in tetrahydrofuran (20 ml), potassium tert-butoxide (948 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. A solution of 4-[1,3-bis(2,2-dimethylpropionyloxymethyl)-7-(2-formylphenyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (1.94 g) in tetrahydrofuran (20 ml) was added to the obtained reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours and 50 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 704 mg of the title compound from the elution fraction of hexane-ethyl acetate (2:1).
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+]([O-])(O)=O>C(OCC)(=O)C.CC(O)=O.[Ag]=O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Br)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Following a modified procedure of Shinkawa et al. and Flader et al.,16,22 the acid 99e (0.291 g, 0.829 mmol) was dissolved in ethyl acetate (10.0 mL) at room temperature, then HNO3 (1.0 mL) and AcOH (6 drops) are added at room temperature. Silver (II) oxide (0.379 g, 3.05 mmol) was then added and the reaction was stirred vigorously at room temperature for 1 hour before being filtered through a pasture pipette and cotton plug, washing the solid with ethyl acetate, and then washing the organic layer with brine. The organic layer was dried over MgSO4, filtered, and condensed. The yellow oil was then purified by either flash column:chromatography (1:1 Et2O:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to afford 39a (0.122 g 0.380 mmol, 46%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([NH2:25])=[O:24].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([NH2:25])=[O:24])=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: NC(=O)c1sccc1N
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1sccc1NC(=O)c1cc(F)c(Br)cc1F

Procedure:
After stirring a mixture of 4-bromo-2,5-difluorobenzoic acid and thionyl chloride for one hour at 80° C., the solution was removed and an oily substance was obtained. A mixture of the obtained oily substance, 3-aminothiophene-2-carboxamide, N,N-diisopropylethylamine and THF was stirred for two hours under ice cooling to give 3-[(4-bromo-2,5-difluorobenzoyl)amino]thiophene-2-carboxamide.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[OH-].[Na+]>CO.O>[N:7]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 25 °C

Procedure:
250 ml of water and 500 ml of methanol are added to 194 g (1 M) of piperazine hexahydrate, while stirring, and the pH is adjusted to 3 with about 163 ml of concentrated hydrochloric acid. The mixture is then cooled to 25° C. and 100 g (0.59 M) of benzyl chloroformate are added dropwise, while stirring, during which the pH is kept between 3 and 4.5 with sodium hydroxide solution (4 M; about 230 ml). About 700 ml are then stripped off on a rotary evaporator and the residue is washed with water, rendered acid with about 1.5 ml of concentrated HCl and extracted twice with 200 ml of toluene each time. The aqueous phase is cooled and brought to pH 12 with about 115 ml of 12.5 N NaOH. The oil which separates out is extracted several times with toluene, and the extract is dried over K2CO3 and concentrated under reduced pressure. Yield: 74 g
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C([O-])([O-])=O.[K+].[K+].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.8 %

Procedure:
A mixture of 2.0 g (12.3 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone, 2.0 g (52 mmol) of K2CO3 and 0.75 g of acetic anhydride in 20 ml of DMF was stirred at room temperature for 2.5 days. The mixture was then warmed to 70°-80° and an additional 1.5 g of acetic anhydride was added and stirring was continued for five hours. The reaction was poured into 250 ml of water and the resulting solid was collected, washed with water, and air dried. It was recrystallized from EtOH and then chromatographed (SiO2, 9:1 methylene chloride/MeOH) to give 0.72 g (29%) of product; mp 189°-193°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
Complexes 7a, 7b, 7c are used for Suzuki coupling reaction of iodobenzene and benzeneboronic acid, as shown in scheme 2, above. Iodobenzene (2.5 mmol, 1 equiv.), benzeneboronic acid (2.75 mmol, 1.1 equiv.), Na2CO3 (560 mg, 5.28 mmol, 2.1 equiv.), palladium complex (0.03 mmol) and water (2.5 ml) are mixed with [C4mim][BF4] (5 ml). The mixture is heated to 110° C. with vigorous stirring for 12 hours, then cooled and extracted with diethyl ether (3×15 ml). The combined organic phase is dried over MgSO4 and filtered. The product, biphenyl, is obtained in 100% yield. If a nitrile ionic liquid, [C3CNmim][BF4], is used in place of the [C4mim][BF4], a similar yield is obtained. Significantly, using [C3CNmim][BF4] the yields can be maintained at above 90% even after six runs of catalysis, while yields decrease rapidly for [C4mim][BF4]. Dissolving PdCl2 in the [C3CNmim][BF4] gives the same result as using complexes 6 and 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:33])[O:23][C:24]2C=CC([N+]([O-])=O)=C[CH:25]=2)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:10]=1.C(O)C[OH:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:33])[O:23][CH2:24][CH2:25][OH:42])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@H:11]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:10]=1
Reactant: CC(C)(C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: OCCO
Product: CC(C)(C)[C@H](NC(=O)OCCO)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrophenyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-1, 500 mg, 0.93 mmol, 1.0 equiv) and ethylene glycol (3 mL, excess) was heated at 100° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel. Elution with 20% ethyl acetate/dichloromethane to 50% ethyl acetate/dichloromethane gave 2-hydroxyethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-2) as a colorless foam. 1H NMR (500 MD, CDCl3) major rotamer: δ 7.38-7.21 (m, 5H), 7.11-6.94 (m, 3H), 6.40 (s, 1H), 5.92 (m, 1H), 5.51 (m, 1H), 5.07 (d, 1H, J=13 Hz), 4.91 (m, 1H), 4.37 (d, 1H, J=10 Hz), 4.20 (m, 2H), 3.81 (t, 2H, J=4.5 Hz), 3.64 (t, 1H, J=4 Hz),) 0.91 (s, 9H). LRMS m/z (M+H) 459.3 found, 459.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COC(=O)CBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cl)cc1C=O
Temperature: 80 °C

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (30 g, 192 mmol), bromo-acetic acid methyl ester (29.4 g, 192 mmol), K2CO3 (53 g, 384 mmol) and KI (9.6 g, 57 mmol) were mixed in acetone (100 mL). Then the mixture was heated at 80° C. for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolve in ethyl acetate and washed with base aqueous solution (1N NaOH). The organic layer was separated, dried and concentrated to give (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester yellow solid. (44 g)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][Na]>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:14][CH3:13])=[N:3][C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CO[Na]
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CO
Product: COc1nc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing 4,7-dichlorquinazoline (250 mg, 0.91 mmol) equipped with a reflux condenser was evacuated and refilled with Ar several times. MeONa (2 mL, 25% wt in MeOH, 8.7 mmol) and anh. MeOH (20 mL) were added and the reaction mixture was heated to reflux under Ar for 5 h. The reaction was cooled to rt and stored at rt overnight then partitioned between DCM (80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (1×). The combined organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.55-8.62 (m, 2H), 8.08 (d, J=9.2 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.52-7.48 (m, 3H), 7.45 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([OH:23])=O.CC[N:26]=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([NH2:26])=[O:23]
Reactant: O=C(O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
To a solution of 3-chloro-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylic acid (190.4 mg) in DMF (dry) (4.9 mL) were added HOBt ammonia complex (112 mg), EDCI (141 mg) and triethylamine (0.205 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO3 and water. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (195 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[C:22]2[C:24]=1[C:15]([CH3:17])=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10](=[O:12])[NH:23]2
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: COc1cc(N)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: COc1cc(OC)c2c(C)c(CCc3ccccc3)c(=O)[nH]c2c1
Temperature: 80 °C

Procedure:
Ethyl 2-(2-phenylethyl)acetoacetate (2.70 g) in xylene (5 ml) was treated with 3,5-dimethoxyaniline (1.60 g) at 150° C. as described in example 19a. Methanesulfonic acid (4.0 ml) was added at room temperature and the mixture heated at 80° C. for 1 hour. The product was isolated as described in example 19a. Yield 1.38 g (41%).
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])O.C(Cl)Cl.[C:9]1([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.C(Cl)(Cl)Cl>[Cl-].[Na+].O>[C:9]1([C:15]2[CH:16]=[CH:17][C:18]([S:1]([Cl:5])(=[O:4])=[O:3])=[CH:19][CH:20]=2)[CH:14]=[CH:13][C:12]([S:1]([Cl:5])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under the nitrogen gas atmosphere, chloro sulfuric acid is diluted by adding chloro sulfuric acid (21.184 mmol) into methylene chloride (40 ml), and biphenyl (6.168 g, 40.00 mmol) is added gradually into a container in which diluted chloro sulfuric acid is contained keeping the temperature at 0° C., then stirred at the room temperature for 6 hours. The obtained reacted mixture is poured into brine, and deposited white insoluble is removed by suction filtration. Since the small amount of product is possible to be remained, the residue is washed well by methylene chloride. Then the filtrate is extracted by methylene chloride (150 ml×3), and the separated organic phase is dried up using magnesium sulfate. Solvent is vaporized off under vacuum condition, and the obtained crude product is isolated by a column chromatography (φ=50 mm, h=100 mm×2; CH2Cl2), further refined by recrystallization (CHCl3) and 4,4′-biphenyldisulfonylchloride is obtained as a colorless crystal (8.201 g, 23.349 mmol, 58%) (compound A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[N+](=[CH2:15])=[N-].CCOCC.[BrH:21]>>[Br:21][CH2:15][C:10](=[O:11])[CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: Br
Solvent: CCOCC
Product: O=C(CBr)Cc1c(Cl)cccc1Cl
Yield: 66 %

Procedure:
The acid chloride, Intermediate A2 (6 g, 26.8 mmol) was added via pipette to a solution of diazomethane in ether (30 mmol) (generated from Diazald by standard Aldrich diazomethane kit) at 0° C. After 35 m, HBr (conc.) (10 mL) was added at 0° C. This was allowed to react for 35 m. The ether was removed and the mixture was neutralized with sodium bicarbonate solution. The organic layer was removed and dried over MgSO4. The mixture was filtered and concentrated under reduced pressure to give 1-bromo-3-(2,6-dichloro-phenyl)-propan-2-one (Intermediate A3) (˜5 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>ClCCl>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])[CH2:11][CH:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: C=CC(=O)O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1OC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CCC(=O)O)CC1OC

Procedure:
A solution of 4-amino-5-chloro-2-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (1 g, 3.2 mmol), and 241 μL of acrylic acid in 50 ml dichloromethane was stirred under nitrogen for 6 hr then concentrated in vacuo. The residue was slurried with hot ethyl acetate and filtered at room temperature to yield 1.15 g of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]C#N)[CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C[O:33]CC1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[O:33])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: C1CCOC1
Reactant: N#CCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: Cc1c(Cl)nnc(C(=O)c2cccnc2)c1C
Reaction time: 16 h
Yield: 93 %

Procedure:
3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) is added to an oven-dried, 250-mL round-bottom flask under N2 followed by THF (50 mL) and pyridin-3-yl-acetonitrile (800 mg, 7.68 mmol). The reaction is degassed with a flow of N2 for 30 min. NaHMDS (14.13 mL, 1.0 M, 14.13 mmol) is added and the reaction is stirred for 16 h. The reaction mixture is then transferred to a beaker and stirred vigorously under open to the atmosphere for several hours. The reaction is quenched with saturated sodium bicarbonate solution, and the organics are extracted with dichloromethane. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2) to afford the title compound (1.3 g, 93%).