Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:4][C:5](=O)[CH3:6])[CH:2]=C.C(=O)C1C=CC=CC=1.CC(CC1C=CC=CC=1)=O.C(C(C1C=CC=CC=1)=O)=CC1C=CC=CC=1.CC(=O)CCC.[CH2:48]([NH:50][C:51]1[CH:56]=[C:55]([Cl:57])[N:54]=[N:53][C:52]=1[NH:58][N:59]=C(C)C(C)=C)[CH3:49].C(NC1C=C(Cl)N=NC=1NN=CC1C=CC=CC=1)C.C(NC1C=C(Cl)N=NC=1NN=CC=CC1(C2C=CC=CC=2)C=CC=CC1)C>>[CH2:48]([NH:50][C:51]1[CH:56]=[C:55]([Cl:57])[N:54]=[N:53][C:52]=1[NH:58][N:59]=[C:5]([CH3:6])[CH2:4][CH2:1][CH3:2])[CH3:49]
Reactant: C=C(C)C(C)=NNc1nnc(Cl)cc1NCC
Reactant: C=CCCC(C)=O
Agent: CC(=O)Cc1ccccc1
Agent: CCNc1cc(Cl)nnc1NN=CC=CC1(c2ccccc2)C=CC=CC1
Agent: CCNc1cc(Cl)nnc1NN=Cc1ccccc1
Solvent: CCCC(C)=O
Solvent: O=Cc1ccccc1
Product: CCCC(C)=NNc1nnc(Cl)cc1NCC

Procedure:
When allylacetone, benzaldehyde, methylbenzyl ketone or phenyl styryl ketone are substituted for 2-pentanone in the process of this example, 4-ethylamino-6-chloro-3-[2-(2-methylbutene-3-ylidene)hydrazino] pyridazine, 4-ethylamino-6-chloro-3-(2-benzylidenehydrazino)pyridazine, 4-ethylamino-6-chloro-3-[2-(1-methyl-2-phenethylidene)hydrazino]pyridazine or 4-ethylamino-6-chloro-3-[2-(1-phenylcinnamylidene)hydrazino]pyridazine, respectively, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](Cl)=[N:13][OH:14])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[CH:18]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([C:12]2[CH2:24][C:23]([C:21]3[CH:20]=[C:19]([Cl:29])[CH:18]=[C:17]([Cl:16])[CH:22]=3)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1nc2c(C(Cl)=NO)ccc(Br)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(Br)c2o1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl chloride (3.63 g) in 2-propanol (100 ml) was added 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (3.43 g) and sodium hydrogen carbonate (1.44 g). The reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 2-25% v/v ethyl acetate in heptane) to give 7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole (3.7 g). 1H-NMR (400 MHz, CDCl3): 7.71-7.42 (m, 5H), 4.50 (d, 1H), 4.06 (d, 1H), 2.73 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[F:20][C:21]([F:31])([F:30])[C:22]1[NH:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:24]3[CH:23]=[C:22]([C:21]([F:31])([F:20])[F:30])[NH:26][N:25]=3)=[O:28])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(C(F)(F)F)[nH]n1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(C(F)(F)F)[nH]n3)n2)ccc(C#N)c1Cl
Yield: 41.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.15 g, 0.546 mmol), 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.108 g, 0.601 mmol), HOBt (0.111 g, 0.819 mmol), DIPEA (0.143 ml, 0.819 mmol) and EDCI (0.157 g, 0.819 mmol) using DCM as solvent using the method of Example 34(d) affording 0.098 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 2.48 (s, 3H), 4.30 (m, 2H), 4.46 (m, 1H), 6.60 (d, 1H), 7.21 (m, 1H), 7.60 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 8.51 (m, 1H), 14.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:21]=[CH:20][C:19]([C:22]([NH2:24])=[O:23])=[C:18]2[C:10]=1[C:11]1[CH2:12][CH2:13][CH:14]([C:25](N(OC)C)=[O:26])[CH2:15][C:16]=1[NH:17]2.[CH3:31][Mg]Br.Cl>C1COCC1>[C:25]([CH:14]1[CH2:13][CH2:12][C:11]2[C:10]3[C:18](=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=[CH:21][C:9]=3[C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[NH:17][C:16]=2[CH2:15]1)(=[O:26])[CH3:31]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide (Example 26-1, 719 mg, 1.739 mmol) in THF (1 mL) was treated with methylmagnesium bromide (3 M in diethyl ether, 2.90 mL, 8.70 mmol) at 0° C. After 20 min, additional methylmagnesium bromide (2.90 mL, 8.70 mmol) was added and stirring was continued for 30 min more. The mixture was treated with 1 M hydrochloric acid and extracted four times with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) and the resulting material was triturated with DCM to provide 2-acetyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as an off-white solid (210 mg, 33%). 1H NMR (400 MHz, methanol-d4) δ 7.59 (1H, d, J=7.91 Hz), 7.39-7.49 (2H, m), 7.01-7.09 (3H, m), 6.90 (1H, d, J=7.91 Hz), 2.86-2.97 (3H, m), 2.24-2.33 (1H, m), 2.22 (3H, s), 2.01-2.18 (2H, m), 1.54-1.66 (1H, m). Mass spectrum m/z 369.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:15])=[O:31])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of 281 (1.1 g, 3.2 mmol) and m-CPBA (77%, 890 mg, 12.8 mmol) in DCM at 0° C. was stirred for 2 hours, diluted with DCM, washed with ice water, NaHCO3 solution and water again; dried and concentrated to give the title compound 284 (1.15 g, quantitative) as a yellowish solid. MS (m/z): 354.0(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18]C(=O)C2C=CC=CC=2)[CH:11]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide (13.4 g; that is prepared as described in Reference Example 11) in methanol (160 mL) and water (60 mL) is treated with anhydrous potassium carbonate (18 g), and stirred overnight at room temperature. It is then brought to pH 7 by treatment with dilute hydrochloric acid (2 N), and concentrated. The residue is treated with water (100 mL) and filtered, and the resulting solid is dried, to give N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (8.8 g), m.p. 227°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C1COCC1>[O:14]=[C:13]1[NH:12][C:11](=[O:15])[CH:10]=[N:9][N:8]1[C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 2-(3-aminophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.2 g, 5.88 mmol) in THF (20 mL) was added acetic anhydride (1.2 g, 11.8 mmol) and the mixture was heated at 50° C. After 2 h the mixture was cooled at room temperature, quenched with water and extracted with ethyl acetate (×3). The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the 900 mg, 62% yield, of N-(3-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 9(D) (900 mg, 62%) which is used in next step without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C1(C=CC=C(O)C=1)O.[Br:30][CH2:31][CH2:32]CCCCCCCCCCOC1C=CC(C=O)=CC=1.[O-]Cl=O.[Na+]>>[Br:30][CH2:31][CH2:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(OCCCCCCCCCCCCBr)cc1
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: O=C(O)c1ccc(OCCCCCCCCCCCCBr)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (2.69 g, 24 mmol), 6 (7.0 g, 19 mmol), NaH2PO4·H2O (8.87 g, 57 mmol), NaClO2 (9.92 g, 110 mmol). Yield 7.32 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (16 H, m, CH2), 1.84 (4 H, m, O—CH2—CH2/Br—CH2—CH2), 3.40 (2 H, t, 3J=6.9 Hz, Br—CH2), 4.06 (2 H, t, 3J=6.5 Hz, O—CH2), 6.93 (2 H, d, 3J=9.0 Hz, Ar—H), 8.04 (2 H, d, 3J=8.9 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.2, 28.7, 29.1, 29.3, 29.4, 29.5, 32.8, 34.0, 68.3, 114.2, 121.3, 132.3, 163.7, 171.4.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].N([O-])=[O:13].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 5 °C
Yield: 91.2 %

Procedure:
p-Cyanobenzamide (14.6 g), sodium nitrite (20.7 g), acetic acid (200 ml), and acetic anhydride (20 ml) were mixed and stirred vigorously at 5° C. To the mixture, trifuloroacetic acid (35 g) was added dropwise over three hours, and further stirred vigorously for five hours. The solvent was removed under reduced pressure, and water (300 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 13.4 g of p-cyanobenzoic acid (yield 92%). The p-cyanobenzoic acid obtained had a purity of 98%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>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>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:14])[N:4]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:3]=[C:2]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Reactant: OB(O)c1ccccc1
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+]
Product: COc1ccc(-n2cc(-c3ccccc3)c3cc(OC)ccc3c2=O)cc1
Yield: 98 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)-isoquinolin-1(2H)-one (0.52 g, 1.44 mmol), tetrakis(triphenylphosphine)palladium (83 mg, 0.07 mmol), potassium carbonate (0.22 g, 1.00 mmol) and phenylboronic acid (0.21 g, 1.73 mmol) were placed in a dry and argon flushed 150 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. 1,2-Dimethoxyethane (10 mL) and water (3 mL) were added via a syringe under argon atmosphere. The reaction solution was stirred and heated to reflux for 20 hours. The reaction was quenched by adding 30 mL of water at room temperature. The mixture was extracted with ethyl acetate (3×20 mL). The extracts were combined, washed with brine (2×10 mL) and dried over anhydrous MgSO4 and 2 g of 3-(diethylenetriamino)propylfunctionalized silica gel followed by filtration and concentration to give a yellow residue. The yellow residue was purified by flash column chromatography (silica-gel, hexanes/ethyl acetate=2/3 v/v) to give a white solid product, 0.50 g, 98.0% yield. MS: m/z 358.3 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) (8.30 (d, 2H, J=9.0 Hz), 7.55-7.40 (m, 8H), 7.29 (s, 1H), 7.21 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.94 (d, 1H, J=2.4 Hz), 3.81 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:13][C:14]([NH2:16])=[S:15].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[C:6]1([C:5]#[C:4][C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=S
Reactant: O=C(C#Cc1ccccc1)CCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(C#Cc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.4 %

Procedure:
1-Chloro-4-phenyl-3-butyn-2-one (245 mg, 1.37 mmol) was dissolved in DMF (1.0 mL), thiourea (126 mg, 1.66 mmol) was added, and the resulting pale brown solution was stirred at ambient temperature for 5 days. The reaction mixture was diluted with Ethyl acetate (50 mL), washed with saturated NaHCO3 solution (10 mL), water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The dark oil was dissolved in methanol, adsorbed onto silica gel and purified by column chromatography eluting with 4:1, 3:1, then 2:1 hexane:ethyl acetate to afford 4-(phenylethynyl)-1,3-thiazol-2-amine (56 mg, 20% yield) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7.53–7.50 (m, 2H), 7.37–7.32 (m, 3H), 6.77 (s, 1H), 5.41 (br s, 2H). MS (EI ionization) 200 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](O)([C:8](F)(F)F)=O>C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:3][C:2]1[NH:1][CH:5]=[CH:6][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc[nH]c1
Solvent: CCOC(C)=O
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Reaction time: 0.5 h
Yield: 381.1 %

Procedure:
To a solution of p-formaldehyde (1100 mg, 35 mmol) in pyrrole (50 ml, 720 mmol), at 50° C., TFA (416 mg, 3.5 mmol) was added. The reaction mixture was kept under magnetic stirring, at room temperature, for 30 minutes, then ethyl acetate was added and the solution washed with NaHCO3 saturated solution, then the organic phase was dried on Na2SO4. After evaporation the crude product was purified by chromatography on silica gel (Petroleum Ether/Ethyl acetate 4/1+1% TEA). 1950 mg (yield 38%) of the product were obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N:7]#CBr.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[O:18]2)[CH2:13][CH2:12]1>C(Cl)(Cl)Cl>[C:10]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[O:18]2)[CH2:13][CH2:12]1)#[N:7]
Reactant: CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Reaction time: 1 h

Procedure:
Milled K2CO3 (25 g, 0.18 mole) was added to a solution of cyanogen bromide (10.6 g, 0.1 mole) in 100 ml chloroform, and the mixture was heated to refux and a solution of 11-[(1-methyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (24 g, 0.085 mole) in 100 ml chloroform was added thereto over a period of one hour.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].[OH-].[Na+].S(=O)(=O)(O)O>O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCCCCS
Yield: 94.1 %

Procedure:
4 g (15.09 mmol) 11-bromoundecanoic acid is added along with 1.505 g thiourea (19.82 mmol) and 15 ml water to a round botton flask, and the mixture is refluxed for 3 hours. 10.2 ml 3M sodium hydroxide (30.6 mmol) was then added and the mixture was refluxed for one additional hour. The reaction mixture was cooled in an ice bath, and dilute sulfuric acid was added dropwise until the solution had a pH of about 2. The cloudy solution was then extracted with ether (2×25 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a white solid (3.1 g, 94%). 1H-NMR (300 MHz, CDCl3) 1.28, m, 10 H; 1.60, m, 7 H; 2.35, t, 2 H, J=7.3 Hz; 2.50, q, 2 H, J =7.5 Hz.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])C.O.[OH-].[Na+]>CCO>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][C:4]([OH:23])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid ethyl ester (5.0 g, 16 mmol) in EtOH:H2O (60 mL 1:1) was stirred as 10N NaOH (16 mL) was added dropwise. The reaction was stirred at rt for 1 hr. The solvent was evaporated and the residue was diluted with water (50 mL) and extracted with CH2Cl2 (2×20 mL). The aqueous layer was then acidified with 3N HCl to pH ˜2-3, extracted with CH2Cl2 (3×30 mL). The CH2Cl2 extracts were dried over MgSO4, and the oil was crystallized from Et2O/MeOH to give 4.5 g (99%) of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid: mp 157-9° C.; MS m/z 283 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][OH:12].[H-].[Na+].O>O1CCCC1>[CH3:11][O:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a stirred solution of 10 g of 2-chloro-5-nitropyridine and 2 g of dry methanol in 40 ml of dry tetrahydrofuran, 2.8 g of sodium hydride (about 60%, in oil) is added under cooling in an ice-water bath. The mixture is stirred at room temperature for 1 hour, and 30 ml of water is added. The mixture is extracted with three 40-ml portions of ethyl acetate, and the combined extracts are dried over magnesium sulfate. The solvent is distilled off to give 8.0 g of crude 2-methoxy-5-nitropyridine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[Na+]>CN(C)C=O.O.C(O)C.Cl>[ClH:16].[CH2:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: C=CCN1CCC(c2noc3cc(Cl)ccc23)CC1
Reaction time: 16 h
Yield: 127.7 %

Procedure:
A suspension of 3.55 g of 3-(4-piperidyl)-6-chloro-1,2-benzisoxazole, 2.0 g of allyl bromide, 2.0 g of potassium carbonate and some crystals of potassium iodide in 47 ml of dimethylformamide was stirred under nitrogen at 85°-90° for 5 hrs. The reaction mixture was cooled and filtered. The crystals were washed with dichloromethane. The combined organic solvents (dimethylformamide+dichloromethane) were distilled in vacuo and to the residue was added with 30 ml ethanol and 500 ml half-saturated sodium chloride, prepared by diluting saturated sodium chloride with an equal volume of water. After 16 hrs, the crystals were filtered, washed with water and dried, yielding base. The base was dissolved in 50 ml of ethanol and 1.2 ml of conc hydrochloric acid. The mixture was heated to 50°. The solvents were evaporated in vacuo. Benzene (60 ml) was added and distilled in vacuo. The residue was triturated with ether, filtered and twice recrystallized from isopropanol-ether, giving 3.0 g (63.9%) of product as the hydrochloride, mp, 178°-180°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)CCc1ccc(Br)cc1
Product: O=C(CCc1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound was prepared from 3-(4-bromophenyl)propanoic acid and pyrrolidine using a similar procedure to that described for Description 8, but without chromatographic purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 0.17 h

Procedure:
4-[(5-bromo-2-chloro-phenyl)methyl]phenol 7c (14.5 g, 48.7 mmol, prepared according to the method in WO2009026537) was dissolved in 300 mL DMF, followed by addition of cesium carbonate (31.7 g, 97.5 mmol). The reaction mixture was stirred for 10 minutes. The reaction mixture was stirred for 8 hours at 80° C. after 2,2,2-trifluoroethyl-4-methylbenzenesulfonate 7b (12.4 g, 48.7 mmol) was added. Thereafter, the reaction mixture was filtered and washed with a small amount of ethyl acetate before the filtrate was concentrated under reduced pressure. The resulting residue was partitioned after 100 mL water and 50 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the organic extract was washed with saturated sodium chloride solution (100 mL), combined and concentrated. The resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 4-bromo-1-chloro-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 7d (7.26 g, white solid), yield: 39.2%. 1H NMR (400 MHz, CDCl3): δ 7.32 (s, 1H), 7.30-7.24 (m, 2H), 7.21-7.14 (m, 2H), 6.98-6.87 (m, 2H), 4.38 (d, 2H), 4.06 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[OH:15][N:14]=[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1cccc(C(=O)O)c1
Yield: 94.8 %

Procedure:
3-Acetylbenzoic acid (10.0 g, 60.9 mmol), hydroxylamine hydrochloride (33.9 g, 487.4 mmol) and sodium acetate (45.0 g, 548.3 mmol) were suspended in ethanol (115 mL) and water (115 mL) and the mixture heated at reflux for 30 minutes. The solvents were removed under reduced pressure, and the residue was triturated with water. The resulting precipitate was isolated by filtration and dried in vacuo to give the sub-title compound as a white solid (10.34 g, 95% yield). 1H NMR (400 MHz, DMSO) δ 2.18 (s, 3H), 7.52 (t, 1H), 7.88 (dd, 1H), 7.91-7.95 (m, 1H), 8.22 (s, 1H), 11.36 (s, 1H) and 12.86 (s, 1H); MS (ES+) 180.3.