Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:13][S:14][C:15]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])([O-])=O.C(O)(=O)C.[OH-].[Na+]>O>[NH2:24][C:21]1[CH:22]=[CH:23][C:15]([S:14][S:13][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[C:9]([NH2:11])=[O:10])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1SSc1ccc([N+](=O)[O-])cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1cc(N)ccc1SSc1ccc(N)cc1C(N)=O
Temperature: 25 °C

Procedure:
2,2'-Dithiobis(5-nitrobenzamide) (2.6 g, 7.0 mmol) was added portion-wise to a refluxing slurry of reduced iron (8.7 g) in 65 mL of water containing 0.1 mL of acetic acid. The resulting slurry was heated at reflux for 2.0 hours, then cooled to room temperature. The slurry was made strongly basic (pH 11) by the addition of 14 mL of 1N NaOH. The alkaline mixture was filtered, and acetic acid was added to the solution to adjust the pH to 7.0. While bubbling oxygen into the solution, a pH=6-7 was maintained with the addition of acetic acid. A solid gradually formed as the pH begins to stabilize. The product (1.1 g) was recovered by filtration, mp 188°-190° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][OH:9])=[NH:7])#[N:2].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=O>ClCCl>[Cl:20][CH2:21][C:22]1[O:9][N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cccc(C(=N)NO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(-c2noc(CCl)n2)c1

Procedure:
3-cyano-N-hydroxy-benzamidine (1.0 g, 6.2 mmol), triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl chloride (0.74 ml, 9.3 mmol) in dichloromethane (12 ml). Purification was performed by decolorizing with silica gel. 1H NMR (CDCl3), d (ppm): 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14](=O)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(OC)c(OC)c3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,4-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]([N:40]2[CH2:43][C:42](=O)[CH2:41]2)[C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:27][CH:26]=1.CS(Cl)(=O)=O>C1COCC1.CN(C1C=CN=CC=1)C.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[C:42]2[CH2:43][N:40]([C@@H:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)[C:32]3[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=3)[CH2:41]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)Cc1cc(F)cc(Br)c1
Reactant: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(=O)C2)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.55 g (58.87 mmol) of methyl (3-bromo-5-fluorophenyl)acetate in 200 mL of THF at −78° C., was added a solution of 56.80 mL (56.80 mmol) (1M in THF) of LHMDS. After the reaction mixture was stirred for 30 min., a solution of 15.60 g (52.57 mmol) of 3-[(S)-(4-chlorophenyl)(3-oxoazetidin-1-yl)methyl]benzonitrile in 50 mL of THF was added and the mixture was stirred for 2.5 h at −78° C. Then 8.35 g (68.33 mmol) of DMAP, 14.65 mL (84.09 mmol) of DEA, and 8.72 mL (110.38 mmol) of methanesulfonyl chloride were added, and the mixture was stirred for 1 h at −78° C. The mixture was then allowed to warm to rt and was stirred at rt for 12 h. The mixture was poured into 300 mL of ether and 100 mL of water. The water layer was extracted with ether (100 mL×2). The combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 3.75(s, 3H), 3.87(s, 2H), 4.23-4.29(m, 2H), 4.59(s, 1H), 6.92 (d, 1H, J=12 Hz), 7.18(s, 1H), 7.20 (d, 1H, J=12 Hz), 7.31-7.38 (dd, 4H, J J11=28.4 Hz, J2=8.5 Hz), 7.42 (t, 1H, J=7.7 Hz), 7.54 (d, 1H, J=7.6 Hz), 7.66 (d, 1H, J=7.6 Hz), 7.76 (s, 1H); Mass Spectrum: m/e=525, (M+1, 35Cl79Br), 527 (M+1, 37Cl79Br/35Cl81Br), 529 (M+1, 37Cl81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[CH2:13]([N+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O-:11])=[O:10])=[CH:6][CH:7]=1.[CH2:26]([N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: Nc1ccc(CC(=O)[O-])cc1

Procedure:
p-Aminophenylacetic acid (3.02 g) was dissolved in 51.9 g of 10% aqueous tetrabutylammonium hydroxide, and the solution was evaporated under reduced pressure to an amber oil. Upon further drying at 0.1 mm pressure at room temperature, a green solid was obtained. After rinsing with tetrahydrofuran there was obtained 4.696 g of nearly colorless crystals of tetrabutylammonium p-aminophenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)NCC2
Yield: 117.7 %

Procedure:
Dissolve 6-chloro-1H-indole (2 g, 0.013 mol) in acetic acid (10 mL) under nitrogen. Add sodium cyanoborohydride (1.24 g, 1.5 eq) and stir 20 minutes at room temperature. Dilute with ethyl acetate and extract with sodium hydroxide (5 N aqueous). Dry over magnesium sulfate, filter and concentrate to give 2.35 g (116%) crude product. MS (ES, m/z): 154.0 (M+1).
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Si:10]([O:17][CH2:18][CH:19](O)[CH2:20][CH:21]([C:28]1[NH:29][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)=[C:31]2[C:36](=[O:37])[N:35]([CH3:38])[C:34](=[O:39])[N:33]([CH3:40])[C:32]=12)[C:22]1[S:23][CH:24]=[C:25]([Cl:27])[N:26]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH:19]([CH2:20][CH:21]([C:22]1[S:23][CH:24]=[C:25]([Cl:27])[N:26]=1)[C:28]1[NH:29][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)=[C:31]2[C:36](=[O:37])[N:35]([CH3:38])[C:34](=[O:39])[N:33]([CH3:40])[C:32]=12)[CH2:18][O:17][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])(=[O:7])=[O:8]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO[Si](C)(C)C(C)(C)C)c3nc(Cl)cs3)c2n(C)c1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methanesulfonic anhydride (347 mg, 1.989 mmol) was added to a solution of 7-(4-((tert-butyldimethylsilyl)oxy)-1-(4-chlorothiazol-2-yl)-3-hydroxybutyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (590 mg, 0.995 mmol) and triethylamine (0.416 mL, 2.98 mmol) in DCM (30 mL). The mixture was stirred at room temperature 20 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26](O)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].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>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@@H:26]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 282.8 %

Procedure:
(R)-Cyclopentylhydroxyphenylacetic acid (20 g, 90.8 mmol), (S)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (18 g, 96.2 mmol) and triphenylphosphine (24 g, 91.5 mmol) were dissolved in THF (100 mL). Diisopropyl azodicarboxylate (19.7 mL, 99.9 mmol) was added slowly at room temperature. The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation. EtOAc was then added and the solution was washed with a saturated NaHCO3 solution, then saturated aqueous NaCl. The organic layer was dried over Na2SO4 then concentrated to yield approximately 100 g of crude title compound, which was used immediately without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:8][C:6]1[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[N:7]=1
Reactant: Cc1nc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1B(O)O
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: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 50 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[(6-bromo-2-methylpyridin-3-yl)methyl]piperazine-1-carboxylate (800 mg, 2.16 mmol, 1.00 equiv), (2-methylphenyl)boronic acid (590 mg, 4.34 mmol, 2.00 equiv), tetrakis(triphenylphosphine)palladium (250 mg, 0.220 mmol, 0.10 equiv), potassium carbonate (898 mg, 6.50 mmol, 3.00 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (22/78) to provide 800 mg (97% yield) of tert-butyl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 382 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]1=[O:16])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:6][CH2:7][CH3:8])[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[C:10]1=[O:16])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Product: CCOC(=O)C(OCC)n1cccc(Nc2cccc(OC)c2)c1=O

Procedure:
Using an analogous procedure as described in example 21.1, (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (example 19.2) was reacted with 3-methoxy phenylboronic acid to give (RS)-ethoxy-[3-(3-methoxy-phenylamino)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester. Light green gum. MS 347.4 ([M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:13][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C:4]([C@@H:3]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:5][C:6]=2[CH:12]=1
Reactant: Cc1cc(C(=O)N[C@@H](CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N[C@@H](CNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90 mg (0.2 mmol) of N-[(1S)-2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is placed in 2 mL of dichloromethane, combined with 0.03 g (0.25 mmol) of triethylamine and while being cooled in the ice bath combined with 0.03 g (0.23 mmol) of methanesulfonic acid chloride. Then the mixture is heated to ambient temperature and stirred for 24 hours. Then the solvent is eliminated in vacuo and the residue purified by chromatography on silica gel (gradient: dichloromethane/methanol=100:5). Yield: 27 mg (25%); Rf value: 0.20 (silica gel; dichloromethane/methanol=95:5); C23H26ClN5O4S (504.01); mass spectrum: (M+H)+=504/506 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]1=[O:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), 2-(3-bromo-propyl)-isoindole-1,3-dione (242 mg), and potassium carbonate (125 mg), and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (108 mg, yield 69%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[Cl:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:9][CH:8]=1
Reactant: N#Cc1cc(Cl)ccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cc(Cl)ccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-5-chlorobenzonitrile was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in the same way as Example 1 to give 4-chloro-2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a grey solid: δH (360 MHz, CDCl3) 7.39-7.43 (1H, m), 7.47-7.64 (1H, m), 7.73 (1H, dd, J 8 and 2), 7.82 (1H, d, J 2), 8.26-8.45 (2H, m).
Reaction SMILES: [C:1]([C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH:15]([OH:33])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:20]([OH:32])[CH:19]=2)=[CH:11][C:10]=1[OH:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](O)(=[O:41])/[CH:38]=[CH:39]/[CH3:40]>>[C:37]([O:33][CH:15]([CH2:14][O:13][C:12]1[CH:34]=[CH:35][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([OH:36])[CH:11]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:20]([OH:32])[CH:19]=1)(=[O:41])/[CH:38]=[CH:39]/[CH3:40]
Reactant: C/C=C/C(=O)O
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Product: C/C=C/C(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Yield: 75.1 %

Procedure:
97 g (0.2 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol were esterified analogously to Example 1 with 103 g (1.2 moles) of crotonic acid. After crystallization from an acetone/ethanol mixture (ratio by volume 1:2), 83 g (75 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl crotonate were obtained in the form of fine white crystals having a melting point of 99° to 103° C. and a purity of 99 percent (HPLC). The structure of the compound obtained was confirmed by UV, IR and NMR spectra.
Reaction SMILES: [ClH:1].CO[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](=[NH:17])[O:14][CH2:15][CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:18][O:19]C1C=CC=CC=1C1(C#N)CC1>>[ClH:1].[CH3:18][O:19][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[C:10]1([C:13](=[NH:17])[O:14][CH2:15][CH3:16])[CH2:11][CH2:12]1
Reactant: CCOC(=N)C1(c2ccc(OC)cc2)CC1
Reactant: COc1ccccc1C1(C#N)CC1
Agent: Cl
Product: CCOC(=N)C1(c2ccccc2OC)CC1

Procedure:
The title compound (50 mg, oil) was prepared by a method analogous to the one used for Intermediate 48 but using 1-(2-methoxyphenyl)cyclopropanecarbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](C)([C:19]([O-])=O)[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 220 °C

Procedure:
Ethyl 2-[4-(4-fluorophenoxy)phenyl]-2-methylmalonate (19.6 g.) was refluxed for 1 hour with a mixture of 2.5N aqueous sodium hydroxide (114 ml.) and ethanol (57 ml.). After cooling and acidification with 5N hydrochloric acid, the resulting oil was extracted into ether. The extract was washed with water, dried and the ether distilled. The residue of crude 2-[4-(4-fluorophenoxy)phenyl]-2-methylmalonic acid was decarboxylated by heating for 20 minutes at 220°C. The product was recrystallised several times from benzene/petroleum ether b.p. 62°-68°C. to give 2-[4-(4-fluorophenoxy)phenyl]propionic acid, m.p. 84°-86°C.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1F)[CH:10]=[O:11]>CS(C)=O>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[S:3]([CH3:2])(=[O:5])=[O:4])[CH:10]=[O:11]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1F

Procedure:
Methane sulfinic acid sodium salt (20.1 g, 200 mmol) was added to a stirred solution of 3,4-difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 ml) at 75° C. After 2 hours the reaction was poured onto ice-water (200 ml). The precipitate was filtered, washed with water and dissolved in chloroform (400 ml). The organic extract was washed with water (2×200 ml), dried over MgSO4, filtered, and the solvent removed to give the title compound as a white solid.
Reaction SMILES: CC1(C)COB([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH:14]3[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15]3)=[CH:10][CH:9]=2)OC1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[NH:30][CH:29]=[C:28]2[CH:35]=[O:36]>C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:18]([N:16]1[CH2:15][CH:14]([CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][C:33]=3[Cl:34])[NH:30][CH:29]=[C:28]4[CH:35]=[O:36])=[CH:22][CH:21]=2)[CH2:17]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CC(COc2ccc(B3OCC(C)(C)CO3)cc2)C1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(COc2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a mixture of 1-(3-{[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]methyl}azetidin-1-yl)ethanone (160 mg, 0.64 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (165.4 mg, 0.64 mmol) in 2 M aqueous potassium carbonate (1.3 mL, 2M), toluene (3 mL) and ethanol (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.064 mmol). The mixture was degassed with nitrogen for 5 minutes. The mixture was heated to 110° C. and stirred under microwave irradiation for 2 hours. The cooled reaction mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate=20:1 to 3:1) to give 5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde (127 mg, 52%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.60-7.39 (m, 5H), 6.99 (d, 2H), 4.30 (m, 1H), 4.20-4.09 (m, 4H), 3.93 (m, 1H), 3.07 (m, 1H), 1.91 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([F:25])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:4]1)[CH3:2].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH2:21][N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[C:19]([F:25])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[N:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(C=O)c(F)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)c(F)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-fluorobenzaldehyde and pyrrolidine provided the title compound. ESMS [M+H]+: 651.4.