Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2(O)[CH3:34])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[CH2:34])=[CH:36][CH:37]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1

Procedure:
A solution of 16 (10 mg, 0.019 mmol) in 3 mL of CH2Cl2 and TFA (30 μL, 0.389 mmol) was aged for 18 hours. Analysis of the reaction demonstrated complete conversion of starting materials to the product. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc and precipitated with hexanes. The mother liquor was removed and the solid residue was washed with hexanes and subsequently with Et2O to yield the product 17 as a solid. 1H NMR (300 MHz, CDCl3) δ 3.97 (s, 3H), 4.99 (s, 2H), 5.04 (d, 1H, J=2 Hz), 5.63 (d, 1H, J=2 Hz), 6.90 (br s, 1H), 7.04 (t, 2H, J=8 Hz), 7.31 (dd, 2H, J=5, 8 Hz), 7.71 (dd, 1H, J=4, 8 Hz), 8.64 (dd, 1H, J=2, 9 Hz), 9.11 (d, 1H J=3Hz); 19F NMR (282.6 MHz, CDCl3) δ 62.1; EI MS (m/z) 351.5 [MH+], 383.3 [M+Na].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[N:16][N:15]=1)[CH:6]=[CH:5]2.C[Al](C)C.[CH2:26]([N:33]1[C:37]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[C:43](OC)=[O:44])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CO.ClCCl.CCCCCC.C1(C)C=CC=CC=1>[CH2:26]([N:33]1[C:37]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[C:43]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[N:16][N:15]=1)[CH:6]=[CH:5]2)=[O:44])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Reactant: CC(C)n1nnnc1CCCn1ccc2cc(N)ccc21
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1nnnc1CCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21

Procedure:
To 2.2 g of 5-amino-1-[3-(1-isopropyl-5-tetrazolyl)propyl]indole was added 40 ml of toluene, then this mixture was stirred under nitrogen gas atmosphere by cooling in a methanol-ice bath. To this reaction mixture was added 4 ml of n-hexane solution of 2M trimethylaluminum dropwise from syringe, then reaction mixture was stirred for 20 minutes, and further stirred at room temperature for 1 hour. 2.18 Grams of methyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate was added to the reaction mixture and was stirred for 5 to 6 hours under refluxing condition. Next, 10% hydrochloric acid was added, and the crystals being separated were collected by filtration. Water-chloroform was added to the crystals, this solution was made alkaline with 10% aqueous solution of potassium hydroxide, then was filtered with Celite, the chloroform layer was washed with water, an aqueous solution saturated with sodium chloride. The chloroform layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: 3% methanol/dichloromethane), and recrystallized from ethyl acetate-n-hexane, there was obtained 2.27 g of 1-benzyl-6-chloro-2-{1-[3-(1-isopropyltetrazol-5-yl)propyl]indol-5-ylaminocarbonyl}benzimidazole as in the form of yellow needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CC1CCCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)O)CCC2
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Intermediate 47 (330 mg) was dissolved in methanol (3 mL) and 2M sodium hydroxide (2.42 mL) was added and the mixture stirred overnight. The mixture was blown down by ca 50% and the pH adjusted to 6 by addition of 2M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried in vacuo to provide the title compound (100 mg) LC/MS MH+ 381, Rt 2.03 mins (5 min run, TFA modifier).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([F:24])[C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Br[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([F:24])[C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]([OH:35])=[O:34])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)S1
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine and tert-butyl bromoacetate following General Procedure I.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=O)C.[BH4-].[Li+].CCCCCC.C(OCC)(=O)C.S(=O)(=O)(O)O>C1COCC1.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3]>[C:15]([O:14][C:12](=[O:13])[NH:11][C:6]1([CH2:4][OH:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=CC1CC1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CC1CC1(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.51 g, 2.0 mmol) in THF (10 ml) at 0° C. was added a 2M solution of lithiumborohydride (4 ml, 8 mmol). The reaction mixture was monitored by TLC (7:3 hexane-ethyl acetate, stained using ammoniummolybdate-cerium sulfate in aq. 10% sulfuric acid) and after stirring overnight at rt, the reaction was carefully quenched using aq. 10% citric acid (25 ml, dropwise addition at 0° C.). The obtained mixture was washed with dichloromethane (3×10 ml), and the combined organic layers were dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue using 1:1 hexane-ethyl acetate as eluent, followed by concentration of the appropriate fractions and drying the residue in vacuum overnight, gave the product as a colourless syrup (0.407 g, 1.91 mmol, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:3]1=2>CO.[Pd]>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCCNc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (350 mg, 1.6 mmol) was dissolved in MeOH. The atmosphere was replaced by Argon and a catalytic amount of Pd/C was added. The atmosphere was replaced by H2 and the reaction was stirred for 72 h at RT. The Pd/C was filtered and the MeOH was removed to give 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[C:3]=1[NH:20][C:21](=O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:4](=[O:19])[C:3]3[NH:20][C:21]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=4)=[N:1][C:2]=3[N:7]([CH3:8])[C:6]2=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(Cn2c(=O)c(NC(=O)Cc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a solution of N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (70 mg, 0.146 mmol) in ethanol (7 ml) was added 2N sodium hydroxide (1 ml). The reaction was stirred at 80° C. for 3 h. The reaction was neutralized with aqueous ammonium chloride, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered and concentrated to give 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (60 mg, 89.1%) as light yellow solid. LCMS retention time 1.499 min; LCMS MH+ 461.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][CH2:26][C@@H:27]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH2:10])[C:23]([NH:25][CH2:26][C@@H:27]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[O:24])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 81A from 132 mg (0.20 mmol) of benzyl{(1S)-1-[({(2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl}amino)carbonyl]-4-[(tert-butoxycarbonyl)amino]butyl}carbamate (Example 119A) in 50 ml of ethanol with the addition of 13 mg of palladium on activated carbon (10%). The product is reacted without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>C(#N)C>[Br:20][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1cc(CO)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(CBr)ccc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
(Step 1) Triphenylphosphine (2.38 g) was suspended in acetonitrile (30 ml), bromine (0.47 ml) was added, and the mixture was stirred for 30 min. [4-Chloro-3-(methylsulfonyl)phenyl]methanol (2.0 g) was added to the reaction mixture, and the mixture was stirred at 85° C. for 8 hr, treated with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:1) to give 4-(bromomethyl)-1-chloro-2-(methylsulfonyl)benzene (1.23 g).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH2:15])=[CH:10][C:11]=1[NH:12][CH3:13].[C:17](OC(=O)C)(=[O:19])C.C(=O)(O)[O-].[Na+]>C(O)=O>[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH:15][CH:17]=[O:19])=[CH:10][C:11]=1[NH:12][CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(NN)nnc1CC(C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CNc1cc(NNC=O)nnc1CC(C)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Thirteen and one half grams of 3-(2'-hydroxypropyl)methylamino-6-hydrazinopyridazine dihydrochloride are dissolved in 25 ml of formic acid, and there are subsequently added thereto at 0° C 6 ml of acetic anhydride and after 30 minutes 8.4 g sodium bicarbonate. The mixture is stirred at 0° C for 30 minutes and left at room temperature overnight. The solvent is removed and the residue consisting of 3-(2'-hydroxypropyl)methylamino-6-(2'-formylhydrazino)pyridazine is recrystallized from acetone/ethanol (8:2). It melts at 130°-132° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[NH2:15][C:13]1[CH:14]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1
Reactant: O=C(c1cc(-c2ccccc2)cc([N+](=O)[O-])c1)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)N2CCOCC2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium on carbon (10 wt %, 67.5 mg, 0.063 mmol) was added to a solution of morpholin-4-yl(5-nitrobiphenyl-3-yl)methanone (198 mg, 0.634 mmol) in ethyl acetate (5.7 mL) and acetic acid (0.57 mL). The mixture was fitted with a hydrogen balloon and stirred for 3 hours at room temperature. Dichloromethane was added, and the mixture was filtered through CELITE, rinsed with dichloromethane rinse and washed with saturated aqueous NaHCO3 (30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (5-aminobiphenyl-3-yl)(morpholin-4-yl)methanone as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.61-7.51 (m, 2H), 7.44 (t, J=7.4 Hz, 2H), 7.37 (dd, J=8.4, 6.2 Hz, 1H), 6.97 (s, 1H), 6.96-6.91 (m, 1H), 6.75-6.63 (m, 1H), 3.89 (s, 2H), 3.85-3.37 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(O)=[O:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccncc1
Product: COc1ccccc1NC(=O)c1ccncc1
Yield: 97.3 %

Procedure:
Using o-anisidine (2.34 g, 19.0 mmol) and 4-carboxypyridine (2.29 g, 19.0 mmol), the procedure of Reference Example 11 was repeated to obtain 4.22 g (97.2%) of the title compound in the form of colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Reactant: Clc1ccc(Oc2cccnc2)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 70 °C

Procedure:
A solution of 93 g of 3-(p-chlorophenoxy)pyridine [Agr. Biol. Chem. 34, 68 (1970)] in 100 ml of glacial acetic acid is treated with 95 g of 40% peracetic acid in acetic acid in four equal portions. The mixture is heated at 35°-40° C. for 16 hours and than refluxed 1 hour. The mixture is cooled to 70° C., 100 ml of isopropanol is added and the reaction heated at 95° C. for 2 hours. The mixture is concentrated in vacuo and dissolved in 700 ml of dichloromethane. The solution is washed with 25 ml of 25% cold sodium hydroxide solution, dried over anhydrous MgSO4, concentrated at reduced pressure to yield crystalline 3-(p-chlorophenoxy)pyridine N-oxide, recrystallized from toluene; mp 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[I:14]Cl>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1[I:14]
Reactant: ClI
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a suspension of 1.06 g (5.31 mmol, 1.0 equiv.) of 4-amino-N-methylbenzenemethanesulfonamide in 20 mL of acetonitrile was added 0.862 g (5.31 mmol, 1.0 equiv.) of iodine monochloride. The reaction was stirred for 15 minutes at room temperature. The mixture was partitioned between 25 mL of ethyl acetate and 15 mL of 20% aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was filtered through a plug of silica gel using 40% ethyl acetate in hexane to yield 1.13 g (65%) of 4-amino-3-iodo-N-methylbenzenemethanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)c1coc2cc(O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Product: COC(=O)c1coc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Methyl 6-hydroxybenzofuran-3-carboxylate (312 mg, 1.62 mmol) was dissolved in N,N-dimethylformamide (5 mL) then added 4-chloro-6,7-dimethoxyquinoline (451 mg, 2.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (77 mg, 0.162 mmol), palladium acetate (36 mg, 0.162 mmol) and potassium phosphate (687 mg, 3.24 mmol). The reaction mixture was stirred at 100° C. overnight. Additional palladium acetate (36 mg, 0.162 mmol) was added to the mixture and the heating was continued at 100° C. for 4 h. Additional 4-chloro-6,7-dimethoxyquinoline (181 mg, 0.812 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (77 mg, 0.162 mmol) were added to the mixture and heating at 100° C. was continued for 2 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The remaining orange oil was redissolved in toluene (5 mL) and DMF (1 mL) then added 4-chloro-6,7-dimethoxyquinoline (225 mg, 1.01 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (38 mg, 0.080 mmol), palladium acetate (18 mg, 0.080 mmol) and potassium phosphate (343 mg, 1.62 mmol). The reaction mixture was heated at 100° C. overnight and concentrated in vacuo. The remaining orange-black oil was purified by silica gel chromatography (1% to 2% methanol in dichloromethane) to afford methyl 6-(6,7-dimethoxyquinolin-4-yloxy)benzofuran-3-carboxylate as a light yellow solid. MS (ESI, pos. ion) m/z: 380.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[CH2:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:30](=[O:31])[C:29]#[C:28][C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: CCN(CC)C(C)COc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)C(C)COc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 67 mg (0.3 mmol) of 4-(2-diethylaminopropoxy)phenylamine and 75 mg (0.3 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 71 mg (52% of theory); melting point: 172° C.-176° C.; C23H24ClF3N2O2 (M=452.90); calc.: molecular ion peak (M+H)+: 453/455; found: molecular ion peak (M+H)+: 453/455; Rf value: 0.30 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.[CH3:12][C:13]([CH3:15])=[O:14].[NH4+].[Cl-]>O>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:13]([OH:14])([CH3:15])[CH3:12]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(C)c(C(C)(C)O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
According to Example 3, mesitylmagnesium bromide (1.20 M in THF; 1.83 mL; 2.20 mmol; 1.10 equiv) was placed in a flame dried schlenk flask under an argon atmosphere and cooled to 0° C. At this temperature, LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv) was slowly added. The resulting mixture was allowed to warm up to room temperature and stirred for 4 h. Then, after cooling to 0° C., acetone (116 mg; 2.00 mmol) was added and the reaction was warmed up to room temperature and stirred for another hour at this temperature. When the end of the reaction was reached (GC-monitoring of aliquots), sat. aq. NH4Cl (2 mL) and water (2 mL) were added. The aqueous layer was extracted with ether (4×10 mL), the combined extracts were dried (Na2SO4) and evaporated in vacuo. Column chromatographical purification (silica; pentane:Et2O 9:1) afforded the desired product as colorless, crystalline solid, mp=106−107° C. (245 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:17]1[CH:22]=CC(C#C)=CN=1>>[CH3:1][C:2]1[C:7]([C:17]#[CH:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1cccnc1C

Procedure:
2-Methyl-3-ethynyl pyridine was prepared from trifluoro-methanesulfonic acid 2-methyl-pyridin-3-yl ester in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:17](=[O:19])[CH3:18])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(=O)OCCCCO
Solvent: O
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCOC(C)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
144.7 g of 4-hydroxybutyl acrylate and 118.7 g of pyridine were charged into a separable flask having a capacity of 1 liter, provided with a stirrer, a Jean-stark water separator, a cooling tube and a nitrogen gas inlet tube, and then 127.8 g of acetic anhydride was dropwise added thereto at 5° C. with stirring over 2 hours, while replacing the flask inside atomosphere with a nitrogen gas. After the dropwise addition, stirring was continued for one hour to conduct reaction. After completion of the reaction, the reaction mixture was recovered by filtration, washed successively with 0.5N hydrochloric acid, an aqueous 2.5% NaHCO3 solution and water, and dehydrated over sodium sulfate. Then pyridine was distilled off under reduced pressure, whereby 142 g of a product of the following chemical formula was obtained: