Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[O:3][C:4](=[O:16])/[C:5](=[CH:7]/[C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)/N=1.Cl.[O:18]1CCOCC1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5](=[O:18])[C:4]([OH:3])=[O:16])=[CH:9][CH:10]=1
Reactant: CSc1ccc(/C=C2\N=C(C)OC2=O)cc1
Reactant: C1COCCO1
Agent: Cl
Product: CSc1ccc(CC(=O)C(=O)O)cc1
Temperature: 25 °C

Procedure:
(4Z)-2-Methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one (17.5 g), 1,4-dioxane (100 ml) and 4N-hydrochloric acid (27 ml) were combined. The reaction mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuo. Ethyl acetate and water were added to the residue, and the precipitate was filtered in vacuo to give 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoic acid (6.7 g) as a pale brown solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20]>CCOCC.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
0.2 mol of butyl-lithium (a suspension in ether, containing 1.8 mol/liter) is placed in a 500 cm3 flask; it is cooled to -20° C. and 37.4 g (0.2 mol) of meta-bromoanisole diluted with 50 cm3 of anhydrous ether are added dropwise; when the addition has ended, the mixture is stirred for 10 to 15 minutes at the same temperature and 15.7 g (0.1 mol) of meta-chlorobenzoic acid dissolved in the minimum amount of THF are added dropwise; the temperature is allowed to return to ambient temperature and the reaction mixture is stirred for 2 hours under these conditions; it is then poured onto water, the ether is decanted and the aqueous phase is extracted with ether; the combined ether phases are washed with sodium bicarbonate and then with water, dried, decolorised and concentrated in vacuo. 26 g of a solid melting at 52° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:10][C:11]1[N:12]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][N:15]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1cccc(O)c1

Procedure:
A stirred mixture of 3-bromoanisole (100 g, 0.53 mole), 2-methylimidazole (41 g, 0.50 mole), potassium carbonate (96 g, 0.60 mole), cuprous chloride (2.5 g) and N-methyl-2-pyrrolidinone (300 ml) was heated at reflux temperature for 15 hr and then concentrated to remove the solvent and excess 3-bromoanisole. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was concentrated to a black syrup that was then dissolved in toluene and extracted twice with water and then extracted with 48% hydrobromic acid solution. The hydrobomic acid extract was heated at reflux temperature for 7 hr and then distillation of water and methylbromide was begun with addition of additional 48% hydrobromic acid solution as necessary to maintain a reasonable volume. Distillation was continued until the distillation head temperature reached 124° C. The mixture was concentrated under vacuum. The concentrate was diluted with 500 ml of water and basified to pH 8 with addition of potassium carbonate in small portions. The precipitate was collected, washed with water, and dried to give 39.7 g. Recrystallization from 50% aqueous ethanol gave 31.4 g (36%), mp 178°-181° C.
Reaction SMILES: C(#N)C.[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([NH:15][CH2:16][C:17]#[N:18])[CH3:14])([O-:6])=[O:5].C([O-])(O)=O.[Na+].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOC(C)=O.C(Cl)Cl>[C:17]([CH2:16][N:15]([CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N+:4]([O-:6])=[O:5])[CH3:14])[C:25](=[O:26])[O:27][CH2:28][CH3:29])#[N:18]
Reactant: CC(NCC#N)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)N(CC#N)C(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 4 %

Procedure:
To the acetonitrile solution containing 2-(1-(2-nitrophenyl)ethylamino)acetonitrile (18) from the previous step was added saturated NaHCO3 (5 mL) and ethyl chloroformate (1.83 g, 16.86 mmol). The reaction mixture was stirred vigorously at room temperature for 14 hours. The reaction was diluted with EtOAc (50 mL) and washed with brine (40 mL). The separated organic phase was dried over Na2SO4, filtered, and concentrated. Purification (Biotage 40 s, 3:1 CH2Cl2:hexanes, then 100% CH2Cl2) provided 37.1 mg (0.134 mmol, 4% yield) of ethyl cyanomethyl(1-(2-nitrophenyl)ethyl)carbamate (19) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:18]=[C:17]([CH3:30])[C:16]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:30][C:17]1[CH:18]=[C:19]([B:21]2[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:20]=[C:15]([CH3:14])[C:16]=1[O:12][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1OC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
To 3-methyl-benzofuran-2-carboxylic acid (500 mg, 2.84 mmol, 1 eq) in 5 mL of dichloromethane under argon was added 2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (704 mg, 2.84 mmol, 1 eq.), 1,3-dicyclohexylcarbodiimide (1.17 g, 5.68 mmol, 2 eq.), and 4-(dimethylamino)pyridine (173 mg, 1.42 mmol, 0.5 eq.). The resulting mixture was stirred at room temperature for 6 h. The reaction was then diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel to provide 3-methyl-benzofuran-2-carboxylic acid 2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl ester in 28% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 2.2 (s, 6 H) 2.7 (s, 3 H) 7.4 (m, 1 H) 7.5 (s, 2 H) 7.6 (m, 1 H) 7.8 (d, J=8.3 Hz, 1 H) 7.9 (m, 1 H).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (15% ethyl acetate/hexane) to yield the title compound as a yellow solid (0.67 g, 91% yield), mp=78–81° C.; MS (−) ESI m/z=366 (M−H)−; [α]-D (25)=+24.2° (c=1, EtOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:17][CH2:24][CH3:25])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Reaction time: 7 h

Procedure:
In a solution of 259 g. (1.1 mol.) of 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester in 1700 ml. of dimethylformamide, 400 g. of well powdered potassium carbonate and 300 g. of ethyl iodide are introduced. The reaction mixture is stirred for 7 hours at 65° and filtered under suction, while hot, from excess potassium carbonate. Upon standing overnight, 165 g. of 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester crystallize out of the solution, m.p. 112°-115°. After evaporation of the mother liquor, an additional 80 g. are obtained. The total yield amounts to 85% of theory. The compound is recrystallized from benzene (90°-100°), m.p. 113°-115°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5.08 g (30 mmol) of 2-aminobiphenyl, 50 ml of ethyl acetate, and 3.1 g (30 mmol) of triethylamine were placed in a flask, to which 4.1 g (30 mmol) of ethyl chloroglyoxylate was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for three hours, and then 50 ml of ethyl acetate was added thereto. The organic layer was washed with 30 ml of 1N hydrochloric acid and 30 ml of brine one by one, and then was dried with anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 6.8 g (24 mmol, yield 85%) of ethyl N-biphenyl-2-yloxamate as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([CH:16]=O)=[C:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C>[ClH:18].[CH2:2]([N:9]1[CH2:15][CH2:14][C:13](=[C:16]=[N:20][OH:21])[CH:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=C=C1CCN(Cc2ccccc2)CCC1Cl
Reaction time: 8 h

Procedure:
45 gm (0.16 mol) of 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine hydrochloride were suspended in 450 ml of ethyl alcohol, and at 30° C. 12.2 gm (0.175 mol) of hydroxylamine hydrochloride were added in batches while stirring. After some hours, a crystalline precipitate separated out of the gradually clearing solution. The reaction mixture was stirred for 2 hours more and then allowed to stand overnight. The crystalline precipitate was suction-filtered off and dried. After evaporation of the mother liquor, another 10 gm were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.N>[Cu].C(OCC)(=O)C>[N:1]1([C:12]2[CH:13]=[C:14]([O:15][CH3:16])[CH:7]=[CH:8][C:9]=2[CH:10]=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C=O)cc1Br
Agent: [Cu]
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c(-n2ccnc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To an aqueous solution (15 mL) of imidazole (5.69 g), 3-bromo-4-methoxybenzaldehyde (3.00 g) and copper powder (86 mg) were added, and the reaction solution was agitated for three days at 100° C. under nitrogen atmosphere. A concentrated ammonia water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:ethyl acetate), and 321 mg of the title compound was obtained.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:33][CH2:34][O:35][CH3:36])=[N:19][C:20]([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:37])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.CO.CCOCC>[CH3:36][O:35][CH2:34][CH2:33][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[C:10]([CH3:37])[CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2CCOC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
A solution of 133 mg (0.25 mmol) 2-{4-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (example 101A]) in 1.5 ml of THF/MeOH (1:1) was cooled (0° C.) treated with 0.75 ml 1N LiOH and stirred for 15 h at RT. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl. The organic phase was dried (Na2SO4) and evaporated. The crude product was suspended in ether (RT to 4° C.) and filtered to give 66 mg of the title compound as a white powder of mp. 140.5–141.5° C., dec.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].Cl.[O-:21][C:22]#[N:23].[K+]>O.CO>[C:22]([NH:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])(=[O:21])[NH2:23]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CNC(N)=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 40A, 192 mg (0.63 mmol) were introduced in 11 ml of water/methanol 1:2 and admixed in succession at RT with 0.63 ml (0.63 mmol) of 1M hydrochloric acid and 166 mg (2.05 mmol) of potassium cyanate. The reaction mixture was stirred at RT overnight and then freed from the methanol on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC [Method 20]. The product fraction was concentrated on a rotary evaporator. Drying of the residue in an HV gave 177 mg (73% of theory) of the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C([Li])CCC.CON(C)[C:18](=[O:27])[C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=1[CH3:26].[Cl-].[NH4+]>C(OCC)C>[S:9]1[C:8]([C:18]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[O:27])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(=O)c1cc(Br)ccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(Br)cc1C(=O)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A solution of thianaphthene (543 mg) in diethyl ether (20 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 1.74 ml). The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was added dropwise to a solution of N-methoxy-N-methyl-5-bromo-2-methylbenzamide (1.15 g) obtained in Reference Example 4-(2) in diethyl ether (10 ml) cooled to −78° C. The mixture was warmed to room temperature and stirred for one hour. Added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-95:5) to give 5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone (995 mg) as a pale yellow syrup. APCI-Mass m/Z 331/333 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (23.4 g, 110 mmol) described in Manufacturing Example 1-1-2, nitromethane (33.6 g, 550 mmol), ammonium acetate (17.0 g, 220 mmol), and acetic acid (200 mL) was stirred for 1 hour and 45 minutes at 100° C. A small amount of water was added thereto while the reaction solution was stirred under ice cooling, and the precipitated solids were filtered, so as to obtain the titled compound (21.0 g, 74.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH3:25])[CH:32]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)ccn1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 2-methoxypyridin-4-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 16 hours under N2 atmosphere. Product and starting material were observed. 0.5 Equivalents of 2-methoxypyridin-4-ylboronic acid and 0.05 equivalents of tetrakis(triphenylphosphine)palladium (0) were added and continued heating for 40 hours. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide as a yellow solid (107 mg, 88%). ESI-MS m/z calc. 415.5. found 416.7 (M+1)+. Retention time 1.74 minutes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14]2)=[O:10])=[C:7]([O:29][CH2:30][CH3:31])[CH:6]=1)(=[O:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:28]([Cl:32])=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14]2)=[O:10])=[C:7]([O:29][CH2:30][CH3:31])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 70 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a stirred solution of 4-acetylamino-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (4.0 g) in dimethylformamide (20 ml) is N-chlorosuccinimide (1.3 g), and the resulting mixture is stirred at 70° C. for 2 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from acetone to give the title compound (3.1 g), mp 161°-163° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:23][O:24][C:25]([C:27]1[C:28]([CH3:35])=[N:29][O:30][C:31]=1[C:32](O)=[O:33])=[O:26]>ClCCl.C(OCC)(=O)C>[N:1]1([C:32]([C:31]2[O:30][N:29]=[C:28]([CH3:35])[C:27]=2[C:25]([O:24][CH3:23])=[O:26])=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1c(C)noc1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)noc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
At -5° C., 3.0 g (35.1 mmol) of piperidine, 10.1 g (100.0 mmol) of methylmorpholine, 1.1 g (9 mmol) of dimethylaminopyridine and 22.9 g of a 50% strength solution of propanephosphonic anhydride in dichloromethane (36.0 mmol) were added one after the other to 5.0 g (27.0 mmol) of 4-methoxycarbonyl-3-methyl-isoxazole-5-carboxylic acid in 100 ml of dichloromethane, and the mixture was stirred for 12 hours at room temperature. The solvent was stripped off under reduced pressure, and the residue was taken up in 200 ml of ethyl acetate and extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 90%, 1H-NMR (250 MHz; CDCl3): δ=1.65 ppm (m; 6H), 2.49 ppm (s; 3H), 3.18 ppm (m; 2H), 3.73 ppm (m; 2H), 3.87 ppm (s; 3H).