Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:10])N)[CH:5]=[CH:6][CH:7]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.Cl>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13]3[CH2:12][N:11]4[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]4)[C:14]=3[N:8]([CH3:10])[C:4]=2[CH:3]=1
Reactant: O=C1CCN2CCC1CC2
Reactant: CN(N)c1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Cn1c2c(c3ccc(Br)cc31)CN1CCC2CC1
Yield: 57.4 %

Procedure:
1-(3-Bromophenyl)-1-methylhydrazine (0.50 g, 2.5 mmol) and 1-azabicyclo[3.2.2]nonan-4-one (0.38 g, 2.7 mmol) were dissolved in isopropanol (4 mL), and concentrated aqueous HCl (0.8 mL) was added. The reaction mixture was heated to reflux for 18 h, concentrated and basified using 2 N NaOH. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (438 mg, 58%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.25 (s, 2H), 3.61 (s, 3H), 3.30-3.24 (m, 3H), 3.14-3.08 (m, 2H), 2.02-1.99 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15](OCC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH2:22][NH2:23].O>CCO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:22][NH2:23])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To the solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (13.6 g, 45.0 mmol) in EtOH (200 mL), NH2NH2.H2O (80%, 14 mL, 225 mmol) was added. The reaction mixture was stirred at RT overnight. The desired compound precipitated from the reaction mixture, filtered and washed with EtOH (50 mL) to afford 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as a light yellow solid (9.7 g, 75%). MS (ES+) C10H7F3N4O3 requires: 288. found: 289 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([S:22][CH3:23])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:24][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([S:22][CH3:23])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(-c4ccccc4)n3C)nc12
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)-[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 37) (50 mg), tetrakis(triphenylphosphino)palladium(0) (28 mg), sodium carbonate (33 mg) and phenylboronic acid (14 mg) in DME (2 mL) and water (1 mL) was heated at 90° C. for 2 hours. After cooling to ambient temperature and extraction into DCM (3×5 mL), the combined organics were dried, filtered and the solvent evaporated in vacuo to give a brown oil. Purification by flash chromatography on silica eluting with EtOAC:hexane (1:9) gave the title compound as a yellow solid (25 mg, 50%);
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)cc1
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol 4-fluorobenzaldehyde, 0.15 mol malonic acid, and 0.1 ml piperidine in 30 ml pyridine is boiled for 10 hours, cooled, and treated with 150 ml HCl having a 10% concentration. The precipitate is filtered and crystallized with ethanol. The yield of 4-fluorocinnamic acid is 68% and the melting point is 211° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH3:17])[N:6]=1.O>C(O)CC>[Cl:15][C:8]1[C:7]([O:16][CH3:17])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: NN
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: CCCO
Solvent: O
Product: COc1nc(NN)c(C(F)(F)F)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10.7 g (0.214 mol) of hydrazine hydrate were added in the course of 10 minutes with stirring at 50° C. to 25.0 g (0.102 mol) of 2,5-dichloro-6-methoxy-3-trifluoromethylpyridine in 100 ml of propanol and the mixture was stirred at 90° C. for 3 hours. After cooling, the resulting suspension was added to 1.2 liters of water, the precipitate was filtered off with suction and taken up in methylene chloride, and the solution was washed with water. The organic phase was dried and concentrated, and the residue was stirred with ether/pentane (1:1). After filtering off with suction and drying, 7.8 g (32% of theory) of the title compound of m.p. 140-142° C. were obtained.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]2[C@H:16]([OH:17])[C@@H:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=3)[CH2:14][S:13](=[O:31])(=[O:30])[CH2:12]2)[CH:7]=[CH:6][C:5]=1[N+:32]([O-:34])=[O:33].BrCC1C=CC([N+]([O-])=O)=C(C=1)C(OC)=O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C@H:15]1[CH2:14][S:13](=[O:31])(=[O:30])[CH2:12][C@@H:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]([N+:32]([O-:34])=[O:33])=[C:4]([CH:9]=2)[C:3]([OH:35])=[O:2])[C@@H:16]1[OH:17])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)ccc1[N+](=O)[O-]
Agent: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3ccc([N+](=O)[O-])c(C(=O)O)c3)[C@@H]2O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 5-[(3S*,4S*,5R*)-5-(3-tert-butyl-benzylamino)-4-hydroxy-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-3-ylmethyl]-2-nitro-benzoic acid methyl ester (434 mg, 0.86 mmol; prepared from methyl 5-(bromomethyl)-2-nitrobenzoate using a procedure analogous to that used in example 1) and NaOH (30% in H2O, 1 mL, 7.4 mmol) in anhydrous THF (5 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc and quenched with 2N aq. HCl to pH 2. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to yield the product as a yellow gum: ESIMS [M+H]+=491, LCMS RtI=0.97 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc(N)c(F)c1
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A cooled solution of 2-Fluoro-4-vinylaniline (20-1, 0.96 g, 7 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.644 mL, 8.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant to afford N-(2-Fluoro-4-vinylphenyl)methanesulfonamide (20-2, LJO-325, 1.372 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Clc1ccc2c(c1)CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(Cl)ccc43)c2cc1OC
Yield: 92 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 92% yield from 5-chloro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 190°14 191° C.; GC/MS: 3.41 (M+); anal. RP18-HPLC RT: 4.58 min.).
Reaction SMILES: [CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH:4]=[CH2:5])=[CH2:2].[C:10]1([PH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:17]1([P:16]([CH2:2][CH2:1][Si:3]([CH2:8][CH2:9][P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH2:6][CH2:7][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:4][CH2:5][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](C=C)(C=C)C=C
Product: c1ccc(P(CC[Si](CCP(c2ccccc2)c2ccccc2)(CCP(c2ccccc2)c2ccccc2)CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of 27.2 g (0.2 mole) of tetravinyl silane and 149.5 g (0.804 mole) diphenylphosphine was reacted in a quartz pressure tube at 200° C. with u.v. light initiation until most of the diphenyl phosphine was converted. The hot, molten reaction mixture was added to 720 g of hot tuluene with stirring. The tetraadduct product precipitated from the solution as a white crystalline solid. The mixture was allowed to cool to ambient temperature and then filtered with suction. After washing with toluene and drying in vacuo, 84 g (47.7%) of crude product was obtained. This was recrystallized from 1200 ml of xylene to obtain 69 g of pure tetrakis-(diphenylphosphinoethyl) silane of mp. 198°-199° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(C)(CN)CO
Product: CCCCn1c(=O)c(C(=O)NCC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 53 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and 3-amino-2,2-dimethyl-1-propanol (0.05 mL) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 53% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.51 (br s, 1 H), 8.56 (s, 1 H), 7.27 (s, 1 H), 7.17-7.13 (m, 2 H), 7.05-7.01 (m, 2 H), 4.14 (s, 2 H), 4.08 (m, 2 H), 3.39 (m, 1 H), 3.30 (m, 2 H), 3.22 (m, 2 H), 1.51 (m, 2 H), 1.33 (m, 2 H), 0.94 (s, 6 H), 0.90 (m, 3 H); MS m/z 456 M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:7][CH:6]=1)=[O:4].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Temperature: 20 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 12.3 mL, 12.3 mmol) slowly at 20° C. After stirring 0.5h, iodomethane (0.96 mL, 15.4 mmol) was added and the mixture was stirred for 3 h at 20° C. After quenching with water, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried (anhyd Na2SO4) and concentrated under reduced pressure to yield 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester as an oil (2.8 g, 92%), which was used in the next step without purification. MS (ES): 298 (MH+). To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([I:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(I)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(I)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(I)c1
Yield: 7.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (3.00 g, 8.74 mmol) in 75 mL of dichloromethane and 3-iodoaniline (3.82 g, 17.5 mmol) in 17 mL of pyridine. The crude product was triturated with hot ethanol, filtered, and recrystallized first from water-DMF, then from ethyl acetate-ether to yield 0.45 g of the title compound, mp 184°-186° C. (dec.).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
Chromium trioxide (951 mg, 9.51 mmole; dried in vacuo over phosphorous pentoxide) was added to a stirred solution of 1.49 g (18.88 mmole) of dry pyridine in 25 ml of dry methylene chloride. The deep red solution was stirred for 15 minutes at room temperature. A solution of (trans)-3-(6-phenyl-1,3,5-hexatriynyl)oxiranemethanol (300 mg, 1.35 mmole; see Example 3) in 5 ml of dry methylene chloride was then added in one portion. A tarry, black deposit separated immediately. After stirring for 20 minutes at room temperature, the solution was decanted and filtered through a pad of silica gel. Several portions of ether were then passed through the silica gel. Solvent was removed from the combined filtrates and the residue was chromatographed on silica gel (ether-hexane) to afford 130 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][B-:5]([F:8])([F:7])[F:6].C(O[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16])C.C(OCC)C>C(Cl)Cl>[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:1][N:2]([CH3:3])[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16]
Reactant: CNC
Reactant: CCOC(=O)C(=CC=[N+](C)C)OCC
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=CC=[N+](C)C)N(C)C

Procedure:
A solution of dimethylamine (233 cc) in methylene chloride is added in the course of 1 hour 20 minutes, at a temperature of approximately 20° C., to a solution of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (1,007 g) in methylene chloride. Anhydrous ethyl ether (2,000 cc) is then run slowly into the reaction medium, and the crystalline product is then separated off by filtration and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of approximately 20° C. N-(3-Dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (925 g), m.p. 102° C., is thereby obtained.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([C:1]([OH:8])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[CH2:13][CH2:14]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N#Cc1ccc(OCCCN2CCC(C(=O)c3ccccc3)CC2)cc1
Reactant: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccccc3)C3CCCC3)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
4-(3-(4-Benzoylpiperidin-1-yl)propoxy)benzonitrile (1.4 g, 4 mmol) was dissolved in dry THF (˜25 mL), heated to 60° C. and a solution of cyclopentylmagnesium chloride (4 mL, 2M) was added and the reaction stirred for 1 h. The reaction was quenched (sat. NH4Cl) and extracted into EtOAc (2×). The organic layers were dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (0-4% MeOH in CH2Cl2). The combined fractions were further purified by reverse phase chromatography to give 117 mg (7% yield) of analytically pure title compound: 1H NMR (400 MHz, CDCl3) δ 7.54 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=7.6 Hz), 7.31 (2H, t, J=7.6 Hz), 7.22 (1H, t, J=7.2 Hz), 6.89 (2H, d, J=8.8 Hz), 4.02 (2H, t, J=6 Hz), 3.12-3.00 (2H, m), 2.74-2.62 (3H, m), 2.09-1.95 (4H, m), 1.80-1.60 (4H, m), 1.58-1.40 (7H, m), 1.25-1.24 (1H, m), 1.11-1.09 (1H, m); LC-MS (>98%) m/z=419.3 [M+H]; HRMS=419.2701 [M+H], 100%, calculated for C27H35N2O2, 419.2699.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11](/[CH:14]=[CH:15]/[N+:16]([O-])=O)=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.Cl.CO>[Pd].C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1

Procedure:
2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan (5.73 g, 20.2 mmol) was dissolved into the mixture of dry methanol (90 ml) and dry ethyl acetate (70 ml). Then, 14.3 ml of 10 w-% HCl-methanol and 2.4 g of 10% palladium on carbon were added. 2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan was hydrogenated at 3 atm at RT for about 4 h. The catalyst was removed by filtrating through Celite®. Removal of solvent under reduced pressure gave a raw product which was purified by flash chromatography on silica gel using CH2Cl2/MeOH (98:2-80:20) as a gradient eluent. 1H NMR (400 MHz, DMSO-d6): 3.04 (2H, m), 3.14 (2H, m), 6.43 (1H, d), 7.07 (1H, d), 7.67 (2H, s), 7.93 (1H, s), 8.19 (3H, broad s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:30](=[O:31])[CH:29]=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[C:25]([F:37])([F:38])[F:24])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C(F)(F)F
Yield: 98.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-trifluoromethylcinnamic acid (2.6 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (4.1 g, 99%) as an amorphous solid product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([CH3:49])=[C:44]([NH2:50])[N:43]=1>C(Cl)(Cl)Cl.CO>[NH2:41][C:42]1[N:43]=[C:44]([N:50]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:45]([CH3:49])=[CH:46][C:47]=1[F:48]
Reactant: Cc1cc(F)c(N)nc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
To 1 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 280 mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added all of 2,6-diamino-3-fluoro-5-methylpyridine as described above together with 2 ml of methanol and 4 ml of chloroform. After allowing to stand at room temperature for 40 minutes, the solution was concentrated under reduced pressure. To the residue were added 600 mg of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirred at 85° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the mixture was allowed to stand overnight. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 171 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:12][CH3:13])[C:5](=[CH:9][C:10]=1[CH3:11])[C:6]([OH:8])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[OH:8][C:6]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=2)[N:12]([CH3:13])[C:14](=[O:16])[CH:15]=1
Reactant: CNc1cc(C)c(C)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(O)cc(=O)n(C)c2cc1C

Procedure:
To a solution of 4,5-dimethyl-N-methyl anthranilic acid (30.0g.; 0.168 mole; m.p. 190°- 191°C) in glacial acetic acid (75 ml.) was added acetic anhydride (75 ml.) and the mixture was refluxed for 4 hrs. After cooling the dark solution was poured onto crushed ice, made alkaline (pH 9), and filtered. On bringing the filtrate to pH5 with concentrated hydrochloric acid the title product separated as a white solid, m,p. (EtOH) 300°- 305°C (Found: C, 70.12; H, 6.30; N, 7.12; C12H13NO2 requires; C, 70.92; H, 6.45; N, 6.89%).