Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[C:6]([CH3:5])=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C)cc1
Yield: 68.8 %

Procedure:
To a suspension of 95.6 g (0.716 mole) of aluminum chloride in 500 ml of methylene dichloride was added, rapidly and with stirring, a solution of 110.1 g (0.551 mole) of 2-methyl-3-nitrobenzoyl chloride in 400 ml of methylene dichloride. The mixture was then transferred to an addition funnel, added with stirring to a solution of 59.8 g (0.551 mole) of anisole over a thirty minute period, and the reaction mixture then heated under reflux for two hours. The mixture was decomposed by the careful addition, with stirring, of 1 liter of water and then filtered. The organic layer was separated from the aqueous layer, dried and taken to dryness, and the residue recrystallized from ethyl acetate to give 102.9 g of 3-(4-methoxybenzoyl)-2-methylnitrobenzene, m.p. 110°-113° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:21]1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: OB(O)c1ccoc1
Product: O=C(Nc1nc2ccc(-c3ccoc3)cn2n1)c1cccnc1
Yield: 21.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and furan-3-boronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (15.6 mg, 21%). HPLC, Rt: 1.82 min. (purity 92.2%). LC/MS, M+(ESI): 306.3, M−(ESI): 304.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:10][C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>C(O)C.O.C(OCC)(=O)C>[Cl:22][C:12]1[C:13](=[O:16])[CH2:14][CH2:15][C:11]=1[NH:10][C:9]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NC2=C(Cl)C(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
To a solution 0.49 g (1.69 mmole) of the 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 1(3) in 5 ml of an ethanol-water (9:1) solution was added 0.25 g (1.86 mmole) of N-chlorosuccinimide. The mixture was stirred at room temperature for 1.5 hours. After the reaction, the solvent was removed in vacuo. Next, the residue obtained was diluted with 100 ml of ethyl acetate and the solution was successively washed with a saturated sodium hydrogencarbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product as a black oil. The crude product obtained here was purified by flash chromatography. The solvent was removed and the residue dried in vacuo to obtain the title compound 0.45 g (yield 82.5%) as a light pink solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11](O)[CH:10]=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[CH:10]=[N:9][N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13](=[O:14])[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(O)cnn1CC1CCCCC1
Product: O=c1cc(Cl)cnn1CC1CCCCC1
Temperature: 85 °C

Procedure:
To 10.5 g of 2- (cyclohexylmethyl)-5-hydroxy-3(2H)-pyridazinone was added 25 ml of phosphorus oxychloride and this mixture was heated for 4 hours at 85° C. After reaction, the excess phosphorus oxychloride was distilled off under reduced pressure. The residual solution was poured into water and to this solution was added aqueous sodium hydroxide solution to be alkalified and the separated solid was extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and filtered off with silica gel. Benzene was distilled off under reduced pressure to obtain 6.4 g of the intended compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22].O>C1C=CC=CC=1>[Cl:29][C:25]1[CH:24]=[C:23]([CH:20]([CH2:21][NH:22][CH:16]([CH3:17])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[OH:19])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)Cc1ccc(OCc2ccncc2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCc2ccncc2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 1-[4-(4-pyridylmethyloxy)phenyl)propan-2-one (2.5 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.78 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water until the reaction was complete. The solvent was evaporated, the residue dissolved in methanol (150 ml), cooled in an ice bath and treated with sodium borohydride (1.0 g). After stirring for 1 hour the methanol was evaporated, the residue partitioned between ethyl acetate and water, the washed organic phase dried and evaporated to give an oil which was chromatographed on Kieselgel 60. Elution with 4% methanol in chloroform gave 3-chloro-α-[[[2-[4-[4-pyridylmethyloxy)phenyl]-1-methylethyl]amino]methyl]benzenemethanol m.p. 85°-110° C. (ethylacetate-ether) as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:32][CH3:33])[C:15]=2[CH3:34])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>FC(F)(F)C(O)=O.ClCCl.C(OCC)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:32][CH3:33])[C:15]=2[CH3:34])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)OC(C)(C)C)cccn23)ccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)O)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
The solution of 0.68 g (1.45 mmol) of methyl 2-amino-5-{[8-(2-tert-butoxy-2-oxoethoxy)-1-methoxy-2-methylindolizin-3-yl]carbonyl}benzoate in 4.44 ml of trifluoroacetic acid and 7 ml of dichloromethane is stirred. After stirring at ambient temperature for 48 hours, the reaction medium is concentrated to dryness and the red solid obtained is taken up in ethyl ether. The solid in suspension is filtered and is dried at 50° C. under vacuum so as to obtain 0.58 g (95%) of an orange powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16](B5OC(C)(C)C(C)(C)O5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.Br[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:33]5[CH:38]=[N:37][CH:36]=[CH:35][N:34]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Reactant: Brc1cnccn1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnccn4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 33.5 mg, 0.080 mmol) and 2-bromopyrazine (Synchem, Huddersfield, UK, 17.2 mg, 0.108 mmol) to give the title compound as a white solid. (HPLC: tR 2.34 min (Method A); M+H=372 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.98 (s, 1H), 8.72-8.70 (m, 1H), 8.62-8.60 (m, 1H), 8.32-8.28 (m, 1H), 8.16-8.13 (m, 3H), 3.94 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C=C)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.52 mmol) 6-amino-4-[(3-ethynylphenyl)amino)-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and chilled to 0° C. under N2. Added 539 μl (3.87 mmol) triethylamine and 322 μl (3.87 mmol) acryloyl chloride. Removed ice bath at 15 minutes and stripped solvent at 1.5 hours. Slurried residue in water, collected solids and air dried overnight. Recrystallized from ethyl acetate, dried in vacuo, giving 302 mg of orange solid: mass spectrum (electrospray m/e): 339.1.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[C:14]([Cl:29])[C:13]=1[CH2:30][CH3:31])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC(=O)C)C>C(O)C>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[C:14]([Cl:29])[C:13]=1[CH2:30][CH3:31])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)cc2)c1Cl
Yield: 85.6 %

Procedure:
A mixture of ethyl(3,5-dichloro-4-[4-nitrophenoxy]phenyl) cinnamate (0.65 g), tindichloride dihydrate (1.0 g), ethylacetate (25 mL) and ethanol (25 mL) was heated at reflux for one hour. The reaction mixture was concentrated and the residue partioned beetween diethyl ether and sodium hydroxide (1 N). After purification on column (silica gel, ethyl acetate/petrolium ether, 3:7), 0.52 g of ethyl(3,5-dichloro-4-[4-aminophenoxy]phenyl) cinnamate was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=c1c(Cl)c(OCC2CCCC2)cnn1C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc(OCC2CCCC2)c1Cl
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A solution of 4-chloro-5-cyclopentylmethoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (1.63 g, 5.21 mmol) in methanol (10 mL, 0.52M) was treated with a 6N aqueous hydrochloric acid solution (4.4 mL). The reaction solution was heated to 110° C., where it stirred for 2.5 h and was then allowed to cool to 25° C. The reaction was then diluted with water (100 mL) and brought to basic pH with a 4N aqueous sodium hydroxide solution. This solution was extracted with methylene chloride (1×100 mL). The aqueous layer was then acidified with a 3N aqueous hydrochloric acid solution. The resulting white precipitate was collected by filtration, washed with water, and dried in vacuo to afford 4-chloro-5-cyclopentylmethoxy-2H-pyridazin-3-one (1.06 mg, 89%) as a white solid; ES+-HRMS m/e calcd for C10H13N2O2Cl [M+H+] 229.0739, found 229.0738. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.40 (m, 2H), 1.47-1.68 (m, 4H), 1.70-1.82 (m, 2H), 2.22-2.38 (m, 1H), 4.22 (d, J=6.8 Hz, 2H), 8.19 (s, 1H), 13.28 (brs, 1H).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([CH:14]=[O:15])=[CH:13][C:7]=2[O:6]1.N#N.O>ClC(Cl)C>[Cl:2][CH2:5][O:6][C:7]1[C:8]([OH:9])=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:13]=1)[CH:14]=[O:15]
Reactant: [Cl-]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: N#N
Agent: [Al+3]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Reaction time: 1.25 h
Yield: 96.7 %

Procedure:
AlCl3 (6 g) and dry dichloroethane (15 ml) are added to a three-neck round bottom flask, which has been purged with N2, and the dispersion is cooled to -5°. A solution of 6-nitropiperonal (3 g; 0.0154 mol) (available from Aldrich Chemical Co.) in 12 ml dry dichloroethane is added to the dispersion, in one portion, while the temperature and N2 atmosphere are maintained. The reaction mixture is stirred for 1.25 hours, and 100 ml H2O (0°) is added. The emulsion is stirred for 15 minutes, then extracted with 3×100 ml ethyl acetate. The combined organics are washed with saturated NaCl, then dried over Na2SO4. After filtration, the ethyl acetate is removed at reduced pressure. Recrystallization from ethyl acetate gives 3.45 g (97%) of (10): mp 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:22])[CH2:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.Cl.ClC1C=CSC=1C(=O)CN.FC(F)(F)C1C=CC(C(Cl)=O)=CC=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:22][C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:9][CH:8]=1
Reactant: O=C(NCC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: NCC(=O)c1sccc1Cl
Agent: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2ncc(-c3sccc3Cl)o2)cc1

Procedure:
N-(2-(3-Chloro-thiophen-2-yl)-2-oxo-ethyl]4-trifluoromethyl-benzamide: The title compound was prepared from 2-(3-chloro-thiophen-2-yl)-2-oxo-1-ethylamine hydrochloride and 4-trifluoromethyl-benzoyl chloride by a procedure similar to Example 98a as a white solid (0.044 g, 30%). 1H NMR (DMSO-d6): 9.06 (m, 1H), 7.99 (m, 3H), 7.77 (d, J=8.4 Hz, 2H), 7.20 (d, J=9.0 Hz, 1H), 4.73 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:21](C([O-])=O)[C:22]([O-:24])=O)([O-])=O.Cl>CCO.C(Cl)(Cl)Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[CH:9]=[C:4]3[C:5]([CH2:21][C:22](=[O:24])[NH:1]3)=[CH:6][CH:7]=2)=[O:20])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(C(C(=O)[O-])C(=O)[O-])c([N+](=O)[O-])c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Nitro-4-(4-nitrobenzoyl)phenyl]malonate (4.15 g, 9.61 mmol) was dissolved in EtOH (24 mL) after which Sn powder (9.16 g, 77 mmol) was added followed by dropwise addition of concentrated HCl(aq) (26 mL). The reaction mixture was allowed to reflux for 3 hours, filtered while hot and then allowed to cool to room temperature. The cooled reaction mixture was diluted with CHCl3 (400 mL) and then extracted once with H2O (400 mL). The aqueous layer was then neutralized with NaHCO3 (pH=7) and then extracted with a 95% EtOAc/5% i-prOH solution (3×400 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solution was then concentrated in vacuo affording the 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one in 51% yield (1.24 g, 4.90 mmol).
Reaction SMILES: [OH:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([I:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(Cl)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[I:12][C:8]1[CH:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2](=[O:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(I)ccnc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1c(I)ccn(-c2ccccc2)c1=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Methyl 2-hydroxy-4-iodonicotinate (123 mg, 441 μmol), phenylboronic acid (161 mg, 1322 μmol), copper acetate (160 mg, 882 μmol) were combined. Dichloroethane (6 mL) was added followed by molecular sieves 4 Å activated (490 mg) and pyridine (143 μl, 1763 μmol). The reaction mixture was stirred at 55° C. for 3 h. LCMS analysis of an aliquot showed the reaction was complete. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite (rinsing with dichloromethane). The filtrate was concentrated in vacuo and purification by MPLC (ISCO, CH2Cl2/MeOH: 100/0 to 97.5/2.5) afforded methyl 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (142 mg, 400 μmol, 91% yield). MS (ESI pos. ion) m/z: 356 (MH+). Calc'd exact mass for C13H10INO3: 355.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH3:18]>C(O)C.CO>[NH2:18][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6]
Reactant: N
Reactant: COC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCO
Product: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
3-Methoxy-3-(4-nitrophenyl)-2-cyanoacrylonitrile (14.4 g, 0.063 mol) was suspended in ethanol (1 L) in a flask equipped with a magnetic stirrer. To the suspension was added 60 mL (ca. 0.20 mol) of a 10% (w/w) solution of ammonia in methanol. The mixture was stirred vigorously for 15 min, at which time HPLC analysis showed the absence of starting material. The now homogeneous mixture was concentrated in vacuo to ca. 80 mL. The solid that had formed was collected with the aid of a small amount of additional ethanol and was pressed well with rubber dam. The cake was washed with of ethanol (2×5 mL) and was left to dry in a hood draft. The dry solid weighed 8.8 g. The filtrate was concentrated and mixed with dichloromethane (10 mL). The resulting solid was collected, washed with dichloromethane (2×2 mL), dried, and combined with the 1st crop to yield 9.9 g (46% for 2 steps). HPLC analysis indicated a purity of 91%. NMR (60 MHz) (DMSO-d6) δ 8.8 (bs, 0.5H); 8.0 (AB, 4H); 3.2 (bs, 1H); 2.8 (bs, 0.5H). The IR spectrum showed nitrile stretches at 2221 and 2207 cm−1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:24]=[CH:23][N:22]=[N:21]1.[I-].[K+].C[O-].[Na+]>CO>[F:18][CH:17]([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:35][C:32]3[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)=[CH:30][CH:31]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: FC(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1

Procedure:
0.286 g (1.00 mmol) 4-Chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole, 0.217 g 1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of a 30% sodium methylate solution were added to 50.0 ml methanol and heated to reflux for 12 h. After removal of solvent, partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed with 10 ml water, 10 ml 0.1 N NaOH, 15 ml water twice and dried over sodium sulphate. The solution was concentrated to a volume of 5 ml until crystallisation of the product started. After leaving for 1 h at room temperature the precipitate was sucked off, washed with ether and dried at 40° C. in vacuo. Yield 0.20 g (43%) 3.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[N:16][OH:17])([O-:3])=[O:2]
Reactant: NO
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C=NO)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 71 %

Procedure:
9.7 parts of 2-nitro-4-dimethylaminobenzaldehyde is dissolved in 50 parts of ethyl alcohol and a solution of 4.1 parts of hydroxylamine hydrochloride and 5 parts of sodium acetate in water is added. After the mixture has been boiled for one hour it is suction filtered. 7.5 parts (71% of theory) of 2-nitro-4-dimethylaminobenzaldoxime is obtained having a melting point of 140° to 143°C: ##SPC18##
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:3]1[O:4][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)c1nc2ccccc2c(=O)o1
Temperature: 65 °C

Procedure:
17.47 ml of 2-chloropropionic acid chloride were added with stirring at room temperature to a solution of 10.3 g of 2-amino-benzoic acid in 20 ml of toluene and the mixture was progressively heated to 65° C. during which a mass was formed and gas disengaged and the mixture fluidized. The mixture was held at reflux for 90 minutes and was evaporated to dryness under reduced pressure. The residue was empasted with petroleum ether (b.p.=60° to 80° C.), was iced and vacuum filtered. The product was washed and dried under reduced pressure at 50° C. to obtain 14.45 g of 2-(1-chloroethyl)-4H-3,1-benzoxazine-4-one melting at 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[N:33]=2)[C:22]=1[CH3:40]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[NH:33][C:34](=[O:38])[CH:35]=[CH:36][CH:37]=4)[C:22]=3[CH3:40])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cccc(=O)[nH]2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (108 mg, 0.48 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (100 μL, 0.40 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (120 mg, 0.40 mmol) (described herein), and NMP (660 μL). The reaction mixture was stirred and heated in a microwave at 150° C. for 180 min. Purification afforded 6-(4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one as a yellow solid. Mass Spectrum (ESI) m/e=479 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Yield: 109.2 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-chlorobenzoyl chloride (29 μL, 0.229 mmol), 44.8 mg (>100%) of the title compound were recovered.