Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].C[O:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11](=[O:10])[CH2:6][C:7]#[N:8])=[CH:14][C:15]=1[O:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: CC#N
Reactant: COCCOc1cc(CC(=O)OC)ccc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(CC(=O)CC#N)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.9 %

Procedure:
To a 250 mL three-necked round-bottomed flask was added 10 mL of anhydrous THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 8.06 mL, 12.9 mmol) was added and the mixture was stirred for 5 min. Anhydrous CH3CN (0.696 mL, 13.3 mmol) in 5 mL of anhydrous THF was added dropwise at −78° C. After 1 h of stirring, 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester (1.10 g, 4.3 mmol) in 10 mL of anhydrous THF was added dropwise to the resulting white colloidal mixture. The reaction mixture was stirred for an additional 2 h, followed by the addition of saturated NH4Cl solution at −78° C. The solution was warmed to r.t., diluted with 100 mL water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with gradient 30-60% EtOAc in hexanes to yield 769 mg (68% yield) of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyronitrile as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)/[CH:5]=[CH:6]/[C:7]([O:9]CC)=O.[CH2:15]([NH2:17])[CH3:16].C[O-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]=[CH:6][C:7]([NH:17][CH2:15][CH3:16])=[O:9]
Reactant: CCOC(=O)/C=C/c1cccc(Br)c1
Reactant: CCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)C=Cc1cccc(Br)c1
Temperature: 45 °C

Procedure:
Trans ethyl 3-bromocinnamate (8.4 g), ethylamine (6.7 g), methanol (18 ml) and 4A molecular sieves (1 g) were combined and heated at reflux for 1/2 hour. The mixture was cooled to about 45° C and sodium methylate (0.6 g) added. The mixture was then heated at reflux 11/2 hour and then cooled. It was acidified with concentrated hydrochloric acid (12 ml). The sieves were removed by filtration. Ice water was added to the filtrate to precipitate trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C (after recrystallization from ethanol/water).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[C:21]([Br:22])=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Br:22][C:21]1[CH:20]=[C:19](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[CH3:11])=[CH:4][CH:5]=2)[CH:18]=[N:17][C:16]=1[O:15][CH2:14][CH2:13][OH:12]
Reactant: C=Cc1ccc(N(C)C)cc1
Reactant: OCCOc1ncc(I)cc1Br
Product: CN(C)c1ccc(/C=C/c2cnc(OCCO)c(Br)c2)cc1

Procedure:
Compound 14a was prepared from 4-dimethylaminostyrene (0.031 g, 0.212 mmol) and 9b (0.073 g, 0.212 mmol) as a light yellow solid (0.022 g, 29% yield). 1H NMR δ 8.07 (d, 1H, J=2.1 Hz), 8.03 (d, 1H, J=2.1 Hz), 7.39 (d, 2H, J=8.8 Hz), 6.94 (d, 1H, J=16.3 Hz), 6.78-6.69 (m, 3H), 4.57-4.52 (m, 2H), 3.99 (t, 2H, J=4.3 Hz), 3.21 (br s, 1H), 3.00 (s, 6H). 13C NMR δ 158.3, 150.4, 143.0, 138.2, 129.9, 129.8, 127.6, 124.9, 118.3, 112.3, 107.5, 69.6, 62.1, 40.3. HRMS calcd for C17H19BrN2O2 (M+), 362.063. found, 362.0629.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:23]([C:25]1([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]1)=[O:24].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]([C:25]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]2)=[O:24])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Reactant: Brc1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-bromoiodobenzene (2150 mg, 7.60 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of 1.67 mol/L n-butyllithium in hexane (4.50 mL, 7.52 mmol) at −78° C. under argon atmosphere. The mixture was stirred at the same temperature for 1 hour, and then thereto was added dropwise a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (synthesized by the method of Organic Process Research and Development 2009, 13, 576, 1000 mg, 5.07 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride solution at −78° C., and then the mixture was warmed to room temperature and extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5) to give (4-bromophenyl)[1-(trifluoromethyl)cyclopropyl]methanone (783 mg, 76%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](I)[C:13]([Cl:17])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[Cl:1][C:2]1[CH:15]=[C:14]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:17])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: C#Cc1ccccc1
Reactant: CCN(CC)CCOc1cc(Cl)c(I)cc1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1cc(Cl)c(C#Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.9 %

Procedure:
To a solution of 19.4 g (0.05 mole) of 1-(2,5-dichloro-4-iodophenoxy)-2-diethylaminoethane and 5.2 g (0.053 mole) of phenylacetylene in 250 ml of triethylamine are added, under nitrogen, 200 mg of the palladium complex PdCl2 [P(C6H5)3 ]2 and 100 mg of copper(I) iodide. After the weakly exothermic reaction has subsided, the reaction mixture is stirred for 15 hours at room temperature, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 4 times with water, dried and evaporated to dryness. The crude product is chromatographed on silica gel, affording 14.3 g (79%) of 1-(2,5-dichloro-4-phenylethynylphenoxy)-2-diethylaminoethane with a refractive index of nD25 :1.6173.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH:33]2[CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCC1
Solvent: O
Solvent: CCO
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCC4)ncnc32)[C@]1(C)F
Yield: 46.5 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added cyclobutylamine (about 0.88 ml, 10.38 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.20 g) as a colorless gummy mass. Yield: 46.5%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)CCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The title C compound, 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (0.58 mmol, 220 mg) is dissolved in 15 mL of THF and cooled to −78° C. LHMDS (1.2 mmol, 1.2 mL of 1.0 M solution) is added and the mixture is stirred to 1 h at −78° C. Benzyl bromide (0.6 mmol, 103 mg) is added and the mixture stirred at −78° C. for 2 h further. The reaction mixture is quenched with aqueous saturated ammonium chloride, the solvent is evaporated and the residue is partitioned between EtOAc and brine. The organic solution is dried and evaporated to an oil. Chromatography on silica (eluent: 35% EtOAc in hexanes) affords 3-cyclopentyl-2-[4-(2-phenyl-ethanesulfonyl)-phenyl]-N-thiazol-2-yl-propionamide: 1H NMR δ 11.8 (s, 1H), 7.86 (d, J=8, 2H), 7.55 (m, 3H), 7.05-7.32 (m, 6H) 3.8 (t, J=7.5, 1H), 3.33 (m, 2H), 3.05 (m, 2H), 2.29 (m, 1H), 1.0-1.9 (m, 8H); e/z (ES) 469 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][CH2:7][C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:7][C:6]=2[CH:16]=1
Reactant: Clc1ccc2c(c1)CNc1ccccc1O2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cc(Cl)ccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a mixture of 0.229 g (1.0 mmol) of 2-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine in 1.0 ml of pyridine under nitrogen is added 0.30 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred at room temperature for 1 hour, heated on a steam bath for 5 minutes and 8 ml of 2N HCl added. The mixture is extracted with ethyl acetate and the extract washed three times with 1 ml of 1N sodium bicarbonate. The organic layer is dried (MgSO4) and the solvent removed. The residue is crystallized from ethyl acetate-hexane to give 0.24 g of crystals., m.p. 207°-208° C. Anal. Calc'd for C28H2N2 O3Cl: C,71.9; H,4.5; N,6.0; Cl,7.6. Found: C,71.6; H,4.6; N,5.9; Cl,7.4.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=O)[CH2:5][CH2:4]1.Cl.[NH2:20][OH:21]>C(O)C>[CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=[N:20][OH:21])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(C)(C=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(C)(C=NO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the title compound of step 2 (5.90 g, 24.0 mmol) and hydroxylamine hydrochloride (2.50 mg, 36.0 mmol) in abs. ethanol (100 mL) were mixed with Amberlyst A 21 (17.0 g) and stirred for 20 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[S:3][C:2]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])=[N:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCCNCCC
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCN(CCC)c1nc(C)c(-c2c(C)nc3c(C(CC)CC)cc(C)nn23)s1
Temperature: 100 °C

Procedure:
35 mg of 3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.09 mmol) and 45 mg of di-n-propylamine (0.44 mmol) and 57 mg of cesium carbonate (0.18 mmol) are place into 4 ml reaction vial with 3 ml of dry THF and the vial is capped with a Teflon cap. The reaction vial is heated at 100° C. for 4 h. The reaction mixture is transferred into microwave reaction vessel and sealed. The reaction mixture is heated at 160° C. for 30 min by microwave. The mixture is concentrated and applied onto silica-gel chromatography column (Hexane:AcOEt=3:1) to give the title compound. 5.3 mg (14%); mass spectrum (m/e): 414; 1H-NMR (CDCl3): 5.59 (s, 1H), 3.45 (m, 4H), 3.36 (m, 1H), 2.57 (s, 3H), 2.47 (s, 3H), 2.17 (s, 3H), 1.80 (m, 8H), 0.99 (t, 6H, J=7.5 Hz), 0.89 (t, 6H, J=9.4 Hz).
Reaction SMILES: C1(N)C=CC=CC=1.[N+:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH:26]=1)([O-:10])=[O:9].[Cl:39]Cl>ClCCl>[N+:21]([C:13]1[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])[C:26]=1[Cl:39])([O-:23])=[O:22]
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1cccc(OC(F)(F)C(F)(F)F)c1Cl

Procedure:
When desired, the above described halogenation reaction can be carried out utilizing less than one molar quantity of halogenating agent, thereby effecting monohalogenation instead of dihalogenation. The monohalogenated product can be further halogenated if desired with the same or a different halogenating agent. For instance a benzenamine such as N-(2,6-dinitro-4-trifluoromethylphenyl)-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine can be reacted with about a 0.5 molar amount of chlorine in dichloromethane at about 25° C. to give N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-3-(1,1,2,2,2-pentafluoroethoxy)benzenamine. The latter compound can be further halogenated, for instance by reaction with about a 0.5 to 1.0 molar amount of bromine in dichloromethane, to provide the corresponding dihalogenated derivative, for example N-(2,6-dinitro-4-trifluoromethylphenyl)-2-chloro-4-bromo-5-(1,1,2,2,2-pentafluoroethoxy)benzenamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=NN=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:16][C:17]([Cl:38])([Cl:37])[C:18]1[N:23]=[C:22]([C:24]([Cl:27])([Cl:26])[Cl:25])[N:21]=[C:20]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](Cl)=[O:32])[N:19]=1>N1C=CC=CC=1>[Cl:27][C:24]([Cl:25])([Cl:26])[C:22]1[N:23]=[C:18]([C:17]([Cl:38])([Cl:16])[Cl:37])[N:19]=[C:20]([C:28]2[CH:29]=[C:30]([C:31]3[O:32][C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15][N:14]=3)[CH:34]=[CH:35][CH:36]=2)[N:21]=1
Reactant: COc1ccc(-c2nnn[nH]2)cc1OC
Reactant: O=C(Cl)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Solvent: c1ccncc1
Product: COc1ccc(-c2nnc(-c3cccc(-c4nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n4)c3)o2)cc1OC

Procedure:
5-(3,4-Dimethoxyphenyl)-tetrazole (20 pbw) and 3-(4,6-bis-trichloromethyl-s-triazin-2-yl)benzoyl chloride (44 pbw) are heated in 400 pbv of pyridine. The mixture is further processed as indicated above.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
A mixture of 0.30 gm (1.1 mMol) 5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.05 gm 10% palladium on carbon in 15 mL ethanol was hydrogenated at room temperature for 18 hours at an initial hydrogen pressure of 50 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate containing 20% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[C:16]1([O:24][CH3:25])[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:18][CH3:19]>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([C:22]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:16]([O:24][CH3:25])[CH:23]=2)=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: O
Product: COc1ccc(CC(=O)c2ccc(OC)c(OC)c2)cc1OC
Reaction time: 24 h
Yield: 60 %

Procedure:
A warm solution of 3,4-dimethoxyphenylacetic acid (10 g) in veratrole (15 ml) was added to 200 g of polyphosphoric acid (PPA). After 24 hrs. at room temperature the acid mixture was added to cold water (800 ml) and the product was collected and recrystallized from aqueous ethanol. The recrystallized intermediate (9.5 g, 60% yield) had a melting point of 104°-105°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CNCCC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CS(O[CH2:31][C:32]1([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]1)(=O)=O>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:13])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:8][N:9]2[CH2:31][C:32]2([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][O:36][C:35]([CH3:38])([CH3:39])[O:34][CH2:33]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)COC(C)(C)OC1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a solution of the product of Example 13, Step B (0.11 g; 0.32 mmol) in anhydrous DMF (0.6 ml) 60% NaH in mineral oil (0.02 g; 0.5 mmol) was added and the mixture was stirred for 1 h at room temperature under N2. To it, a product of Step A (0.13 g; 0.383 mmol) was added and the resulting mixture was stirred for 3 days at ˜55° C. under N2, cooled to room temperature and diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, CH2Cl2/EtOAc 8:2) to give the title compound (0.07 g; 37%) as a colourless solid. 1H-NMR (CDCl3) 1.23 (s, 9H); 1.46 (s, 3H); 1.53 (s, 3H); 3.71 (d, 2H, J=11.8 Hz); 3.84-3.94 (m, 15H); 4.12 (s, 1H); 4.76 (s, 2H); 6.96 (dd, 1H, J=2.2, 8.8 Hz); 7.06 (s, 2H); 7.16 (d, 1H, J=2.2 Hz); 7.44 (s, 1H); 8.24 (d, 1H, J=8.8 Hz).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][C:12]([C:14]1[N:15]([CH2:30][CH3:31])[C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:19]([F:29])=[CH:18][CH:17]=2)=O)C.O>C(O)(=O)C>[CH2:30]([N:15]1[C:16]2[CH:17]=[CH:18][C:19]([F:29])=[CH:20][C:21]=2[C:22]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12](=[O:11])[C:14]1=2)[CH3:31]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)C(=O)OC)c2cc(F)ccc2n1CC
Solvent: CC(=O)O
Solvent: O
Product: CCn1c2ccc(F)cc2c2c(C(=O)OC)nn(-c3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
18.4 ml (187.2 mmol) of phenylhydrazine are added, at room temperature, to a solution of 14 g (43.6 mmol) of methyl 2-(ethoxycarbonyl)-1-ethyl-5-fluoro-α-oxo-1H-indole-3-acetate in 150 ml of acetic acid and the reaction mixture is stirred for 30 min at room temperature and then for 2 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is separated by filtration, the insoluble material being washed on sintered glass with a 70/30 mixture of water and acetone. 10.5 g (28.6 mmol) of white solid are thus isolated, which solid is used as is in the following stage.