Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[CH2:20])[CH2:15][N+](C)(C)C)=[CH:9][CH2:8][CH2:7]2.[CH3:21][OH:22]>[Ag]=O.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([CH2:15][C:13]1([CH2:12][CH3:11])[C:21](=[O:22])[CH2:6][CH2:5][C:4]1=[O:3])=[CH2:20])=[CH:9][CH2:8][CH2:7]2
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ccc21
Reactant: CO
Agent: O=[Ag]
Agent: [I-]
Solvent: O
Product: C=C(CC1(CC)C(=O)CCC1=O)C1=CCCc2cc(OC)ccc21
Reaction time: 3 h

Procedure:
A solution of 13 parts of 2-(6-methoxy-3,4-dihydro-1-naphthyl)-2-propen-1-yltrimethyl ammonium iodide in 200 parts by volume of methanol and 1 part of water is cooled to 0.5° and 4.5 parts of silver oxide is added. The resulting mixture is stirred for about 3 hours and the solid which forms is removed by filtration. At that time 5 parts of 2-ethylcyclopentane-1,3-dione is added to the filtrate. The resulting solution is concentrated to a small volume and 400 parts by volume of xylene together with 2 parts by volume of hexamethylphosphoramide and 5 parts by volume of triethylamine are added. That reaction mixture is slowly distilled to remove water and methanol, in the amount of approximately 50 parts by volume and the resultant mixture is heated at the reflux temperature for about 20 hours. After cooling that mixture is washed with water, 5% hydrochloric acid, water 5% aqueous sodium bicarbonate and the water again. Drying of that solution over anhydrous sodium sulphate followed by removal of the solvent under reduced pressure and crystallization of the resulting residue from methanol affords pure 2-(6-methoxy3,4-dihydro-1-naphthyl)-3-(2-ethylcyclopentane-1,3-dione-2-yl)propene, melting at about 100°-125°. This compound exhibits an ultraviolet absorption maxima at about 273 millimicrons with a molecular extinction coefficient of approximately 11,100.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[O:13]([C:20]1[CH:28]=[CH:27][C:23](C(O)=O)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:23]1[CH:27]=[CH:28][C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21][CH:22]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Product: C[C@@H](C#N)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
General procedure D was used to deprotect 1.2 mmols of 4 and immediately coupled to 1.2 mmols of 25 using general procedure F. The title product was purified by flash chromatography with ethyl acetate and hexanes to yield 0.53 mmol (0.14 g). 1H NMR (300 MHz, CDCl3) δ 7.87-7.65 (m, 3H), 7.39 (t, J=7.8, 2H), 7.20 (d, J=6.7, 1H), 7.10-6.90 (m, 5H), 6.76 (s, 2H), 5.26-5.03 (m, 1H), 1.65 (d, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-(aminomethyl)pyridine in DME. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:24][CH:25]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N-(4-Amino-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide (0.105 grams, 0.31 mmole) and triethyl amine (0.047 grams, 0.46 mmole) in methylene chloride was cooled to 0° C., and Acetyl chloride (0.029 grams, 0.37 mmole) was added. The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 30 minutes. The mixture was diluted with water and extracted with methylene chloride. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a solid . Recrystalization from ethyl acetate/hexane gave a white solid. (0.082 g). M.P. 128-130° C.; Anal. calcd. for C21H18N3O3F: C, 66.48; H, 4.78; N, 11.08. Found: C, 66.14; H, 4.47; N, 11.08.
Reaction SMILES: BrC1C2C(=CC=C(NC(OC3CCCC3)=O)C=2)N(C)N=1.BrCC1C=CC(C(OC)=O)=CC=1OC.[CH:35]1([O:40][C:41]([NH:43][C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[N:49]([CH3:53])[N:48]=[C:47]3[CH2:54][C:55]2[CH:64]=[CH:63][C:58]([C:59]([O:61]C)=[O:60])=[CH:57][C:56]=2[O:65][CH3:66])=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:35]1([O:40][C:41]([NH:43][C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[N:49]([CH3:53])[N:48]=[C:47]3[CH2:54][C:55]2[CH:64]=[CH:63][C:58]([C:59]([OH:61])=[O:60])=[CH:57][C:56]=2[O:65][CH3:66])=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)c1ccc(Cc2nn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)c1ccc(CBr)c(OC)c1
Product: COc1cc(C(=O)O)ccc1Cc1nn(C)c2ccc(NC(=O)OC3CCCC3)cc12

Procedure:
The process may be carried out, for example, using a stoichiometric amount of activated zinc dust and a catalytic quantity of a transition metal catalyst, such as, for example, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) or dichlorobis(triphenylphosphine)nickel (II) to couple, for example, 3-bromo-5-(cyclopentyloxycarbonyl)amino-1-methylindazole with, for example, methyl 4-bromomethyl-3-methoxybenzoate to afford methyl 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindazol-3-ylmethyl]-3-methoxybenzoate; followed by decomposition of the ester to afford 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindazol-3-ylmethyl]-3-methoxybenzoic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14]C)=O)[CH:11]=1)[NH:8][CH:7]=[CH:6][C:5]2=[O:16].[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH2:22])[CH3:18].C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH:22][C:12]([C:10]1[CH:11]=[C:2]([I:1])[CH:3]=[C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][C:5]2=[O:16])=[O:14])[CH3:18]
Reactant: COC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Reactant: CCN(CC)CCN
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CC)CCNC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Yield: 86.3 %

Procedure:
This compound was prepared, starting from compound 99 (2.00 g, 6.08 mmol) and N,N-diethylethylenediamine (1.21 mL, 8.56 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 14 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 96/4, v/v) to give compound 100 (2.17 g, 5.25 mmol) as a beige solid. Yield 86%; Rf (Al2O3, CH2Cl2/EtOH, 96/4, v/v) 0.51; mp 141-143° C.; IR (KBr) ν 1392, 1491, 1560, 1617, 1641, 2800-3000, 3293 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.07 (t, 6H, J=7.1 Hz), 2.62 (q, 4H, J=7.1 Hz), 2.71 (t, 2H, J=6.3 Hz), 3.50 (m, 2H), 6.30 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.07 (d, 1H, J=1.9 Hz), 8.79 (d, 1H, J=1.9 Hz); ESI-MS m/z 413.8 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.84 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (4.78 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 479.06, observed 479.0;
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[C:6]([NH:9][CH:10]3[CH2:12][CH2:11]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:15]1([NH:18][C:19](=[O:37])[C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>C(O)(C)C>[CH:15]1([NH:18][C:19](=[O:37])[C:20]2[CH:21]=[C:22]([F:36])[C:23]([CH3:35])=[C:24]([C:2]3[CH:14]=[CH:13][C:5]4[C:6]([NH:9][CH:10]5[CH2:12][CH2:11]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:25]=2)[CH2:16][CH2:17]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(NC3CC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(NC3CC3)noc2c1
Yield: 43.7 %

Procedure:
A mixture of 6-bromo-N-cyclopropyl-1,2-benzisoxazol-3-amine (Intermediate 53) (0.02 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.02 g) saturated aqueous sodium hydrogen carbonate (0.5 ml) and tetrakis(triphenykphosphine)palladium(0) in isopropanol (2 ml) was heated in a microwave at 150° for 10 min. The residue was absorbed onto silica Merck 7734) and applied to a Varian Bond Elut SPE cartridge (silica, 5 g) elutin with cyclohexane:ethyl acetate (75:25 to 0:100) to give the title compound (10 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:19][CH3:20])=[C:9]2[CH2:14][C:13]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH2:11][C:10]=12)=[O:5])C.[Li+].[OH-]>>[CH2:17]([C:13]1([CH2:15][CH3:16])[CH2:12][CH2:11][C:10]2=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]([S:19][CH3:20])=[C:9]2[CH2:14]1)[CH3:18]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(CC)(CC)C2
Agent: [Li+]
Agent: [OH-]
Product: CCC1(CC)CCc2c(C(=O)O)sc(SC)c2C1

Procedure:
5,5-Diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester is treated with LiOH as described in Example K to give 5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid; LC-MS: tR=1.06 min, [M+1]=285.0; 1H NMR (CDCl3): δ 2.96 (t, J=6.4 Hz, 2H), 2.54 (s, 3H), 2.31 (s, 2H), 1.55 (t, J=6.4 Hz, 2H), 1.37-1.20 (m, 4H), 0.83 (t, J=7.3 HZ, 6H).
Reaction SMILES: Br[CH:2]([C:4]12[O:11][CH2:10][C:7]([CH2:12][CH3:13])([CH2:8][O:9]1)[CH2:6][O:5]2)[CH3:3].CC(C)([O-])C.[K+].O>O1CCCC1>[CH:2]([C:4]12[O:5][CH2:6][C:7]([CH2:12][CH3:13])([CH2:8][O:9]1)[CH2:10][O:11]2)=[CH2:3]
Reactant: CCC12COC(C(C)Br)(OC1)OC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC12OCC(CC)(CO1)CO2
Yield: 82.3 %

Procedure:
25 g (0.1 moles) of the product obtained in step (b) above was added dropwise over about one hour at room temperature to a solution of 11 g (0.1 moles) of potassium t-butoxide in 100 ml of tetrahydrofuran placed in a 250 ml flask. The mixture was heated at reflux temperature for 5 hours and the reaction solution obtained was poured into water. The resulting solution was extracted with ethyl ether and the organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation of the ether. The residue was distilled under reduced pressure to give 14 g (83%) of the title compound with a boiling point of 68°-72° C./2 mmHg and a specific gravity of 1.216 (Method D).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][CH:23]([CH3:28])[CH2:24][C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:25](=[O:26])[CH2:24][CH:23]([CH3:28])[CH3:22])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CC(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of N-t-butoxycarbonyl-1,4-phenylene diamine (0.2 g) in dry tetrahydrofuran (20 ml) were added pyridine (0.15 ml) and 3-methylbutyryl chloride (0.13 g) and the reaction mixture was stirred for 1 hrs. The solution was diluted with ethyl acetate (50 ml), washed with a 3 N solution of hydrochloric acid (30 ml) and brine (30 ml), dried and concentrated in vacuum to give the title compound (0.27 g). T.l.c. cyclohexane/ethyl acetate 1/1, Rf =0.71.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:13])(O)[C:10]#[N:11]>C(OCC)(=O)C>[CH3:8][C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[C:10]#[N:11]
Reactant: Nc1ccccc1
Reactant: CC(C)(O)C#N
Solvent: CCOC(C)=O
Product: CC(C)(C#N)Nc1ccccc1
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of aminobenzene (0.931 g, 10 mmol) and acetone cyanohydrin (2 ml) was heated to reflux and stirred for 20 h. After being cold to room temperature, the reaction mixture was poured into ethyl acetate (40 ml) and washed with cold water (2×30 ml). The organic layer was dried over MgSO4, concentrated under vacuum to dryness to yield 2-methyl-2-phenylaminopropanenitrile, 6a (1.51 g, 9.4 mmol, 94%) as slurry brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH:28]1(I)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Na+].[Cl-]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Reactant: IC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OC3CCCCC3)cc(Cl)c2OC1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 17a, Step 3 (1.00 g, 3.10 mmole) in anhydrous DMF (10.0 mL) was added KI (51.5 mg, (0.310 mmole), K2CO3 (1.29 g, 9.30 mmole) and cyclohexyl iodide (1.20 mL, 9.30 mmole). The suspension was heated at 50° C. for 17 h and then the temperature was slowly raised to 80° C. and stirred overnight. Additional cyclohexyl iodide (1.20 mL, 9.30 mmole) was added and the temperature was maintained at 100-120° C. for 3 days. The mixture was then cooled and poured into H2O (200 mL), which was saturated with solid NaCl. Following extraction with EtOAc (2×100 mL), the combined extracts were washed with brine (3×100 mL) and concentrated in vacuo. Purification by silica chromatography (6:1 hexanes:EtOAc) gave 45 mg (3.5% yield) of the product: EIHRMS m/z 404.0999 (M+, C19H20ClF3O4, Calc'd 404.1002).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].CN(C)[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccccc1C=O
Reaction time: 1 h

Procedure:
A third of a solution of 22 g of 2-nonylbromobenzene in 35 ml of tetrahydrofuran is added to a mixture, stirred under an argon atmosphere, of 3.4 g of magnesium turnings, 25 ml of tetrahydrofuran and 3 drops of carbon tetrachloride and the whole is heated at the boil under reflux for 30 minutes. The remainder of the 2-nonylbromobenzene solution is then added dropwise over a period of one hour and the reaction mixture is maintained under reflux for 2 hours. After dilution with 40 ml of tetrahydrofuran the whole is cooled in an ice bath to approximately 5° and a solution of 11.6 ml of dimethylformamide in 20 ml of tetrahydrofuran is added dropwise over a period of 15 minutes. After stirrin9 for one hour at room temperature, 250 ml of saturated ammonium chloride solution are added to the reaction mixture, the organic layer is separated off and the aqueous layer is extracted three times with ether. The residue that remains after the combined ethereal extracts have been dried and concentrated by evaporation is purified by chromatography on silica gel with mixtures of petroleum ether with an increasing amount of methylene chloride, yielding the desired 2-nonylbenzaldehyde in the form of a pale yellow liquid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].CN(C=O)C>C(Cl)Cl>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:11]#[N:12]
Reactant: COc1cccc(C)c1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C)c1C#N
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 2-bromo-1-methoxy-3-methylbenzene (7.5 g, 37 mmol), CuCN (6.7 g, 75 mmol) followed by addition of DMF (60 mL); the resulting mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately. The solids were filtered, re-dissolved in DCM, absorbed into silica gel and loaded into column with Hexanes:EtOAc (1:1) to afford the title product.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-].O>[NH2:20][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[NH:9][CH2:8][C:2]([CH3:1])([CH3:23])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CCOC(=O)C(C)(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Part D A mixture of ethyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propanoate (59 g), sodium hydrosulfite (109 g, 532 mmol), potassium carbonate (103 g, 744 mmol), and ethyl viologen dibromide (0.50 g, 1.3 mmol), dichloromethane (350 mL), and water (350 mL) was stirred overnight at ambient temperature. The aqueous layer was separated and extracted with dichloromethane (100 mL). The combined organic fractions were washes with water (4×75 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 46.1 g of ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate as a dark oil. Part E
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([F:17])[CH2:15]Br)=[CH:10][CH:9]=1>CCCCC>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])=[CH2:15])=[CH:10][CH:9]=1
Reactant: FC(CBr)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Product: C=C(F)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In several portions, 796 mg (7.09 mmol) of potassium tert-butoxide were added to a solution, cooled to 0° C., of 1.0 g (3.55 mmol) of 1-bromo-4-(2-bromo-1-fluoroethyl)benzene in 10 ml of pentane. The resulting suspension was stirred at 0° C. for 30 min and then at RT for 1 h. The solid was filtered off, and the filtrate was washed with saturated ammonium chloride solution, dried over magnesium sulphate and carefully concentrated under reduced pressure. This gave 0.61 g (85.6% of theory) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([O:22]COC)=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl>CO>[F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Temperature: 50 °C
Yield: 79.6 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.747 mmol) in methanol (75 mL) was added concentrated hydrochloride (5 mL) and the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to RT, concentrated under reduced pressure, the obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (700 mg, 79.6%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(NCC)(C)C.[CH3:19][O:20][CH2:21]Cl.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CCNC(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc2ccc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-hydroxycoumarin (100 g) and isopropylethylamine (161 ml) in anhydrous dimethylformamide (DMF; 500 ml) was added dropwise methoxymethylchloride (70.3 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 4 hours. To the reaction mixture were added hexane/ethyl acetate (2/1, 1000 ml) and a saturated aqueous solution of sodium bicarbonate (1000 ml) and the mixture was extracted twice with ethyl acetate. The organic layer was washewd with water (twice) and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data. The obtained crude product was used to the next step without further purification.