Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:28][C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19])([CH3:26])[CH3:27]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 20 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, and the precipitate which appears is filtered out and rinsed with ethyl acetate After the solution is concentrated under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered out. The solvent is eliminated under vacuum and the residue is precipitated from diethyl ether. The solid is recovered by filtration, rinsed abundantly with diethyl ether in order to produce a white powder with a yield of 65%. Melting point: 277-278° C.
Reaction SMILES: N.[Li].[CH:3]#[CH:4].[Si](O[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15]1)(C(C)(C)C)(C)C>CS(C)=O.C1COCC1>[CH2:13]([CH:14]1[CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][CH2:19]1)[C:3]#[CH:4]
Reactant: C#C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: N
Agent: [Li]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C#CCC1CCC(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to −78° C. and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1 hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30° C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5° C. and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5° C. The mixture was allowed to stir at 5° C. for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4×100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours 2 under N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3×100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 3.45 (d, J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94-1.69 (m, 4H), 1.52-1.34 (m, 2H), 1.16-0.83 (m, 4H); 13C NMR (CDCl3) δ 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccsc1C(=O)OC
Yield: 98.4 %

Procedure:
To a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (2.39 g, 15.2 mmol) in benzene (51 mL) was added K2CO3 (6.30 g, 45.6 mmol) followed by ethyl chloroformate (1.74 mL, 18.2 mmol). After heating at reflux for 12 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (3.43 g), which was used in the next step without further purification. MS: 230.0. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.6 Hz, 1H), 4.23 (q, J=7.1, Hz, 2H), 3.86 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C.CCCCCC.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
25.0 g of methyl 5-bromo-2-chlorobenzoate was dissolved in 130 ml of dichloromethane. To this solution, 230 ml of a 0.96 M DIBAL (diisobutylalminium hydride) hexane solution was added at −40° C. in a nitrogen atmosphere, followed by stirring at room temperature for 4 hours. To this reaction solution, 10% hydrochloric acid was carefully added while cooling, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 20.8 g of 5-bromo-2-chlorobenzyl alcohol as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)N(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture, under nitrogen, of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate (1.5 g, 3.53 mmol) in dry ethanol (5 ml) was added ammonium formate (1.12 g , 17.69 mmol) followed by the addition of 10% palladium on carbon (0.50 g). The mixture was stirred overnight at room temperature and then heated at 80° C. for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness in vacuo to give a semisolid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C=O)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[NH:10]3)=[CH:15][CH:14]=2)=[O:19])=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid. (17 mg, 60 μmol), 4-tert.-butylaniline (10 μL, 9.4 mg, 63 μmol) and HATU (33 mg, 87 μmol) in DMF (3 mL) was stirred, initially at ambient temperature, then at 60° C. for 18 h. The mixture was poured into ethyl acetate and extracted once with water and five times with brine. The organic layer was dried, filtered, and solvent was removed under reduced pressure. The residual material was chromatographed using a gradient of 20-60% heptane/ethyl acetate to give 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid (4-tert-butylphenyl)-amide. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, broad, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.56 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 6.46 (s, 1H), 2.18 (s, 6H), 1.33 (s, 9H). MS (m/z) 397.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CO>[NH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1ncccc1[N+](=O)[O-]

Procedure:
2-Chloro-3-nitropyridine (100 g, 0.63 mol), hydrazine monohydrate (70.4 mL, 72.6 g, 1.45 mol) and methanol (1.3 L) were mixed and heated to reflux with stirring. After 30 min the reaction mixture was cooled and filtered collecting the insoluble materials. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained as well as the insoluble materials from the filtration were diluted with water. The insoluble solids present were collected by filtration, washed with water, and dried to obtain 95.2 g (98 percent of theory) of the title compound as a bright yellow powder melting at 168°-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]=[C:13]=[O:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH:17][CH2:18][CH:19]=[O:20])[CH3:16]>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]=[O:20])[C:13]([NH:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14])[CH3:16]
Reactant: COc1cccc2sc(N=C=O)nc12
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nc2c(OC)cccc2s1
Reaction time: 1 h

Procedure:
4-Methoxybenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(4-methoxybenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCN1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1

Procedure:
Distilled THF (5 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one (104 mg, 0.33 mmol), thionyl chloride (86.83 mg, 0.73 mmol, 0.05 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one was produced as an orange oil (105 mg, 0.33 mmol) which was used immediately without further purification. Distilled THF (6 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (211.2, 0.66 mmol), cis-cyclopentene diol (330 mg, 3.3 mmol) and potassium carbonate (456 mg, 3.3 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a colourless oil (160.2 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as an colourless viscous oil. (129 mg, 0.43 mmol, 51% yield). 1H NMR: (300 Hz, DMSO) δ ppm 0.76 (t, 3H, H11), 1.36 (m, 1H, H13/H13′), 1.49, 1.76 (m, 1H, H13/H13′), 3.12 (m, 2H H10) 3.96 (m, 1H, H9/H9′), 4.26 (m, 1H, H9/H9′), 5.29, 5.87, (dd, 1H, H15/H16) 5.74, 5.79 (dd, 1H, H15/H16) 7.23 (d, 1H,), 7.38 (m, 4H, H1-H5), 7.61 (m, 2H, H6-H7), 7.76 (d, 1H, H8). IR: 1365, 1682, 2969, 3363 cm−1.
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]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.O1CCOCC1.[Pd]>[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:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[N:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 1 %

Procedure:
A solution of 200 mg (0.60 mmol) 2-amino-4-furan-2-yl-6-(4-isopropenyl-benzylamino)-pyrimidine-5-carbonitrile in 15 ml ethanol and 15 ml dioxane was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. HPLC afforded 2 mg (1%) 2-amino-4-furan-2-yl-6-(4-isopropyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]([CH2:15][CH2:16][C:17]#[N:18])[C:13]#[N:14]>C(OCC)C>[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][CH2:16][C:17]#[N:18])[C:13]#[N:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: C=C(C#N)CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CCCC(C#N)COCc1ccccc1
Reaction time: 24 h

Procedure:
A 50% dispersion of sodium hydride in mineral oil (200 mg.) was added to benzyl alcohol (32.4 g.) and the mixture was stirred until effervescence had ceased. The solution was treated with 2-methyleneglutaronitrile (15.9 g.)and the mixture was kept at room temperature for 24 hours. The reaction mixture was diluted with diethyl ether and the solution was washed three times with water, and then dried and evaporated to dryness to give 2-(benzyloxymethyl)glutaronitrile (32 g.). The crude 2-(benzyloxymethyl)glutaronitrile was reduced with borane-dimethyl sulphide complex in a similar process to that described in Example 1 to give 2-(benzyloxymethyl)pentane-1,5-diamine dihydrochloride, m.p. 159°-161° (after crystallisation from ethanol).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>C1COCC1>[C:5]([CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:3]([O:9][CH2:10][CH3:11])=[O:8])(=[O:6])[CH3:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC=C(C)C)C(C)=O
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
Sodium hydride was added portionwise to a stirred solution of ethyl acetoacetate (0.1 mole, 13.0 g) in 300 ml THF. The solution was stirred for 30 minutes. 5-Bromo-2-methyl-2-pentene (0.11 moles, 17.9 g) was added dropwise over 30 minutes. The solution stirred at room temperature for 40 hours. The solution was concentrated in vacuo. Ethyl acetate and water were added. The organic phase was dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with a gradient of 0-40% ethyl acetate in hexane to yield 4.5 g of ethyl 2-acetyl-6-methyl-5-heptenoate.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry tetrahydrofuran (THF, 8 ml) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, N,N-dimethyl carbamoyl chloride (265 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 8k as solid. Yield: 0.796 g, 76.19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.C(OC(=O)C)C>CN(C)C=O>[Br:24][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(c2ccc(Br)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
N,N-bis(4-methoxyphenyl)aniline 1 (9.0 g, 29.5 mmol) was dissolved in 100 mL dimethylformamide in a 250 mL round bottom flask. N-bromosuccinimide (5.25 g, 29.5 mmol) was dissolved in 30 mL dimethylformamide and added dropwise to the reaction mixture. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography (TLC) (Reaction Time=23 h). The reaction mixture was quenched using 600 mL water and extracted with 4×150 mL dichloromethane. The organic layers were combined and washed with 4×150 mL saturated sodium thiosulfate solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified along with materials prepared previously using flash chromatography on silica gel eluting with 5:1 hexanes:ethylacetate (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 4H), 6.90 (d, J=9.0 Hz, 4H), 6.73 (d, J=9.0 Hz, 2H), 3.77 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=C)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].C[O:13]CCOC>O=[Os](=O)(=O)=O.O>[CH3:1][N:2]1[C:6]([CH:7]=[O:13])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: COCCOC
Reactant: C=Cc1cnc([N+](=O)[O-])n1C
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 0.67 g. of 1-methyl-2-nitro-5-vinylimidazole in 20 ml. of 1,2-dimethoxyethane, a solution of 2 g. of NaIO4 in 5 ml. of water, followed by 0.025 g. of OsO4 is added with stirring at room temperature. After stirring for four hours, the mixture is allowed to stand overnight. The residue which is obtained by evaporation of the reaction medium to dryness under vacuum is extracted with ethyl acetate. The resulting solution after filtering is concentrated, yielding 0.43 g. of a product which, after crystallization from ethyl acetate, melts at 114°-115° C. Yield 63%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[S:26][C:27]([CH2:31][NH2:32])=[C:28]([CH3:30])[N:29]=1.O>C(#N)C>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH2:31][C:27]4[S:26][C:25]([CH3:24])=[N:29][C:28]=4[CH3:30])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1nc(C)c(CN)s1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: O
Solvent: CC#N
Product: COc1cc2c(NCc3sc(C)nc3C)c(C(N)=O)cnc2cc1-c1c(C)noc1C

Procedure:
To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 0.5 g,) in acetonitrile (50 ml) was added a solution of [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (0.64 g, dihydrochloride available from Matrix Scientific) in acetonitrile (10 ml). The reaction mixture was heated at reflux for 3 h, whereupon another portion of amine (0.5 g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2SO4 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (0.33 g) as white crystals.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([O:28]CC2C=CC=CC=2)=[O:27])[NH:17]1>C(O)C.[Pd]>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([OH:28])=[O:27])[NH:17]1
Reactant: O=C(OCc1ccccc1)C1Cc2ccccc2CN1
Agent: [Pd]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2CN1
Reaction time: 3 h
Yield: 197.1 %

Procedure:
Phenylmethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate camphor sulphonic acid salt (Preparation 121, 8.3 g, 18.9 mmol) was dissolved in ethanol (600 ml) and palladium on carbon (10%, 0.8 g) was added at room temperature under nitrogen. The reaction mixture was hydrogenated at room temperature at 30 psi for 3 h. The catalyst was removed by filtration and the filtrate was concentrated to give the title compound (6.6 g, 100%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([O:28][CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH3:27])=[CH:10][C:9]1([CH3:34])[CH3:33])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:29]([O:28][CH:26]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH:13]=2)[NH:8][C:9]([CH3:34])([CH3:33])[CH:10]=1)[CH3:27])/[CH:30]=[CH:31]/[CH3:32]
Reactant: C/C=C/COC(C)C1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reaction time: 1 h

Procedure:
A mixture of 58 mg of [4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 2 mL of methylene chloride was treated with 0.05 mL of 99% trifluoroacetic acid (TFA) at room temperature. The reaction mixture was allowed to stir at the same temperature for 1 hour. TLC showed starting material was still remaining so another 0.05 mL of TFA was added. Ten minutes later, the reaction was quenched with water and extracted with EtOAc three times. The organic layers were combined, washed sequentially with water, saturated aqueous sodium bicarbonate, water, brine, dried with magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 28 mg of the title compound as an oil.