Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CI>C1COCC1>[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]([CH3:1])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
THF (5 ml) was taken in a RBF, diisopropyl amine (0.19 ml, 1.29 mmol) was added and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (0.8 ml, 1.29 mmol) was added and stirred at same temperature for 30 mins. At this stage methyl 2-(quinolin-6-yl)acetate (0.2 g, 0.99 mmol) was added and stirred at −78° C. for 30 mins. Then methyl iodide (0.17 g, 1.2 mmol) was added and stirred at −78° C. for 30 mins and then slowly brought to rt. At rt the reaction mixture was allowed to stir overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer dried on anhydrous Na2SO4 and EtOAc removed using a rotary evaporator to obtain the crude product, which was purified by column chromatography on 60-120 mesh silica gel and EA and Petether (25:75) as eluent. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.89-8.86 (m, 1H), 8.13 (d, J 7.8, 1H), 8.07 (d, J 8.7, 1H), 7.76-7.64 (m, 2H), 7.42-7.37 (m, 1H), 3.92 (q, J 7.2, 1H), 3.68 (s, 3H), 1.60 (d, J 7.2, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[C:9]([F:21])=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23])=O.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[NH2:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:8][C:9]([F:21])=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][NH:27][CH:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=Cc1ccc(Oc2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc2F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(CNC3Cc4ccccc4C3)cc2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,2-trifluoro-N-{4-fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}acetamide (0.300 g, 0.806 mmol), 2-aminoindane (0.161 g, 1.21 mmol), and acetic acid (0.5 mL) in CH2Cl2 (3 mL) was stirred for 30 min and then Na(OAc)3BH (0.205 g, 0.967 mmol) was added slowly over 2 min. The reaction mixture stirred for 1 hour at ambient temperature and then H2O (3 mL) was added. The layers were separated and the aqueous layer extracted one additional time with CH2Cl2. The combined organics were washed 1× brine, then dried (Na2SO4), filtered and concentrated to give ({4-[(5-Amino-2-fluoro-4-nitrophenyl)oxy]phenyl}methyl)2,3-dihydro-1H-inden-2-ylamine. No further purification was necessary.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:15]([O:16][CH3:17])=[C:9]2[N:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[N:10][C:9]2=[C:15]([O:16][CH3:17])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2ncc(Cl)cc2nn1CC(C)(N)C#N
Product: COc1c2ncc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (15 mg, described in Example 171) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (20 mg, 67%). MS (ES): M/Z [M+H]=470. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.67 (s, 3H), 4.86 (d, J=14.2 Hz, 1H), 7.77-7.82 (m, 3H), 7.93 (d, J=8.2 Hz, 2H), 8.31 (d, J=1.9 Hz, 1H) and 8.82 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) in absolute ethyl alcohol (20 mL) was added p-toluenesulfonic acid monohydrate (100 mg). After 16 h at reflux, the reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 770 mg (Y: 58%) of the title product; 1H-NMR (CDCl3): δ 8.16-8.00 (m, 3H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (DCI) m/e: 214 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([Cl:10])[N:3]=1.[C:11](Cl)(=[O:15])[C:12](Cl)=O.[CH3:17]S(C)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:17][C@H:12]2[CH:11]=[O:15])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: CS(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@H]1c1cc(Cl)nc(Cl)c1

Procedure:
The above alcohol (0.21 g) was oxidised using the conditions of Swern (oxalyl chloride, 0.1 ml; dimethyl sulphoxide. 0.15 ml; triethylamine. 0.66 ml) to give (±)-[trans-2-(2,6-dichloro-4-pyridyl)cyclopropyl]methanal (0.2 g). NMR 1H: 9.44(1H,d), 6.96(2H,s),
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([CH:6]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][NH:8][C:7]1=S)[CH:4]=[CH2:5]>C(O)C>[CH2:3]([CH:6]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][NH:8]/[C:7]/1=[N:1]\[NH2:2])[CH:4]=[CH2:5]
Reactant: NN
Reactant: C=CCC1CCC(c2cccc(F)c2F)CNC1=S
Solvent: CCO
Product: C=CCC1CCC(c2cccc(F)c2F)CN/C1=N\N
Reaction time: 4 h

Procedure:
Hydrazine (anhydrous; 1.11 mL, 35.40 mmol) was added to a solution of 3-allyl-6-(2,3-difluorophenyl)azepane-2-thione (249 mg, 0.885 mmol) in ethanol (8 mL). After 4 h, the reaction mixture was concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×). The organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound. (MS 280.2 (M+1).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.ClCCl.Cl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][C:17]([CH:22]=[O:23])=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7]
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
7.6 ml (44.4 mmol) of TMP are initially introduced at −20° C. in THF, and 26.7 ml (42.4 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min at this temperature, a solution of 11.7 g (38.6 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene in 80 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −40° C., and N-formylmorpholine is added. The reaction mixture is warmed to RT and stirred for 4.5 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is briefly stirred vigorously, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is digested in cold ethanol, and the solid is filtered off with suction. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a violet solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26]C1(C2C=CC(C=O)=CC=2)CC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][O:26][C:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC1(c2ccc(C=O)cc2)CC1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-methoxy-cyclopropyl)-benzaldehyde (105 mg, 0.60 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (113 mg, 0.60 mmol) and sodium borohydride (34 mg, 0.89 mmol). The desired product was isolated without further purification as a colorless oil. MS (ISP) 350.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:3]=1.[CH3:20][C:21]1(C)C2(CS(O)(=O)=O)C(C[CH:22]1CC2)=O.COC(OC)(C)C.C([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:21]([CH3:22])([CH3:20])[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NCC(=O)N1CCOCC1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)OC
Solvent: CC(=O)N(C)C
Product: CC1(C)NC(=O)c2sc(Br)cc2N1CC(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 394.9 %

Procedure:
A mixture of 5-bromo-3-[(2-(morpholin-4-yl)-2-oxoethyl)amino]thiophene-2-carboxamide (120 mg, 0.345 mmol), CSA (10 mg), 2,2-dimethoxypropane (1.0 mL) and DMA (1 mL) was stirred at 80° C. for 0.5 h. Then, water and saturated aqueous NaHCO3 were added to quench the reaction. The precipitate was collected by filtration to afford the title compound (66 mg) as a pale brown solid. From the filtrate, the organic layer was collected, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (50 mg) as a pale brown solid. Total yield of the title compound (66+50 mg) was 87%:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.F[C:23]1[CH:46]=[CH:45][C:26]2[N:27]3[CH2:44][CH2:43][C:42]4[C:28]3=[C:29]([CH:39]=[CH:40][CH:41]=4)[C:30](N3CCN(C)CC3)=[N:31][C:25]=2[CH:24]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.[NH2:31][C:25]1[CH:24]=[C:23]([Br:11])[CH:46]=[CH:45][C:26]=1[N:27]1[C:28]2[C:29](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:30][CH2:43][CH2:44]1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: c1ccc2c(c1)CCCN2
Reactant: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Product: Nc1cc(Br)ccc1N1CCCc2ccccc21
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCCc2ccccc21

Procedure:
Starting with 1,2,3,4-tetrahydroquinoline and 5-bromo-2-fluoronitrobenzene and following the steps of 1a to 1f of Example 2, one may obtain, in sequence, 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline, 1-(2-amino-4-bromophenyl)-1,2,3,4-tetrahydroquinoline, N-[2-{1-(5-bromophenyl)-1,2,3,4-tetrahydroquinolin-1-yl}]-4-methyl-1-piperazine carboxamide, and 10-bromo-7-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-quino[18-ab)[15]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:6]([OH:8])=O.Cl.[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([C:6]([C:20]2[CH:21]=[N:22][N:23]([CH3:24])[C:19]=2[OH:18])=[O:8])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cn1nccc1O
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a stirred mixture of 3-methoxy-2-methyl-4-(methylsulfonyl)benzoic acid (340 mg, 1.39 mmol) and 5-hydroxy-1-methylpyrazole hydrochloride (230 mg) in anhydrous methylene chloride (10 mL) were added DCC (dicyclohexylcarbodiimide) (315 mg) and triethylamine (260 mg) at room temperature, followed by stirring for 2 hours. The reaction mixture was subjected to filtration through Celite, the filtrate was concentrated, and the obtained residue was dissolved in 10 mL of anhydrous acetonitrile. Triethylamine (260 mg) and acetone cyanohydrin in a catalytic amount were added thereto, and the reaction solution was stirred overnight at room temperature. 150 mL of ethyl acetate was added to the reaction mixture, and the solution was washed once with a 1N hydrochloric acid aqueous solution and washed once with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to obtain 5-hydroxy-1-methylpyrazol-4-yl 3-methoxy-2-methyl-4-(methylsulfonyl)phenyl ketone (115 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:13](O)(=O)CC(O)=O.Cl.O>C(N(CC)CC)C>[C:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[C:3]=1[C:8]([OH:7])=[O:9])(=[O:6])[CH3:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2c(F)cccc21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(F)c1C(=O)O

Procedure:
9 g of 3-fluorophthalic anhydride and 6.8 g of malonic acid are mixed in 80 ml of triethylamine and heated in an oil bath at 71-72° until evolution of gas ceases. The reaction mixture is mixed with 50 ml of 10% HCl/H2O and extracted with ether. The ether is evaporated off and the resulting black oil chromatographed on a column using 1 l of 20% of ethylacetate/hexane followed by 1 l of 30% ethylacetate/hexane to yield first the 3fluoro-isomer followed by the desired 6-fluoro isomer; m.p. 76-81.5°.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4].[H][H].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>CN(C)C=O>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4]
Reactant: CCC1=Nc2ccccc2C(=O)C1
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(OCc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2n1
Reaction time: 16 h
Yield: 64.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 60 mg) was added to a stirred solution of 2-ethyl-4-quinolone (260 mg) prepared by the method described in Org. Syn., 1955, Coll. Vol. III, p.374 and p593), in N,N-dimethylformamide (DMF)(2.5 ml). The mixture was stirred until evolution of hydrogen had ceased and then a solution of the bromomethyl compound (C) (460 mg) in DMF (1 ml) was added. The reaction mixture was stirred for 16 hours. The solvent was removed by evaporation and the residue was partitioned between water (10 ml) and ethyl acetate (2×5 ml). The organic phase was washed with water, followed by saturated sodium chloride solution and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography, eluting with ethyl acetate/dichloromethane (1:4 v/v) to give methyl 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carboxylate (A) as a solid (385 mg), m.p. 132°-134° C.; NMR: 1.41(t,3H), 2.97(q,2H), 3.68(s,3H), 5.34(s,2H), 6.77(s,1H), 7.44-7.7(complex m,9H), 7.87(dd,1H), 8.0(d,1H), 8.26(dd,1H); mass spectrum (positive chemical ionisation [+ve CI]: 398 (M+H)+, 225, 174; 13C NMR: (benzylic CH2) 69.73.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:16])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](Cl)=[O:36]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[N:16][C:35]([C:30]1[C:31]2[C:26](=[C:25]([Br:24])[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1)=[O:36])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=N)Cc1cccc2ccccc12
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(Cc1cccc2ccccc12)=NC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
According to the procedure of Soto et al, Synthesis, 483, (1983), to a stirred suspension of methyl-2-(1-naphthalenyl)acetimidate hydrochloride (prepared in Step 1) (11.7 g, 0.050 mol), in dry toluene (150 mL) was added triethylamine (11.5 g, 0.114 mol). 5-Bromo-1-naphthoyl chloride (13.4 g, 0.050 mol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours. The precipitated salt was removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give an orange oil (21.5 g, 100%) which was used without purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1[OH:13].O(C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O(C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[C:40](O)(=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]CC>>[C:40]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 79 %

Procedure:
Methyl-D-glucopyranoside (19.8 g, 0.10 mol, a 1:1 mixture of methyl α-(D)-glucopyranoside and methyl β-(D)-glucopyranoside, both Sigma Chemicals) was esterified with dodecanoic acid (31 g, 0.15 mol) by the procedure described in Example 1, using 3 g of an immobilized lipase (derived from Candida antarctica). The reaction was complete in 24 hours (HPLC showed>90% conversion) and the enzyme was removed by filtration. Purification by chromatography provided the title compound in a yield of 79% (30 g) as a crystalline powder, m,p. 70°-72° C.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:31]([C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[O:32])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Temperature: 25 °C

Procedure:
35 ml of nitrobenzene are cooled in an ice-bath and then treated in succession with 5.2 g of aluminum chloride and 5.0 g of 4-methylbiphenyl. The mixture is brought to room temperature and then treated with 7.7 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred at room temperature, poured into water and extracted with methylene chloride. The extracts are washed with 2N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with toluene/ethyl acetate 9:1. 3,4-Dichlorophenyl 4'-methyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][CH:8]=1)#[N:2].[ClH:14]>CO.[Pd]>[Cl-:14].[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[N:7]=[CH:8][C:3]([CH2:1][NH3+:2])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccc(C#N)cn1
Reactant: Cl
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(C[NH3+])cn1
Product: [Cl-]
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(5-cyanopyridin-2-yl)acetate (1.2 g, 6.8 mmol) in methanol (20 ml) was added hydrogen chloride in methanol (4 M, 20 ml), and then Pd/C (200 mg). Then the reaction mixture was hydrogenated under hydrogen atmosphere overnight. The reaction mixture was filtered, the filtrate was concentrated to give the crude product and was washed by ethyl acetate to give the desired product. LC-MS: m/z (M+H)=181.5
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[O:32]1[C:37]2[CH:38]=[CH:39][C:40](C=O)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1>>[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:17][NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([C:10]4[S:11][C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:30])[CH2:23][CH2:24]3)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: COc1cccc2scnc12
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: COc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)nc12

Procedure:
Using 4-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a off-white solid (41 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][NH:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[NH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(NCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 2-[4-(4-hydroxy-butyl)-benzylamino]-3-methyl-chromen-4-one (100 mg, 0.30 mmol) in dichloromethane (37 mL) was added p-toluenesulfonylchloride (68 mg, 0.36 mmol), dimethylaminopyridine (43.4 mg, 0.36 mmol), and triethylamine (62 μL, 0.44 mmol) in a 0° C. ice bath. The reaction slurry stirred overnight under N2 atmosphere, warming to room temperature slowly overnight. The next day, the reaction mixture was concentrated and purified by flash column chromatography (3:1→1:1 Hexane:ethyl acetate →100% ethyl acetate) to obtain the product as an oil (45 mg, 31% yield). 1H NMR (600 MHz, CDCl3): δ 8.19 (dd, 1H, J=1.5 and 7.9 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.76 (m, 1H), 7.32 (d, 2H, J=7.9 Hz), 7.29 (d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.13 (d, 2H, J=8.0 Hz), 4.90 (t, 1H, J=5.1 Hz), 4.64 (d, 2H, J=5.6 Hz), 4.02 (t, 2H, J=5.9 Hz), 2.57 (t, 2H, J=7.3 Hz), 2.43 (s, 3H), 1.96 (s, 3H), 1.65 (m, 4H); 13C NMR (150 MHz, CDCl3): δ 174.9, 160.2, 152.8, 144.7, 141.5, 135.4, 133.1, 131.4, 129.8, 128.9, 127.9, 127.7, 125.9, 124.6, 122.8, 116.2, 93.4, 70.3, 45.5, 34.7, 28.4, 27.1, 21.6, 7.6.