Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([O:7][CH2:8]CC2C=CC=CC=2)[CH:4]([NH:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:38])[CH:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:26])=[O:18])[CH2:3]1.N(C(OC[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=O)[C@H](C(O)=O)C.C1CN[C@@H](C(O)=O)C1>>[CH2:8]([O:7][CH:5]1[CH:4]([NH:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:38])[CH:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:26])=[O:18])[CH2:3][C:2](=[O:1])[O:6]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(O)[C@H]1CCCN1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 69 %

Procedure:
Prepared according to the procedure used to prepare 98a using Cbz-Ala-D-pro-OH to afford 230 mg of title compound (69% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.30 (d, 1.2H), 1.45 (d, 1.8H), 1.62-2.40 (m, 4H), 2.40-3.10 (m, 2H), 3.30-3.97 (m, 2H), 4.33-4.95 (m, 5H), 5.30 (s, 0.5H), 5.68 (d, 0.5H), 6.80 (d, 1H), 7.25-7.95 (m, 7H). Analytical HPLC: 11.56, 11.91 min. LC-MS (ES+): m/e=529.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Br:24][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:16]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 31.2 g (0.1 mole) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzenemethanol (Example 16) in 350 mL of CCl4 is added 34.8 (0.227 mole) of bromotrimethylsilane. After 40 minutes at room temperature the reaction mixture is evaporated to dryness on a rotary evaporator with the water bath temperature at 35° C. The brown oil residue is used immediately without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8]1.COC1C=CC(O)=CC=1.O=O>[Cl-].C[N+](C)(C)C>[C:1]([O:6][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCCC1CO1
Agent: COc1ccc(O)cc1
Agent: C[N+](C)(C)C
Agent: O=O
Product: C=C(C)C(=O)OCCCCCCCCO

Procedure:
Hydroxyoctyl methacrylate (HOMA) is prepared by reacting 28.8 parts of methacrylic acid with 40.0 parts 1,2-epoxyoctane in the presence of 0.07 parts of tetramethylammonium chloride and 0.21 parts of hydroquinone monomethylether for 4 hours at 140° C. with O2 bubbled through the reaction mixture. The product is distilled at 95°-110° C./0.4 mm to yield 46 parts of HOMA which was identified by IR and NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CCN2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Brc1cnc2[nH]ccc2c1
Yield: 100.6 %

Procedure:
To a stirred solution of azaindoline 5 (7.00 g, 35.2 mmol) in CH2Cl2 (664 mL) was added activated MnO2 (3.06 g, 35.2 mmol), and progress of the reaction was monitored by 1H NMR of reaction aliquots. After 3 days the mixture was filtered through a pad of silica, and the pad was washed with EtOAc. The filtrates were concentrated to afford the azaindole 27 (6.98 g, 100%) as a brown solid. 1H NMR data as in Method 1.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C@@H:12]([C:14]1[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=1)[CH3:13])=[CH:7]2.CI.[CH2:31](Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH3:31][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C@@H:12]([C:14]3[N:18]4[N:19]=[C:20]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: C[C@@H](c1ccc2n[nH]cc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Reactant: ClCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](c1ccc2c(cnn2C)c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of NaH (4.8 mg, 0.1 mmol) in THF (0.5 mL) cooled to 0° C. was added (3-[(S)-1-(2H-indazol-5-yl)-ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 195, 34.3 mg, 0.10 mmol). The RM was allowed to warm up to rt and stirred 15 min. Then it was cooled down again and methyliodide (21.3 mg, 0.150 mmol) was added dropwise. The RM was allowed to warm up to rt and stirred for 5 h. It was then taken into DCM and brine, extracted, and the organics were joined dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in EtOAc) to afford the title compound after evaporation of the solvent and drying of the material under vacuum (tR 3.72 min (conditions 3), MH+=358, 1H-NMR in DMSO-d6: 8.35 (s, 1H); 8.03 (d, 1H); 8.00 (s, 1H); 7.94 (s, 1H); 7.73 (s, 1H); 7.70 (s, 1H); 7.52 (d, 1H); 7.45 (d, 1H); 7.43 (d, 1H); 4.73 (q, 1H); 4.74 (s, 3H); 3.89 (s, 3H); 1.77 (d, 3H)).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O.O1CCOCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:11][C@@H:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:8]([OH:10])=[O:9])(=[O:30])=[O:29])=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H](C(=O)O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of L-phenylglycine (0.227 g, 1.5 mmol) in water (5 ml) and dioxane (5 ml) was added triethylamine (0.42 ml, 3.0 mmol) followed by slow addition of 4-nitrobenzene sulphonyl chloride (0.5 g, 2.3 mmol) in dioxane (5 ml) at 0° C. After stirring for 45 minutes the reaction mixture was evaporated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution (2×20 ml) and water (10 ml). The EtOAc layer was dried over Na2SO4, filtered and evaporated to dryness. LCMS purity 75%, (molecular ion not observed) yield 0.58 g, (76%). This material was used without any purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ncc1Br
Solvent: C1CCOC1
Product: OCc1cc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0° C. solution of 5-bromo-2-chloroisonicotinic acid (5.008 g, 21.18 mmol) in THF (30 mL) was treated with borane tetrahydrofuran complex (52.9 ml, 52.9 mmol). The solution was stirred at room temperature for 16 hours. The reaction was slowly quenched with water until gas formation stopped. Then 25 mL of 3 N NaOH was added and the resulting mixture was heated in a 100° C. oil bath for about 75 minutes. The reaction was cooled and the volatiles removed by rotary evaporation. Ethyl acetate and brine were added, after which the layers were separated. The organic was dried over Na2SO4, filtered and the filtrate concentrated and dried to give a yellow solid that was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.41 (s, 1H), 7.58 (s, 1H), 4.74 (s, 2H), 2.23 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[N:14]=[N:15][C:16](Br)=[CH:17][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:8][C:16]1[N:15]=[N:14][C:13]([Br:12])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CO
Reactant: Brc1ccc(Br)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Br)nn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
277.8 mg (2.1 mmol) of hydroxyacetic acid tert-butyl ester and 100.9 mg of sodium hydride (55% in mineral oil) in 15 ml of DMF were stirred at room temperature for 30 min. Then 500 mg (2.1 mmol) of 3,6-dibromopyridazine were added, and the reaction mixture was stirred at 60° C. for 2 h. After evaporation to dryness, the residue was stirred with ethyl acetate, the solution filtered, evaporated, and the crude product (450 mg) directly employed in the subsequent step.
Reaction SMILES: [OH-].[K+].N1C=CC=CC=1C1C=CC=CN=1.[CH:15](=[CH:22][C:23](=[O:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>CC(O)C>[C:16]1([CH2:15][CH2:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(C)O
Product: CC(=O)CCc1ccccc1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
RuClCp* (cod) (3.8 mg, 0.01 mmol), KOH (0.04 mmol), 2,2′-bipyridyl (3.1 mg, 0.02 mmol) and benzalacetone (730.95 mg, 5.0 mmol) were dissolved into 10 ml of 2-propanol, and deaerated by argon substitution, after which the total amount of the resulting mixture was transferred into a 100-milliliter metallic autoclave. Hydrogen was then charged to a predetermined pressure (4 atm), and the reaction was started at room temperature (28° C.) After the reaction solution was stirred for 18 hours, the reaction pressure was brought back to atmospheric pressure, and the reaction product, 4-phenyl-2-butanone (yield 87.7%), was identified and quantitatively determined by TLC monitor (silica gel: n-hexane/ethyl acetate=4/1) and gas chromatography of the reaction solution. At this time, 12.3% of the raw material, benzalacetone, was recovered.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19](O)=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.C([N:25](CC)CC)C.ClC(OCC)=O.N>CN(C=O)C.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([NH2:25])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: CCN(CC)CC
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CCOC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(N)=O)cn(C3CC3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a suspension of 5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (4.97 g, 16.0 mmol) in DMF (200 mL), triethylamine (3.35 mL, 24.0 mmol) and ethyl chloroformate (1.84 mL, 19.2 mmol) were added. After stirring at 0° C. for 2 h., 25% aq. NH3 (5 mL) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (1.5 L) and the resulting precipitate was collected by filtration, washed with water and dried to give 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxamide (4.83 g, 97%) as a pale brown solid.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
At first, a mixture of the 4-(diallylethoxysilyl)iodobenzene (148 mg, 0.41 mmol) obtained in Example 2, tetrakistriphenylphosphine palladium (Pd(PPh3)4: 14.3 mg, 0.012 mmol), potassium carbonate (K2CO3: 85.1 mg, 0.62 mmol), and phenyl boronic acid (60 mg, 0.49 mmol) was added with distilled toluene (dist.toluene: 5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 13 hours to obtain a reaction mixture. Thereafter, the reaction mixture was diluted with ether, and a salt thus formed was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1), and thereby 4-(diallylethoxysilyl)biphenyl (a second organosilane compound of the present invention) was obtained (99.6 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[CH:16]N(C)C)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[N:23][C:22]([NH2:24])=[N:21][CH:16]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 74.2 %

Procedure:
A suspension of 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (7.49 g, 27.1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) and potassium carbonate (22.4 g, 162 mmol) in N,N-dimethylformamide (105 ml) was stirred at 70° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with water. The resulting crystals were collected by filtration and washed with water, to give the title compound (5.48 g, 74%) as a pale yellow solid.
Reaction SMILES: C(NCC)C.C[O:7][CH2:8][CH:9]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][O:11]C.Cl>>[OH:7][CH2:8][CH:9]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][OH:11]
Reactant: CCN(CC)C(COC)COC
Agent: Cl
Solvent: CCNCC
Product: CCN(CC)C(CO)CO

Procedure:
This compound is obtained in a similar manner by heating 69.3 g of 1,3-dimethoxy-isopropyl chloride with 110 g of diethylamine in an autoclave and hydrolyzing the 1,3-dimethoxy-2-diethylamino-propane obtained (boiling point 65° C. at 16 torr) by boiling it with azeotropic, aqueous hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)nc23)CC1
Yield: 44 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 gm (0.56 mMol) 4-cyanobenzoyl chloride, 0.068 gm (44%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]I.[Cu]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[O:19][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(O)c1cnccc1Cl
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
To a suspension of 10 g (63.47 mmol) 4-chloronicotinic acid (commercially available; CAS RN 10177-29-4) and 11.38 g (69.81 mmol) 2,5-dichlorophenol (commercially available CAS RN 583-78-8) in 50 mL dry N,N-dimethylformamide were added 17.55 g (126.94 mmol) potassium carbonate, 1.21 g (6.35 mmol) copper(I) iodide and 1.21 g (19.04 mmol) copper nanopowder. The green suspension was stirred at 120° C. (oil bath temperature) for 3 hours and then cooled down to 80° C. At that temperature, 400 mL water were added, the suspension was stirred at 80° C. for 5 min., filtered over Dicalite® speed plus (Acros) and the filter cake washed twice with 50 mL water. The resulting filtrate was extracted three times with ethyl acetate and then the pH was adjusted to 4-5 using 140 mL 1M aqueous hydrochloric acid. The resulting green, turbid solution was treated with ethyl acetate, stirred for 5 min. and filtered. The blue solid that had formed was filtered off and the layers of the filtrate were separated. The aqueous layer was saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. To the resulting solid 200 mL saturated aqueous potassium carbonate solution and 200 mL ethyl acetate were added. The aqueous layer was extracted twice with 200 mL ethyl acetate and the pH was adjusted to 4 using 25% aqueous hydrochloric acid. The resulting suspension was extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine, dried over magnesium sulfate, filtered and evaporated to give the desired compound as a light brown solid (7.29 g, 40%). MS (ESI): m/z=281.8 [M−H]−.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(Cl)cc1Cl
Yield: 60.5 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2,4-dichloroaniline (2.43 g, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base, triturated with ethanol and recrystallised from ethyl acetate to give 3-butyryl-4-(2,4-dichlorophenylamino)-8-methylquinoline (2.26 g), m.p. 169°-170°.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@@H:5]([NH2:14])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:14][C@@H:5]([CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: COC(=O)[C@@H](N)CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H](CO)CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (R)-2-amino-3-phenylsulfanyl-propionic acid methyl ester hydrochloride (0.50 g, 2.0 mmol) in tetrahydrofuran (10 ml) under an argon atmosphere was added slowly lithium aluminum hydride (0.153 g, 4.0 mmol) and the mixture was stirred overnight at room temperature. For work-up water (1.5 ml) and 2N sodium hydroxide solution (0.5 ml) were added and the mixture was stirred for 30 min. After filtration the solvent was evaporated and the residue was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/EtOAc=1:1 to yield a light yellow oil, (0.095 g, 26%); MS (ISP): 183.9 ((M+H)+.).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[NH:3]1.O[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=2[O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=4[O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24]3)=[O:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1CCc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)CCCOc1ccccc1N1CCN(CCCO)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccccc1N1CCN(CCCOC(=O)c2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid 22 (0.21 g, 0.001 mol), ethyl 4-(2-(4-(3-hydroxypropyl)piperazin-1-yl)phenoxy)butanoate 27 (0.38 g, 0.001 mol), dicyclohexylcarbodiimide (0.21 g, 0.001 mol), 4-(dimethylamino)pyridine (0.12 g, 0.001 mol) in 20 mL THF was stirred at room temperature for 12 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated; the residue was diluted with DCM (25 mL). The filtrate was washed with saturated aqueous NaHCO3 solution (25 mL×2) and water (25 mL×2), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-100% gradient of hexane and ethyl acetate to give the pure 3-(4-(2-(4-ethoxy-4-oxobutoxy)phenyl)piperazin-1-yl)propyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate 28. Colorless oil, 0.075 g (13%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.2 Hz, 3H); 1.99 (quintet, J=7.2 Hz, 2H); 2.13 (quintet, J=7.2 Hz, 2H); 2.50-2.65 (m, 8H); 2.99 (t, J=7.6 Hz, 4H); 3.08 (broad s, 4H); 4.01 (t, J=6.4 Hz, 2H); 4.12 (q, J=7.2 Hz, 2H); 4.38 (t, J=6.4 Hz, 2H); 6.81-6.89 (m, 4H); 7.20 (d, J=8.0 Hz, 1H); 7.50 (d, J=1.6 Hz, 1H); 7.64 (dd, J=1.6, 8.0 Hz, 1H, 9.00 (broad s, 1H). MS (ESI): m/z=524.50 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
K2CO3 (66.8 g, 0.48 mol) was added to a stirred solution of ethyl 3-hydroxybenzoate (1) (40.0 g, 0.24 mol) and (chloromethyl)benzene (33.5 g, 0.26 mol) in DMF (256 mL) and the reaction mixture was heated at 90° C. for 3 h. The reaction mixture was filtered through Celite, the filtrate was diluted with water (500 mL), extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give ethyl 3-(benzyloxy)benzoate (2) as colorless liquid. Yield (61.0 g, 98%); 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.53 (m, 2H), 7.47-7.44 (m, 3H), 7.39 (t, J=7.2 Hz, 2H), 7.35-7.29 (m, 2H), 5.17 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20](O)=[O:21])=[CH:15][CH:14]=[CH:13]3)[CH:6]=[CH:5][N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:21])=[CH:15][CH:14]=[CH:13]3)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Reactant: COc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(Oc2ccc3c(C(=O)Nc4ccc(OC)cc4)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(2-Methylaminopyridin-4-yloxy)-1-naphthoic acid (170 mg, 0.58 mmol), p-anisidine (107 mg, 0.87 mmol), DIPEA (149 mg, 1.16 mmol) and TBTU (223 mg, 0.69 mmol) were combined in DMF (3.0 mL) and the reaction mixture was stirred at RT for 16 h, quenched by addition of a 6M aqueous NaOH solution. The precipitate was filtered off, treated with DCM, sonicated. The title compound was isolated by filtration. MS (ESI, pos. ion) m/z: 400.1 (M+1). Mass Calc'd for C24H21N3O3: 399.45.