Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[CH:4]=[C:3]2[N:9]=[C:10]3[NH:18]C(=O)NC(=O)[C:11]3=[N:12][C:2]=12.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:18][C:10]1[CH:11]=[N:12][C:2]2[C:3](=[CH:4][C:5]([Cl:8])=[C:6]([Cl:7])[CH:1]=2)[N:9]=1
Reactant: O=c1[nH]c(=O)c2nc3cc(Cl)c(Cl)cc3nc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cnc2cc(Cl)c(Cl)cc2n1
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
A solution of 10 g of 4,5-dichloro-o-phenylenediamine, 9 g of alloxan hydrate, 1.5 g of boric acid and 250 ml of glacial acetic acid was stirred overnight at room temperature to obtain a brown-black solution which was filtered. The yellow-buff crystalline solid was well washed with water to obtain 15.9 g of 7,8-dichloro-alloxazine melting at >370° C. A solution of 2 g of 7,8-dichloro-alloxazine in 10 ml of concentrated sulfuric acid was slowly heated to 240° C. and held there for 10 minutes. The mixture was cooled and poured onto ice and the mixture was made alkaline with sodium hydroxide addition. The mixture was extracted several times with ether to obtain 0.73 g of 2-amino-6,7-dichloro-quinoxaline as an orange crystalline solid melting at 220° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:18][CH3:19])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])C.C[Al](C)C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[F:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([CH3:16])=[C:6]([C:4]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)=[O:5])[C:7]([O:18][CH3:19])=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(OC)nc2cc(F)ccc2c1C
Reactant: NCc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1nc2cc(F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 110 °C
Yield: 30.9 %

Procedure:
To a stirred solution of 400 mg (1.52 mmol) 7-fluoro-2-methoxy-4-methylquinoline-3-carboxylic acid ethyl ester in toluene (10 ml) were added 3.04 ml (2M solution in toluene, 6.1 mmol) Me3Al at RT followed by the addition of 700 μl (6.1 mmol) 4-fluorobenzylamine. The reaction mixture was heated at 110° C. for 16 h. Then the reaction was quenched with water (10 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 160 mg (0.47 mmol, 31%) 7-fluoro-N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic acid amide (example 46) were obtained. MS: m/z 343.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:33])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Br[C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[NH:41][CH:42]=[CH:43][C:36]=12.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].CN(C=O)C>C(Cl)(Cl)Cl.CC(O)C.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].O>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:35]5[CH:40]=[CH:39][N:38]=[C:37]6[NH:41][CH:42]=[CH:43][C:36]=56)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:33])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Ba+2]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cnc(NCCn2ccnn2)nc1-c1cc2cccc(-c3ccnc4[nH]ccc34)c2s1
Temperature: 80 °C
Yield: 73 %

Procedure:
Combine N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.28 g, 0.6 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.51 mmol), barium hydroxide octahydrate (0.48 g, 1.52 mmol), Pd(dppf)Cl2 (40 mg, 0.05 mmol) in 4 mL of mixed solvent of DMF and water (4/1, v/v). Heat the reaction mixture to 80° C. for 45 min. Cool it to RT. Dilute with chloroform/IPA (3:1, v/v) 50 mL. Wash with water and saturated aqueous sodium chloride and dry over magnesium sulfate. Remove the organic solvent to give the crude product. Purify by column chromatography (hexane to ethyl acetate) to afford the title compound (0.17 g, 75%). MS (ES) m/z 457 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][C:30]([F:29])([F:40])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: OCc1ccccc1OC(F)(F)F
Product: FC(F)(F)Oc1ccccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (2-trifluoromethoxy-phenyl)-methanol. MS (ESI) m/z 554.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([C:12]([CH2:14][CH3:15])=[O:13])=[CH2:11].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:11][CH2:10][C:12](=[O:13])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: C=CC(=O)CC
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)CCC(=O)c1ccc(F)cc1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
A mixture of 36.61 g (295 mmol) of 4-fluorobenzaldehyde, 25 g (297.2 mmol) of ethyl vinyl ketone, 29 mL (206.9 mmol) of triethylamine and 11.94 g (44.25 mmol) of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride is stirred and heated at 70° C. for six hours. The cooled solution is diluted with 2 liters of diethylether and washed with 2×300 mL of water, 2×100 mL of 2M hydrochloric acid, 100 mL of water, 200 mL of a saturated solution of sodium bicarbonate and brine. The organic layer is separated, dried (magnesium sulfate), filtered, and concentrated to provide 55 g of 1-(4-fluorophenyl)-1,4-hexanedione after recrystallization from methanol; mp 56°-57° C.
Reaction SMILES: [C:1]([C:4]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[O:14][CH2:13][CH2:12]1)(C(O)=O)C(O)=O)([OH:3])=[O:2]>CC(O)=O>[F:30][C:26]1[CH:25]=[C:24]([S:21]([C:17]2[CH:16]=[C:15]3[C:20]([CH:11]([CH2:4][C:1]([OH:3])=[O:2])[CH2:12][CH2:13][O:14]3)=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(C(=O)O)(C(=O)O)C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Solvent: CC(=O)O
Product: O=C(O)CC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 100 °C

Procedure:
The crude 2-Carboxy-2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-malonic acid of step 3 was dissolved in HOAc (50 ml), and the mixture was heated to 100° C. overnight. HOAc was removed via vacuum, and he residue was dissolved in EtOAc, washed with H2O, brine, dried with MgSO4, filtered and concentrated to give [7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-acetic acid as a colorless oil which turned to a white solid upon standing: 2.55 g; MS 373(M+Na)+, 723.3 (2M+Na)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:29]=[C:28]([CH2:30][OH:31])[O:27][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:40]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:29]=[C:28]([CH2:30][OH:31])[O:27][N:26]=4)[CH:23]=[C:24]([I:40])[C:19]=3[NH:18][C:17]3[N:32]=[C:33]([C:36]([F:38])([F:37])[F:39])[CH:34]=[CH:35][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4noc(CO)n4)cc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3c(I)cc(-c4noc(CO)n4)cc32)cc1
Reaction time: 2 h

Procedure:
To a solution of {3-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1,2,4-oxadiazol-5-yl}methanol (Example 437, 49 mg, 0.0877 mmol) (1.5 mL) and N-iodosuccinimide (21 mg) in DCM at 0° C. was added trifluoroacetic acid (30 mg, 0.263 mmol). After stirring for 2 h, the reaction was quenched with 10% aqueous Na2S2O3 and the product was extracted with EtOAc. The combined extracts were washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography, eluting with 50% EtOAc in hexanes, to provide the title compound. LC/MS: m/e 586.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.55 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=1.8 Hz), 7.64 (1H, d, J=7.6 Hz), 7.28 (1H, s), 7.20 (1H, J=7.5 Hz), 7.13 (2H, J=8.4 Hz), 6.86 (2H, J=8.5 Hz), 5.02 (2H, s), 4.30-5.0 (2H, br), 2.75 (1H, s br), 1.30 (9H, s).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: c1ccc(CC2CCCNC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2CCCC(Cc3ccccc3)C2)cc1
Yield: 68.9 %

Procedure:
To a solution of the 3-phenylmethylpiperidine (1.75 g, 10 mmol) obtained in Example 1 (ii) and triethylamine (2.1 ml, 15 mmol) in tetrahydrofuran (10 ml) at 0° C. was added dropwise a solution of 4-methoxyphenylacetyl chloride (2.21 g, 12 mmol) in tetrahydrofuran (10 ml). The resultant mixture was stirred for 2 hours and the precipitate filtered off. The filtrate was then washed with saturated aqueous sodium bicarbonate (5 ml), dried with sodium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using 1:1 then 2:1 ethyl acetate: hexane as eluant to give 3-phenylmethyl-N-(4'-methoxyphenyl)acetylpiperidine as a light yellow syrup (2.23 g), M+ found: 324.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1)(=[O:17])=[O:16]
Reactant: Nc1ncc(Sc2ncccn2)s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ncc(Sc2ncccn2)s1
Yield: 43.8 %

Procedure:
To a solution of 2-amino-5-(2-pyrimidinylthio)thiazole (1.0 g) in a pyridine (20 ml) was dropwise added methanesulfonyl chloride (0.8 ml) at 5° C. with stirring. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give solid. The solid was recrystallized from 50% ethanol to give 2-methanesulfonylamino-5-(2-pyrimidinylthio)thiazole (0.60 g, yield: 43.8%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[Na+:32]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O-:29])=[O:28])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1.[Na+:32]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1cccc(O)c1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 65 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 3 (4.7 g), 1 mol/L of an aqueous sodium hydroxide solution (35 mL), and methanol (300 mL), to give the captioned compound (2.8 g, 65%) as crystals.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][C:6]=1[F:26].[OH-].[Na+]>CO.O1CCCC1.O>[F:11][C:10]1[CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=[C:6]([F:26])[C:5]=1[C:4](=[O:27])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)C(=O)c1c(F)cc(OCCOc2ccc3ccccc3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1c(F)cc(OCCOc2ccc3ccccc3c2)cc1F
Yield: 88.2 %

Procedure:
A solution of 2,6-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.51 g of 2,6-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 157°-158° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].C(=O)([O-])[O-].[Na+].[Na+].[CH:43](B1OC(C)(C)C(C)(C)O1)=[CH2:44].O1CCOCC1>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].C(Cl)Cl.O>[Cl:36][C:3]1[CH:4]=[C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[CH:43]=[CH2:44]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.00 g, 1.69 mmol), PdCl2(dppf)-CH2Cl2 adduct (138 mg, 0.169 mmol), sodium carbonate (537 mg, 5.07 mmol) and vinylboronic acid pinacol ester (0.573 mL, 3.38 mmol) in a 9:1 mixture of 1,4-dioxane and water (20 mL) was degassed and heated at 80° for 16 h. The mixture was cooled to rt, then poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. The light brown oily residue was purified by flash chromatography (silica gel, gradient of 0 to 50% EtOAc in hexanes) to afford the title compound (821 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, 1H), 8.08-8.14 (m, 1H), 7.92-8.02 (m, 2H), 7.70-7.76 (m, 1H), 7.34-7.47 (m, 4H), 7.17-7.24 (m, 1H), 6.96 (dd, 1H), 5.87 (d, 1H), 5.44 (d, 1H), 3.39-3.47 (m, 3H), 2.83 (d, 3H), 2.04-2.16 (m, 1H), 0.73-1.03 (m, 3H), 0.36-0.55 (m, 1H). LCMS (m/z, ES+)=539 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:26][C:27]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)(=O)=O.O>CN(C=O)C>[CH2:32]([O:31][CH2:30][C:27]1([CH2:26][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:29][CH2:28]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)OCC1(COCc2ccccc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.62 g, 44.4 mmol) in DMF (12 mL) was treated with cesium carbonate (14.6 g, 44.4 mmol) and stirred at RT for 10 min. A solution of {1-[(benzyloxy)methyl]cyclopropyl}methyl methanesulfonate (Compound 63D, 12 g, 44.4 mmol) in DMF was added and heated to 70° C. for 24 hrs. The reaction mixture was cooled to RT, poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to give 12 g (73%) of required compound as a colorless gum which was used without further purification. 1H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H), 7.68 (s, 1H), 7.25-7.34 (m, 5H), 4.48 (s, 2H), 4.15 (s, 2H), 3.16 (s, 2H), 1.33 (s, 12H), 0.71 (s, 2H), 0.56 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH2:23].CO.[BH4-].[Na+]>ClCCl>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH:23][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC1CCCCN1CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCCN1CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Naphtaldehyde 1 g (6.4 mmol), 3-(2-methyl-piperidin-1-yl)-propylamine 0.99 g (6.4 mmol), in 25 mL of dry dichloromethane was added 5 g of molecular sieve. The reaction was stirred overnight at room temperature. The molecular sieve was filtered and dichloromethane was concentrated under vacuum. To the mixture was added 15 mL of dry methanol and sodium borohydride 0.3 g (8 mmol) after 30 minutes reaction goes to completion, methanol was concentrated under vacuum, and was diluted with chloroform, organic layer was washed with 2 times 20 mL water, followed with brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The compound was purified using silica gel chromatography elution, with 3.5% methanol in chloroform, yield 0.6 g oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH3:32])[CH:28]=4)[NH:23][C:22](=[O:33])[C:21]=3[C:34]([O:36][CH3:37])=[O:35])=[CH:19][C:14]=2[O:13][CH2:12]1.NC1C=CC(OCC)=CC=1C(=O)C1C=CC2OCOC=2C=1.ClC(CC(OC)=O)=O.C1OC2C=CC(C=O)=CC=2O1.C(OC(NC1C=CC(OCC)=CC=1)=O)(C)(C)C.C([Li])(C)(C)C>ClCCl.C(N(C(C)C)C(C)C)C.C[O-].[Na+].C1COCC1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH3:32])[CH:28]=4)[N:23]([CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=4[O:2][CH3:1])[C:22](=[O:33])[C:21]=3[C:34]([O:36][CH3:37])=[O:35])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: COc1ccccc1CCl
Reactant: CCOc1ccc2[nH]c(=O)c(C(=O)OC)c(-c3ccc4c(c3)OCO4)c2c1
Agent: CCOc1ccc(N)c(C(=O)c2ccc3c(c2)OCO3)c1
Agent: CCOc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: COC(=O)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OC)c(=O)n2Cc1ccccc1OC
Reaction time: 4 h

Procedure:
A 50% solution of 0.4 g of 2-methoxybenzyl chloride ("A") in dichloromethane is added to a solution of 0.4 g of methyl 4-(1,3-benzodioxol-5-yl)-1, 2-dihydro-6-ethoxy-2-oxoquinoline-3-carboxylate (obtainable by reacting 1-amino-2-(3,4-methylenedioxybenzoyl)-4-ethoxybenzene and methyl chloroformylacetate in dichloromethane and ethyldiisopropylamine with subsequent cyclization of the intermediate in sodium methanolate solution, m.p. 224°-225°; 1-amino-2-(3,4-methylenedioxybenzoyl)-4-ethoxybenzene is obtainable by reacting 3,4-methylenedioxybenzaldehyde and N-(tert-butyloxycarbonyl)-p-ethoxyaniline, m.p. 113°-114°, in THF, tert-butyllithium at -78°, subsequently oxidizing the resulting 3', 4'-methylenedioxy-2-(N-tert-butyloxy-carbonylamino)-5-ethoxydiphenylmethanol and eliminating the amino protective group, EI-MS 285) in 5 ml of DMF and 0.17 g of potassium carbonate. The reaction mixture is stirred for 4 hours and worked up as usual. This results in the N-alkylation product methyl 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylate, m.p. 182°-183° and the -alkylation product methyl 4-(1,3-benzodioxol-5-yl)-6-ethoxy-2-(2-methoxybenzyloxy) quinoline-3-carboxy-late, m.p. 157°-158°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:39]([C:36]1[CH:35]=[CH:34][C:33]([S:32][CH3:31])=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(SC)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.626 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.593 g of 4-methylsulphanylbenzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow oil.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C=O)C.[Br:11][C:12]1[C:21]([I:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH2:23]O)=[CH:17]2>C(Cl)Cl>[Br:11][C:12]1[C:13]2[C:18](=[CH:17][C:16]([CH2:23][Br:3])=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:21]=1[I:22]
Reactant: OCc1ccc2c(Br)c(I)ccc2c1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: BrCc1ccc2c(Br)c(I)ccc2c1
Reaction time: 0.17 h

Procedure:
To a solution of POBr3 (662 mg, 2.3 mmol) in 4.5 mL of CH2Cl2 at 0° C. was added DMF (2.25 mL) dropwise. The reaction was stirred for 10 minutes and then a solution of (5-bromo-6-iodo-2-naphthyl)methanol (280 mg, 0.77 mmol) in 5 mL of CH2Cl2 was added. The reaction mixture was stirred for 30 minutes, quenched with a saturated solution of NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness to afford the titled product which was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][N:18]=[C:19]=[S:20]>>[CH3:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6]
Reactant: CN=C=S
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CNC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 65.6 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and methyl isothiocyanate (124 μL, 1.813 mmol), 22.0 mg (66%) of the title compound were recovered.