Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26]Br)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[Ca+2]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][OH:30])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CBr)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CO)cc1Cl
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-bromomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.3 g, 0.58 mmol) in dioxane (10 mL) and water (2 mL) was added CaCO3 (0.29 g, 2.89 mmol). The resulting turbid solution was heated to reflux for 64 hours, and then cooled to ambient temperature. The reaction mixture was concentrated to remove dioxane and purified by flash chromatography on silica followed by precipitation from CH2Cl2 and hexane to afford 0.15 g of N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.7 (s, 1), 8.4 (d, 1), 7.9 (s, 1), 7.7 (d, 2), 7.5 (d, 1), 7.3 (d, 2), 7.0 (s, 1), 4.6(s, 2) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][N:4]=1.[SH:12][C:13]1[NH:17][C:16]2[CH:18]=[C:19]3[C:23](=[CH:24][C:15]=2[N:14]=1)[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[C:20]3([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:12][C:13]2[NH:14][C:15]3[CH:24]=[C:23]4[C:19](=[CH:18][C:16]=3[N:17]=2)[C:20]([CH3:28])([CH3:29])[C:21](=[O:27])[C:22]4([CH3:26])[CH3:25])[C:8]=1[CH3:9]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: COc1ccnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 690 mg of 2-chloromethyl-3-methyl-4-methoxypyridine and 400 mg of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one in 40 ml of absolute acetone was treated with 1.9 g of finely ground potassium carbonate, whereupon the mixture was stirred at room temperature under argon for 18 hours. After concentrating the mixture in vacuo the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (10:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ethyl acetate/ether there was obtained 5,7-dihydro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 218°-220°.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(Cl)Cl.C(O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[C:21]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 g, 6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The oil thus obtained (2.54 g, 90%) was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p.=100°-102° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]3[N:21]([C:31]4[N:32]=[CH:33][N:34]=[C:35]([NH2:38])[C:36]=4[N:37]=3)[C@@H:22]3[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:23]3[OH:24])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(OC([NH:49][C:50](N1C=CC=N1)=[NH:51])=O)C1C=CC=CC=1>O1CCCC1.[Pd].CO>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]3[N:21]([C:31]4[N:32]=[CH:33][N:34]=[C:35]([NH2:38])[C:36]=4[N:37]=3)[C@@H:22]3[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:23]3[OH:24])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[C:50]([NH2:51])=[NH:49]
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Reactant: NCCCOc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)NCCCOc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
8-[3′-(3-Aminopropoxy)biphenyl-4-ylmethylamino]-adenosine (0.2 g) was suspended in tetrahydrofuran (2 mL), N-benzyloxycarbonyl-1H-pyrazole-1-carboxamidine (0.47 g) was added, and the resulting mixture was stirred at 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=8/1-6/1). A mixture of the compound obtained and 10% palladium on carbon (43.8 wt % H2O, 0.05 g) in methanol (2 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give the title compound (0.05 g).
Reaction SMILES: [ClH:1].C(C1C=CC=CC=1C=CC1C=CC=CC=1)#[N:3].Cl.C(O[C:22](=[NH:37])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)C.C(=N)([O-])C1C=CC=CC=1.N>CO.C(O)C.C1C=CC=CC=1>[ClH:1].[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH2:37])=[NH:3])=[CH:28][CH:27]=1)=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N#Cc1ccccc1C=Cc1ccccc1
Reactant: CCOC(=N)c1ccc(C=Cc2ccccc2)cc1
Agent: Cl
Agent: N
Agent: N=C([O-])c1ccccc1
Solvent: CO
Solvent: CCO
Solvent: c1ccccc1
Product: N=C(N)c1ccc(C=Cc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Hydrogen chloride is bubbled through a mixture of 4L -cyanostilbene (13.5 g., 0.065 mole), obtained according to the method of Belgian Patent 641,415 (Chem. Abs. 63: 3092g (1965)), in 35 ml. of dry benzene and 17.5 ml. of absolute ethanol at 0° to 5° C. for a period of 3 hr. The reaction is maintained at 0° to 5° C. for 48 hr. and the solvent and excess hydrogen chloride removed under reduced pressure. The residue stirred with 50 ml. of dry benzene and collected provides 13.0 g. of ethyl-4-styrylbenzimidate hydrochloride. A methanol solution of the benzimidate salt is cooled to 5° to 10° C., saturated with ammonia and heated at a temperature of 100° C. for a period of 3 hr. in an enclosed container. Concentration of the reaction mixture provides 4-styrylbenzamidine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8]N)[N:3]=1.CCO.[CH3:13][C:14]([CH2:16][CH3:17])=O>C(O)COCCO>[Br:1][C:2]1[N:3]=[C:4]2[NH:8][C:14]([CH3:13])=[C:16]([CH3:17])[C:5]2=[CH:6][CH:7]=1
Reactant: CCC(C)=O
Reactant: NNc1cccc(Br)n1
Solvent: CCO
Solvent: OCCOCCO
Product: Cc1[nH]c2nc(Br)ccc2c1C
Yield: 15.7 %

Procedure:
A suspension of 2-bromo-6-hydrazinopyridine (32,5 g, 0.17 mol) in abs EtOH was treated with ethyl methyl ketone (20 ml, 0.22 mol) for 1 h at reflux. The reaction mixture was allowed to cool and treated with additional ethyl methyl ketone (10+3+1 ml) until all starting material had dissapeared according to TLC. The reaction mixture was taken up in 150 ml diethylene glycol and the EtOH evaporated at reduced pressure at 70° C. The remaining solution was deaerated and heated to reflux for 22h. The reaction mixture was cooled and paritioned between 1250 ml CH2Cl2 and 1000 ml 2M HCl (reextracted with 250 ml CH2Cl2). The organic layer was washed with further 500 ml 2M HCl and 500 ml H2O dried over MgSO4, and evaporated. Chromatography (silica, CH2Cl2 /diethyl ether; 95/5) afforded 6 g 6-bromo-2,3-dimethyl-pyrrolo[2,3-b] pyridine. Recrystallization from 120 ml abs EtOH gave 4,2 g (11%). (1H-NMR, 500 MHz, CDCl3) 2.19(s,3H), 2.42(s,3H), 7.16(d, 1H), 7.59(d, 1H), 9.12(b, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].C[CH2:39][N:40](CC)CC.Cl.Cl.[NH:47]1[CH:51]=[CH:50][N:49]=[C:48]1NC>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:39][C:48]3[NH:47][CH:51]=[CH:50][N:49]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN(CC)CC
Reactant: CNc1ncc[nH]1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (1.37 g, 2.54 mmol) in DCM (127 mL) were added Et3N (1.78 mL, 12.7 mmol) and (1H-imidazol-2-yl)-methylamine dihydrochloride (0.625 g, 3.81 mmol). The mixture was stirred at room temperature over night and concentrated under vacuum. Flash chromatography [mobile phase DCM/DCM (90)+MeOH(7)+NH4OH(3)] then provided the title compound as a white solid 1.23 g (85%). MS (ES) m/z 571 (M+H)+; 1H-NMR (MeOD) δ 2.16 (s, 1.5H), 2.32 (s, 1.5H), 3.18 (d, J=4.4 Hz, 0.75H), 4.11 (d, J=5.2 Hz, 0.25H), 4.21 (d, J=5.0 Hz, 1H), 4.50 (m, 1H), 6.37 (d, J=9.6 Hz, 1H), 6.85 (s, 2H), 7.29 (s, 2H), 7.43 (m, 2H), 7.57 (m, 3H), 8.18 (m, 3 H), 11.60 (s, br, 1H), 12.64 (s, br, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17]CCC=O)=[O:16])[S:14][C:7]=12.[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:52]1[CH2:56]OC[CH2:53]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:53][CH2:52][CH2:56][N:41]3[CH2:42][CH2:43][CH:38]([OH:37])[CH2:39][CH2:40]3)=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC=O)sc34)cc2F)c1
Reactant: OC1CCNCC1
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCC(O)CC5)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF were added 4-hydroxypiperidine (59 mg, 0.58 mmol) and acetic acid (10 mg, 0.17 mmol). The mixture was stirred at room temperature for 40 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60 ml, 0.60 mmol) and stirring was continued for another 30 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 10-20% of MeOH in CHCl3 to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 70 mg, 40%.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(OC)cc3)noc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(-c3ccc(OC)cc3)noc2c1O
Yield: 38.7 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (200 mg, 0.45 mmol), phenylboronic acid (111 mg, 0.91 mmol), Pd(PPh3)4 (105 mg, 0.091 mmol) and cesium carbonate (444 mg, 1.36 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, 3 mL of 1,2-dimethoxyethane was added and the resulting suspension was refluxed for 16 h. The reaction mixture diluted with EtOAc (50 mL) and the solid was filtered. The solid was added to a mixture of 10% hydrochloric acid and extracted several times with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-40% EtOAc/hexanes) to afford 68 mg of the title compound. MS: (+) m/z 391.41 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1CCOS(C)(=O)=O
Temperature: 5 °C
Yield: 92.2 %

Procedure:
10 g (0.0734 mol) of 2-methylphenethyl alcohol were dissolved in 200 mL of dry CH2Cl2 under a nitrogen atmosphere; the solution was cooled to 5° C., 16.4 mL (0.1175 mol) of triethylamine were added, followed by a solution of 9.1 mL (0.1175 mol) of methanesulfonyl chloride in 100 mL of dry CH2Cl2, keeping the temperature below 15° C. The reaction mixture was allowed to warm to room temperature in 2 h, then 250 mL of water were added, the organic phase was collected and the solvent was removed in vacuo. The resulting oil was taken up in Et2O and washed with 1N HCl and successively with saturated NaHCO3 solution, the solvent was removed in vacuo, yielding 14.5 g of the title product which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:25]2[S:29][C:28]([C:30]([OH:32])=O)=[C:27]([CH3:33])[C:26]=2[CH3:34])=[CH:11][CH:10]=1.[CH3:35][N:36]([CH:38]=O)[CH3:37].C(N(CC)CC)C.Cl.[CH3:48][NH:49][O:50][CH3:51]>ClCCl>[CH3:38][N:36]([CH:35]=[N:22][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=[C:12]([C:25]3[S:29][C:28]([C:30]([N:49]([O:50][CH3:51])[CH3:48])=[O:32])=[C:27]([CH3:33])[C:26]=3[CH3:34])[CH:13]=2)=[CH:20][CH:19]=1)(=[O:23])=[O:24])[CH3:37]
Reactant: CNOC
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2sc(C(=O)O)c(C)c2C)cc1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc(C(=O)N(C)OC)c(C)c2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
Oxalyl chloride (0.09 g, 0.06 ml, 0.72 mmol) was added drop wise to a solution of 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-3,4-dimethylthiophene-2-carboxylic acid (9f, 0.16 g, 0.36 mmol) in dichloromethane (10 ml) and DMF (0.05 g, 0.06 ml, 0.72 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 1.5 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (10 ml) and to this was added triethylamine (0.18 g, 0.25 ml, 1.79 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.07 g, 0.72 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. Dichloromethane (10 mL) was added to the reaction mixture. The resultant mixture was washed with water (2×10 ml). The separated organic layer was dried over anhydrous sodium sulphate and concentrated at reduced pressure to get a crude product. The crude product so obtained was purified by column chromatography using 30% ethyl acetate in hexane as an eluent to obtain the title compound 9g (0.12 g, 65%).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (52 mg, 3.41 eq, 0.36 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 7.3 mg (17%). (55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.03 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56 & 1.58 (2×d, 6H, J=6.63 & 6.79 Hz, —CH(CH3)2), 1.69-1.91 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.55 (d, 1H, J=1.74 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.76-3.87 (m, 1H, —NHCH(CH2CH3)CH(C (CH3)3)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.80-4.89 (m, 2H, —HNCH2-Pyr), 5.22-5.35 & 6.07-6.23 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.24-7.36 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (s, 1H, Pyr-H), 7.74 (d, 1H, J=7.58 Hz, Pyr-H), 8.50-8.74 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (80). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[NH2:9])([O-:3])=[O:2].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[N:9]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c([N+](=O)[O-])cnn23)ccc1Cl)S(C)(=O)=O
Yield: 37.6 %

Procedure:
A mixture of 0.050 g (0.39 mmol) of 4-nitro-2H-pyrazol-3-ylamine and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 56 mg of N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 77%).
Reaction SMILES: B.C([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.[NH2:17][C:18]1C=CC=C[CH:19]=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[OH:9][C:10]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: B
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccccc12

Procedure:
In CHART C, carboxylic acid C-1, 3-methyl-3-(4-nitrophenyl)butanoic acid prepared by carbonylation of the corresponding Grignard, is reduced to the corresponding alcohol with borane. The resulting alcohol C-2 is protected as the benzyl ether and the corresponding nitro functionality is reduced to aniline C-3. Heating C-3 with diethyl ethoxymethylenemalonate followed by thermolysis in refluxing diphenylether affords the 4-hydroxyquinoline C-4. Aminolysis of compound C-4 with 4-chlorobenzylamine at about 190 ° C. provides amide C-5 which is then alkylated at the pyridone nitrogen with an alkylhalide and potassium carbonate to afford compound C-6. Deprotection of the benzyl ether under hydrogenolysis conditions affords the desired hydroxyalkyl 4-quinolone carboxamide of formula I of the present invention.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: COc1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-methoxybenzaldehyde yields the (E)-1-methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=255 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(C(C)C([NH2:26])=O)=CC=1>>[C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([NH2:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC(C(=O)O)c1ccccc1
Reactant: COc1ccc(C(C)C(N)=O)cc1
Product: CC(C)CC(C(N)=O)c1ccccc1
Yield: 94 %

Procedure:
The titled compound was prepared from 2-phenyl-4-methylpentanoic acid in 94% yield in the same manner as the preparation of 2-(4-Methoxyphenyl)propionamide in Example 188b. MS (ESI) 192 (MH+)