Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]3[C:21](=[CH:22][C:23]([C:32]([F:35])([F:34])[F:33])=[CH:24][CH:25]=3)[N:20]=2)=[C:15](SCC)[CH:14]=1.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]3[C:21](=[CH:22][C:23]([C:32]([F:34])([F:33])[F:35])=[CH:24][CH:25]=3)[N:20]=2)=[C:15]([S:39]([CH2:2][CH3:3])(=[O:43])=[O:41])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNc1nc(-c2ccc(Cl)cc2SCC)nc2cc(C(F)(F)F)ccc12
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCNc1nc(-c2ccc(Cl)cc2S(=O)(=O)CC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
375 mg of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 306 mg of 2-(4-chloro-2-ethylsulfanylphenyl)-4-ethylamino-7-trifluoro methylquinazoline and 5 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 270 mg of 2-(4-chloro-2-ethylsulfonylphenyl)-4-ethylamino-7-trifluoro methylquinazoline (Compound of Present Invention 16).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:31])C>OO>[OH:28][CH2:27][CH2:26][N:24]1[CH:25]=[C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N+:1]([O-:31])=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)[CH:22]=[N:23]1
Reactant: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: CC(=O)O
Agent: OO
Product: [O-][n+]1cccc2cc(Cn3nnc4ccc(-c5cnn(CCO)c5)nc43)ccc21
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of example 146 (0.100 g, 0.269 mmol) in acetic acid (1 ml), hydrogen peroxide solution (50%, 1 ml) and heated to 100° C. After 12 h, the mixture was concentrated, extracted with chloroform, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using dichloromethane: methanol to afford the title compound as an off-white solid (0.015 g, 14%). M.P.: 222-224° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.58-8.48 (m, 4H), 8.19 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.85 (dd, J=9.0, 1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 6.0 Hz, 1H), 6.12 (s, 2H), 4.95 (t, J=5.2 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH:22]1[O:26][CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])=[CH:17][C:16]=1[CH:22]1[O:23][CH2:24][CH2:25][O:26]1
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Reactant: COCOc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1cc(C#N)ccc1Oc1ccc(Br)c(C2OCCO2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A mixture of 4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, 182 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)phenol (44.6 g, 182 mmol), and potassium carbonate (30.1 g, 218 mmol) in N,N-dimethylformamide (370 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was passed silica gel short column (3:1 hexane/ethyl acetate) followed by trituration with hexane/ethyl acetate to give 4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-methoxymethoxybenzonitrile (32.6 g, 44%),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:22]C4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[N:11]=[C:10]2[O:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)=[N:6][CH:7]=1.C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[N:11]=[C:10]2[O:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:43])[F:44])[CH:36]=2)=[N:6][CH:7]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cn1
Solvent: CC(=O)Cl
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of 7-((5-chloropyridin-2-yl)methyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (80 mg, 0.14 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give crude product which was purified by preparative HPLC to give 7-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 19.0% yield) as white solid. 1H-NMR (CD3OD) δ 8.33(d, 1H), 7.70(dd, 1H), 7.35(t, 1H), 7.26(d, 1H), 6.87(dd, 1H), 6.76(s, 1H), 5.43(s, 2H), 4.86-4.87(m, 2H), 4.33-4.35(m, 2H), 4.04(t, 2H), 3.56(t, 2H), 3.54(s, 3H), 1.80-1.85(m, 2H). LCMS retention time 2.606 min; LCMS MH+ 570.
Reaction SMILES: [CH3:1]N(C=O)C.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH3:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=1>ClCCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:18]=[C:19]([CH3:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:1]2
Reactant: CCOC(=O)C=C(C)Nc1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cc2cc(Cl)ccc2nc1C
Temperature: 25 °C

Procedure:
To a solution of 6.2 g (83 mmol) DMF in 50 ml of 1,2 dichloroethane was carefully added 19.1 g (126 mmol) of phosphoryl chloride. After stirring for 10 min at ambient temperature a solution of 20 g (83 mol) of ethyl 3-(4-chlorophenylamino)but-2-enoate in 50 ml of 1,2 dichloroethane was added slowly, while the mixture turned dark in an exothermic reaction. Stirring at ambient temperature was continued for another hour followed by heating with reflux for 6 h. The mixture was poured on to crushed ice, washed twice with water, dried over sodium sulfate, and concentrated under reduced pressure. The title ester was obtained from the residue via flash chromatography on silica gel with dichloromethane/hexane 4:1.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:17])[NH:7][S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].C=[O:19].[CH2:20]([OH:22])[CH3:21]>>[OH:22][CH2:20][N:7]1[C:6](=[O:17])[C:5]2[C:11](=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:4]=2[CH:1]([CH3:3])[CH3:2])[S:8]1(=[O:9])=[O:10].[C:20]([O:19][C:13](=[O:15])[CH3:14])(=[O:22])[CH3:21]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Reactant: CCO
Reactant: C=O
Product: CC(=O)OC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CO)C2=O

Procedure:
Condensation of 4-isopropyl-6-methoxysaccharin with aqueous formaldehyde in ethanol gives 2-hydroxymethyl-4-isopropyl-6-methoxysaccharin, acetylation of which with acetic anhydride and a catalytic amount of sulfuric acid gives 2-acetoxymethyl-4-isopropyl-6-methoxysaccharin.
Reaction SMILES: [P:1]([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:22])[CH3:21])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CCO.[OH-].[Na+:54]>[Pd].O>[P:1]([O-:11])([O-:3])([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:21])[CH3:22])=[O:2].[Na+:54].[Na+:54]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)([O-])[O-])nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A 1 L round bottom flask was charged with (R)-dibenzyl 2454243-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (9.37 g, 13.61 mmol), EtOH (300 mL), water (150 mL), Pd/C (10 wt % dry basis, wet, Degussa type, 3 g) and 1 M aqueous NaOH (27.22 mL, 27.22 mmol). The suspension was evacuated for 3 min (needle to pump) then placed under an atmosphere of hydrogen gas (balloon). After stirring 2.5 h at 23° C., the reaction was filtered through a 0.22 μm PES membrane (disposable Corning filter system, 1 L, polystyrene, #431098) to remove catalyst and washed with EtOH (50 mL). The resulting solution was concentrated, the residue dissolved in water (80 mL), treated with MeCN (80 mL), then frozen and lyophilized to give disodium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (W) (7.10 g, 12.81 mmol, 94.12%) as a white solid. ESMS (M+1)=509.3; 1H NMR (300 MHz, D2O) δ 8.58 (s, 2H), 6.92 (d, J=6.3 Hz, 1H), 5.13 (t, J=7.5 Hz, 1H), 3.98-3.81 (m, 2H), 3.04 (q, J=7.2 Hz, 2H), 2.26 (t, J=5.7 Hz, 1H), 1.97-1.92 (m, 2H), 1.67 (s, 6H) and 1.01 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH3:6])=[O:4].CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[O:17][C:20]([CH3:22])([CH3:21])[O:1]1)=[O:4]
Reactant: COC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 1-methyl 6-tert.-butyl 2,4-dihydroxyadipate (4.98 g, 20.01 mmol) in methylene chloride (2 dimethoxypropane (9.6 ml, 78 mmol) and pyridinium p-toluenesulfonate (2.01 g, 8 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 40° C. for 3 hours while azeotropically removing methanol with methylene chloride. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and poured in water. Then, the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=3:1) to give pure 2-methoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (4.89 g, 17.01 mmol). Yield, 85 %.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][CH2:11]O.C1C=CC=CC=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>O>[Cl:19][CH:20]([Cl:24])[C:21]([N:8]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:11][CH2:10][CH2:9]1)=[O:22]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NCCCO
Reactant: O=C1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(C(Cl)Cl)N1CCCOC12CCCCC2

Procedure:
From a boiling mixture of 17.6 g. (0.18 moles) of cyclohexanone and 11.2 g. (0.15 moles) of 3-aminopropanol in 50 ml. of benzene the water formed is continuously distilled off. Boiling is continued until 2.7 ml. of water are separated. The reaction mixture is then cooled and 16 ml. (0.165 moles) of a 40% aqueous sodium hydroxide solution are added followed by a subsequent dropwise addition of 22.1 g. (0.15 moles) of dichloroacetyl chloride, with external salt/ice cooling.
Reaction SMILES: C([O:5][N:6]=[O:7])(C)(C)C.[CH2:8](Br)[CH:9]=[CH2:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([N+]([O-])=O)[CH:21]=1)N)([O-:14])=[O:13]>CC#N>[N+:6]([CH:10]=[CH:9][CH2:8][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=[CH:20][CH:19]=1)([O-:7])=[O:5]
Reactant: C=CCBr
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])C=CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of t-butylnitrite (84.6 ml, 0.71 mol) and allylbromide (530 ml, 6.15 mol) in 25 ml CH3CN, 3,5-dinitroaniline (75 g, 0.41 mol) was added spoonwise, so that the temperature was maintained between 11 and 15° C. During the addition of the final ½ of 3,5-dinitroaniline, more t-butylnitrite (21 ml, 0.18 mol) was added. The reaction mixture was then stirred at room temperature for 1 h. Excess t-butylnitrite, allylbromide and CH3CN was distilled from the reaction mixture at reduced pressure and the residue was dissolved in toluene (500 ml). The solution was filtered through two Al2O3 pads. The toluene was distilled off at reduced pressure and to the remaining residue 3,3,5-trimethylpentane (200 ml) was added. The mixture was heated to 60° C. and stirred for ½ h and then cooled to −60° C. The pentane phase was decanted and the mixture was crystallized from 2,2,4-trimethylpentane at −50° C. The crystals were then triturated twice with 2,2,4-trimethylpentane at −50° C. The remaining pentane was then removed at reduced pressure, to give 78.7 g (93%) of 3,5-dinitroallylbenzene as yellow oil containing approximately 4% of 3,5-dinitrobromo benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[C:8]([C:10]([F:13])([F:12])[F:11])=[N:9][C:5]=2[CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27].C(N=C=NCCCN(C)C)C.CCOC(C)=O>C(Cl)(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:20][C:17]1[CH:16]=[N:15][C:14]([N:7]2[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([F:12])([F:13])[F:11])=[CH:19][N:18]=1)=[O:27]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (30 mg, 0.10 mmol). To this was added 2,6-difluorobenzoic acid (30 mg, 0.19 mmol), 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC) (100 mg, 0.52 mmol) and N,N-dimethylamino-pyridine (DMAP) (70 mg, 0.57 mmol) followed by CHCl3 (10 mL). The resulting solution was stirred at 55° C. overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the resultant solution was diluted with 20 mL of CHCl3, washed with 20 mL of H2O and dried over Na2SO4. After removal of the solvent and volatile components under reduced pressure, the residue was purified by eluting through a silica gel column with a 1:5 EtOAc/PE solvent system. This resulted in 20 mg (46%) of 2,6-difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide (Compound 1) as a white solid.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](Cl)[N:28]=3)[C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21]2)[C:15]([F:19])=[CH:16][C:17]=1[F:18])=[O:10])[CH3:7].[NH2:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>C(O)C>[CH:37]([O:32][CH:23]([CH3:22])[CH3:24])([CH3:41])[CH3:38].[NH2:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:27]2[N:28]=[C:29]3[C:24]([C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21][N:20]3[C:14]3[C:15]([F:19])=[CH:16][C:17]([F:18])=[C:12]([NH:11][C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:13]=3)=[CH:25][C:26]=2[F:31])[CH2:38]1
Reactant: CCOC(=O)Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: N[C@H]1CCNC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCOC(=O)Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 193 %

Procedure:
To 350 μl of N,N-dimethylformamide were added 68 mg of 1-(3-ethoxycarbonylamino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 70 mg of (3S)-3-aminopyrrolidine. The solution was stirred at 80° C. for 20 minutes. Then 0.5 ml of ethanol was added. The reaction solution was allowed to cool down whereupon the precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 73 mg of the title compound.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl.C(OCC)(=O)C>[C:46]([N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@@:9]([CH3:38])([C:7]([NH:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8])[CH2:10]1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@](C)(C(=O)NOC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (323 mg, 0.597 mmol) was dissolved in CH2Cl2 (5 mL). The solution was cooled to 0° C., then triethylamine (100 μL) and acetylchloride (50 μL) were added. The reaction was stirred for 1 h, then diluted with ethyl acetate and washed with saturated aqueous Na2CO3 (2×) and brine (2×). The organic layer was isolated, dried over Na2SO4, concentrated, and then purified via column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give (3S,4R)-1-acetyl-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (341 mg, 0.585 mmol, quant) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.09 (s, 3H) 1.22-1.28 (m, 9H) 1.55 (qd, J=12.93, 4.67 Hz, 1H) 1.88 (ddd, J=13.52, 2.78, 2.65 Hz, 1H) 2.07-2.10 (m, 3H) 2.33-2.39 (m, 1H) 2.75 (s, 3H) 3.09-3.18 (m, 1H) 3.24 (ddd, J=12.19, 8.53, 3.79 Hz, 1H) 3.78 (dt, J=13.58, 2.18 Hz, 1H) 4.76 (dd, J=14.91, 2.53 Hz, 1H) 5.55 (s, 2H) 7.08-7.14 (m, 2H) 7.42 (s, 1H) 7.53-7.58 (m, 1H) 7.70-7.75 (m, 1H) 7.83-7.87 (m, 2H) 7.89-7.93 (m, 1H) 8.07-8.11 (m, 1H) 9.93 (s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]1.C(OCC)(=O)C.CC(C)=O>CO.[Pd]>[ClH:1].[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]1
Reactant: Cc1ccccc1C(=CCOCCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(CCOCCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Yield: 26.4 %

Procedure:
The acid prepared in Example 31 (0.75 g, 1.7 mmol) was dissolved in methanol (25 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with a mixture of ethyl acetate and acetone and filtered to give a solid which was recrystallised from toluene to give 0.20 g (26%) of the title compound as a solid. TLC: rf=0.39 (SiO2 ; methanol/dichloromethane=1 1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH3:28]>C(Cl)Cl>[C:33]([N:32]([CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:37])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCOC(=O)CNC(=O)CC
Reactant: ClSCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)C(=O)CC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to 31 5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for 2 hours. After cooling to -10° to -5° C., a solution of 8 g (0.05 mole) of N-propionylglycine ethyl ester in 10 ml of methylene chloride was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 14.3 g (69.8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 88.2 %

Procedure:
A mixture of 2 g (11.59 mmol) of 2-chloro-4-methyl-5-nitropyridine, 1.41 g (11.59 mmol) of phenylboronic acid, 1.33 g (1.16 mmol) of tetrakis(triphenylphosphine)palladium and 4 g (28.97 mmol) of potassium carbonate suspended in 50 ml of degassed dioxane is refluxed for 12 hours. The mixture is then cooled, diluted with 50 ml of ethyl acetate, successively washed twice with 20 ml of water and then with 20 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluents: heptane/ethyl acetate) and then recrystallized from an isopropanol/isopropyl ether mixture. 2.19 g of a yellow solid are thus isolated, and are used without further purification in the following synthesis.