Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([CH2:21][C:22]([OH:24])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[NH:48]1)=[O:46].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[N:48]1[C:22](=[O:24])[CH2:21][N:13]1[C:14]2=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=[C:19]2[C:11]([C:8]([NH2:9])=[O:10])=[N:12]1)=[O:46]
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(C(N)=O)nn(CC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)Nc3cccc(OC(F)(F)F)c3F)c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)acetic acid trifluoroacetate salt (3.87 g, 11.1 mmol; prepared as described in Scheme A27) in DMF (45 mL) were successively added (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate salt (5.00 g, 11.1 mmol), DIPEA (7.77 mL, 44.5 mmol) and HBTU (5.06 g, 13.3 mmol). The reaction mixture was stirred at 25° C. for 2 h and was then concentrated in vacuo. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 5% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined and volatiles were evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHCO3, and then was extracted with CH2Cl2 (×3). The combined organic extracts were dried (phase separator) and concentrated under vacuum to afford the title compound as a white solid. MS: 521 [M+H]+; tR (HPLC conditions c): 3.81 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[NH2:6])[CH3:2].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([N:6]=[C:14]=[O:15])[CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOc1c(C)cc(N)cc1CC
Solvent: Cc1ccccc1
Product: CCOc1c(C)cc(N=C=O)cc1CC
Temperature: 25 °C
Yield: 101.9 %

Procedure:
A mixture of 3-ethyl-4-ethoxy-5-methylaniline (1.8 g) in toluene (20 ml was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-ethyl-4-ethoxy-5-methylphenyl isocyanate (2.1 g). The thus obtained crude substance was added to an isopropanol solution (20 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3-ethyl-4-ethoxy-5-methylphenyl)carbamate (Compound No. 93) ((2.4 g) in a yield of 91% (calculated from the starting 3-ethyl-4-ethoxy-5-methylaniline). M.P., 68°- 69.5° C.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:14][P:15]([NH:22][CH:23]([CH2:25][CH3:26])[CH3:24])([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])=[S:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=O>C(O)C>[CH:23]([NH:22][P:15]([CH2:14][NH:5][CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])=[S:16])([CH2:25][CH3:26])[CH3:24]
Reactant: CCCCOC(=O)CN(CP(=S)(NC(C)CC)NC(C)CC)C(=O)C(F)(F)F
Solvent: CCO
Product: CCCCOC(=O)CNCP(=S)(NC(C)CC)NC(C)CC
Temperature: 0 °C
Yield: 23.9 %

Procedure:
N-trifluoroacetyl-N-[bis(sec-butylamino)phosphinothioylmethyl]glycine, butyl ester (4 g, 8.9 mm), was dissolved in ethanol (30 ml) and cooled to 0° C. on an ice bath. The solution was stirred and sodium tetrahydrido boron (339 mg, 8.9 mm) was added portionwise over a ten minute period. The solution was allowed to warm to room temperature and stirred for an additional 45 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel with 5% diethyl ether in dichloromethane (V:V) to yield N-[bis(sec-butylamino)phosphinothioylmethyl]glycine, butyl ester (750 mg), as a yellow oil, ND25 =1.708 and having the following analysis: Calculated: C, 49.93; H, 9.70; N, 11.65. Found: C, 50.11; H, 9.49; N, 11.60.
Reaction SMILES: C[S:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:4]([SH:2])[CH:5]=[N:6]2
Reactant: COc1cccc2ncc(S(C)=O)cc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2ncc(S)cc12
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylsulfinyl)-5-methoxyquinoline (2.21 g, 10 mmol) in CH2Cl2 (50 mL) is added TFAA. The resulting solution is stirred at 20-50° C. for 1 hour. The solution is then treated with NEt3 affording the title compound.
Reaction SMILES: O.[Cl:2][C:3]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].I[CH3:14].[H-].[Na+]>CN(C)C=O>[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH3:14])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)c(Cl)c1
Reaction time: 16 h
Yield: 62.5 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid hydrate (2.0 g, 12 mmol), iodomethane (2.9 mL, 46 mmol) and N,N-dimethylformamide (50 mL) was added sodium hydride (1.9 g, 46 mmol; 60% dispersion in mineral oil) in one portion. After stirring the mixture vigorously for 16 h, the reaction was quenched with water and washed with ethyl acetate. The aqueous layer was then acidified with aqueous hydrogen chloride (6N) to give a white precipitate. The mixture was filtered, washed with water, and the filter cake was dried in a vacuum oven to give the desired acid as an off-white solid (1.4 g, 65%). MS (ESI) 187.1, 189.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:22].[K+].[K+].OP([O-])([O-])=O.C(OCC)C>CN(C)C=O.O>[CH3:8][C:7]1[C:2](=[O:1])[C:3]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH3:10])[C:5](=[O:22])[C:6]=1[CH3:9]
Reactant: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC1=C(C)C(=O)C(C(O)CCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4 in the free form) (0.32 part) in dimethyl formamide (20 volume parts) was added all at once a mixture of Fremy's salt (0.5 part) and potasium biphosphate (0.5 part) in water (50 volume parts). The mixture was stirred for 3 hours at room temperature. The reaction product was taken up with diethyl ether. The diethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with ethyl acetate-diethyl ether (4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (formula IV-3 wherein R=H3C, n=4, in the free form) (0.26 part) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:8]2=[O:21])#[N:2].Cl.Cl.[NH2:26][CH2:27][C:28]12[CH2:35][NH:34][CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][C:28]12[CH2:35][N:34]([C:4]3[C:3]([C:1]#[N:2])=[C:12]4[C:7]([C:8](=[O:21])[CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]4[CH:13]4[CH2:15][CH2:14]4)=[CH:6][C:5]=3[F:22])[CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2
Reactant: CCOC(=O)c1cc(=O)c2cc(F)c(F)c(C#N)c2n1C1CC1
Reactant: NCC12CNCC1CCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(=O)c2cc(F)c(N3CC4CCOC4(CN)C3)c(C#N)c2n1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
350 mg (1.21 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro4-oxo-quinolinecarboxylate and 260 mg (1.2 mmol) of (1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochloride in 30 ml of absolute acetonitrile are admixed with 470 mg (4.64 mmol) of triethylamine and stirred at room temperature overnight. The mixture is concentrated and the residue is purified chromatographically (silica gel; dichloromethane/methanol 9:1). 450 mg (86% of theory) of ethyl 7-([1SR,5RS]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate are isolated, melting point: 193° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([NH2:9])[CH3:8].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1>C1COCC1.C(#N)C>[CH2:7]([NH:9][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]([C:20]([F:23])([F:21])[F:22])[CH:12]=1)[CH3:8]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCNc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
K2CO3 (4.15 g, 30.01 mmol), and 2.0 M solution of EtNH2 (15 mL, 30.01 mmol) in THF are added o a solution of 4-chloro-5-nitro-2-trifluoromethyl-pyridine (3.4 g, 15.0 mmol) in acetonitrile (30 mL) under cold conditions. The reaction is complete after stirring at 0° C. for 2 h. Usual work up affords ethyl-(5-nitro-2-trifluoromethyl-pyridin-4-yl)-amine as an yellow-orange viscous oil. 1H NMR (300 MHz, CDCl3): δ 9.24 (s, 1H), 7.09 (s, 1H), 3.45 (t, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH:12]([C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=1)[C:13](=O)[CH3:14]>O1CCOCC1>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:10][C:13]=2[CH3:14])=[CH:21][C:20]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: NC(=S)Nc1cnccn1
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 70 °C

Procedure:
Pyrazin-2-yl-thiourea (1a) (0.07 g, 0.57 mmol) is added to a stirred solution of 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b) (0.15 g, 0.46 mmol) in 1,4-dioxan (10 ml) at room temperature. The reaction mixture is heated to 70° C. for 2 h. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].[CH3:22][C:23]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26]C[O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:32][C:23]1([CH3:22])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:26][O:24]1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: CC1(C)OCC[C@H](CON)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (25 mL) is added to the product of Example 31, Step D, (R)-O-(2,2-dimethyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine (0.38 g, 2.57 mmol), triethylamine (0.54 mL, 3.85 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.34 g, 2.57 mmol) and allowed to stir at ambient temperature for 90 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate, then 3:1 hexanes/ethyl acetate affording a white foam (0.515 g, 56.7%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([Br:24])[C:11]2=[O:25])=[CH:6][CH:5]=1.CN1CC[O:30][CH2:29][CH2:28]1.C(Cl)(=O)C.CN=C=O>CN(C)C=O.ClCCl>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:29](=[O:30])[CH3:28])=[CH:5][CH:6]=2)[C:11](=[O:25])[C:12]=1[Br:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reactant: CN1CCOCC1
Agent: CN=C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one hydrochloride (0.150 g, 0.389 mmol) was dissolved in N,N-dimethylformamide (3.5 mL). A stock solution of 4-methylmorpholine in N,N-dimethylformamide (1.5 mL, 1.0 M) was added and the reaction stirred at room temperature for 10 minutes. A stock solution of acetyl chloride in N,N-dimethylformamide (3.0 mL, 0.2 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at 200 RPM for 2 hours at room temperature. At this time the reaction was diluted with dichloromethane (4 mL) and treated with approximately 1.8 g of polyamine resin (2.63 mmol/g) and approximately 0.8 g of methylisocyanate functionalized polystyrene (1.7 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were further rinsed with dichloromethane (3×5 mL) and combined with the partially concentrated filtrate. The resulting filtrate was concentrated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) to give an off-white solid (0.083 g, 50%). 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J=7.79 Hz, 1H), 7.48-7.29 (m, 9H), 6.55 (d, J=7.79 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H), 1.98 (s, 3H). ES-HRMS m/z 427.0625 (M+H C21H19BrN2O3 requires 427.0652).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][CH2:7][C:5]1[S:6][C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=2)=[CH:3][CH:4]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1

Procedure:
In analogy to example 1, step 3, N-(5-bromo-thiophen-2-ylmethyl)-2-chloro-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 440.3 ([M−H]−)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.C(OC(C)C)(C)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[OH:1]
Reactant: COc1cc2ncc(C(=O)O)c(O)c2cc1OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)OC(C)C
Product: COc1cc2nccc(O)c2cc1OC
Temperature: 250 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
A mixture of 9.24 g of 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylic acid in 185 cm3 of diphenyl ether was maintained, with mechanical stirring, at a temperature in the region of 250° C. for 1.3 hours. After cooling the reaction mixture to about 20° C., 100 cm3 of diisopropyl ether were added. The suspension was stirred for 8 hours and filtered, and the filter cake was washed with 3 times 100 cm3 of diisopropyl ether. 7.96 g of 6,7-dimethoxyquinolin-4-ol were obtained in the form of a brown solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([NH2:38])(=[O:37])[CH2:35]O>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:35][C:34](=[O:37])[NH2:38])=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: NC(=O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 15.5 g (0.05 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 8.50 g (0.052 mol) of 1.1'-carbonyldiimidazole in 350 ml of tetrahydrofuran is stirred at room temperature for 2 hours and 4.00 g (0.052 mol) of glycolamide are added thereto. After stirring at room temperature overnight, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatoqraphy on silica gel with methylene chloride-methanol (20:1) and crystallization from ethyl acetate/ether gives carbamoylmethyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate as white crystals with melting point 114-116°.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N)CCCCCCCCCCC.[C:33]1(=O)[O:37][CH2:36][CH2:35][CH2:34]1>O>[CH2:1]([N:19]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: CCCCCCCCCCCCN
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN1CCCC1=O
Yield: 96 %

Procedure:
The procedure described in Example I was repeated except that octadecylamine (Armeen 18D) was substituted for n-dodecylamine and the product was stripped of water and excess butyrolactone and was discharged at about 75° C. to provide 96% pure N-octadecyl-2-pyrrolidone solid in a yield of 96%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([NH:23][NH2:24])[N:12]=1.[N:25]([O-])=O.[Na+]>CC(O)=O>[N:23]([C:13]1[N:12]=[C:11]([O:10][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=1)=[N+:24]=[N-:25]
Reactant: O=N[O-]
Reactant: NNc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
As shown in Scheme 1 above, to a solution of 2-[2-(pyridin-2-yloxy)-ethoxy]-6-hydrazino-4-morphlinopyrimidine (4.98 g, 15.00 mmol, 1.00 equiv.) in 40 mL HOAc was added NaNO2 (1.553 g, 22.50 mmol, 1.50 equiv.) in six portions over a period of 1 hour. The reaction mixture was stirred at room temperature for 1 hour, and subjected to usual workup to yield 6-azido-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine as green viscous oil (5.0 g, 14.57 mmol, 97% yield). This oil was dissolved in 80 mL THF, and subjected to hydrogenation in the presence of 10% Pd on carbon (0.775 g of 10% Pd/C, 0.73 mmol, 0.05 equiv.) to yield 6-amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine as light yellow solid (4.25 g, 13.4 mmol, 89% total yield).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[CH3:10][C@@H:11](O)[CH2:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:11]([CH3:10])[CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC[C@@H](C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methanesulphonic anhydride (8.33 g, 47.8 mmol) in dichloromethane (30 ml) was added dropwise over 30 minutes to an ice-cooled solution of (R)-2-butanol (4.0 ml, 43.5 mmol) and triethylamine (6.65 ml, 47.8 mmol) in dichloromethane (70 ml). The reaction was then allowed to warm to room temperature and stirred for 18 hours. The mixture was then washed with water, 2N hydrochloric acid, then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a pale yellow oil, 7.0 g.
Reaction SMILES: [CH2:1]([C:8]1[C:9](I)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:24](=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH:24]([OH:28])[CH:25]([CH3:27])[CH3:26])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Ic1nc2ccccc2cc1Cc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(O)c1nc2ccccc2cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-benzyl-2-iodoquinoline 11 (1 eq., 1.45 g) in dry tetrahydrofuran (20 ml) at −78° C., was added isopropyl magnesium chloride (3 eq., 6.3 ml). The color of the solution was changed from green to orange in 1 h. Isobutyraldehyde 12 (3 eq., 1.15 ml) was added and the reaction mixture was allowed to warm up to room temperature and stirred for another hour. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography to yield 150 mg of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-ol 13.