Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CN(C)C=O>[O:19]=[C:13]1[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[C:11]2[CH2:30][CH2:31][C:32](=[O:33])[C:10]=2[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]1[CH2:15][C:16](=[O:18])[N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: C1CSCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)N2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 30 mg, 66 μmol) and triethylamine (30 μL, 0.22 mmol) in N,N-dimethylformamide (1.25 mL) is treated with N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (21 mg, 66 μmol) and stirred at room temperature for 15 min. This mixture is then added to a solution of thiomorpholine (13 mg, 0.13 mmol) in N,N-dimethylformamide (0.25 mL) and stirred for 72 h. The mixture is filtered and the filtrate is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of methanol in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=541; Retention time HPLC: 1.17 min (001_CA03).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]([CH3:59])[C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:52](=[O:53])[C@H:51]([C:55]([CH3:57])([CH3:56])[CH3:58])[NH:50][C:48](=[O:49])[N:47]([CH3:59])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 63C (0.013 g, 0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.022 g, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75(m, 9H), 0.78(m, 9H), 1.35-1.22(m, 1H), 1.65-1.54(m, 1H), 2.77-2.60(m, 4H), 2.79(s, 3H), 3.57(s, 3H), 3.83-3.77(m, 1H), 3.94-3.83(m, 1H), 4.09-4.06(d, J=8.82 Hz, 1H), 4.21-4.10(m, 1H), 4.51-4.38(m, 2H), 4.77-4.75(d, J=5.52 Hz, 1H), 5.43-5.40(d, J=8.82 Hz, 1H), 6.85-6.82(d, J=9.52 Hz, 1H), 7.26-7.10(m, 10H), 7.35-7.30(m, 1H). 3H), 7.60-7.57(d, J=9.19, 1H), 7.79-7.77(d, J=7.72 Hz, 1H), 7.93-7.82(m, 4H), 8.65-8.62(m, 1H).
Reaction SMILES: [Li].[CH3:2][C:3]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([CH3:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.O>O1CCCC1>[CH3:9][C:3]([NH:10][S:11]([CH2:14][CH:21]([OH:22])[C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:13])([CH3:2])[CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)CC(C)(C)NS(C)(=O)=O
Reactant: O=Cc1cccnc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
nButyl lithium (1.6M in hexanes) (31.3 mL, 50 mmol) was added dropwise to N-(1,1,3,3-tetramethyl-butyl)-methanesulfonamide (5.23 g, 25 mmol) in tetrahydrofuran (30 mL) at −78° C. under an atmosphere of nitrogen. The mixture was warmed to 0° C. for 30 minutes then cooled to −78° C. 3-Pyridine carboxaldehyde (2.4 mL, 25 mmol) in tetrahydrofuran (20 mL) was added dropwise to the mixture over 20 minutes and the mixture was warmed to room temperature and stirred for a further 1 hour. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (2×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a pale yellow solid. The solid was washed with dichloromethane (10 mL) in heptane (100 mL) to afford 2-hydroxy-2-pyridin-3-yl-ethanesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide as a pale yellow solid (5.67 g, 72%).
Reaction SMILES: [O:1]=[C:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=O.C(N=C=NCCCN(C)C)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:24]([N:26]([CH2:27][CH3:28])[C:3](=[O:5])[C:2](=[O:1])[CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH3:25]
Reactant: O=C1CCC(C(=O)C(=O)O)CC1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Compound 13 was synthesized starting from treating oxo-(4-oxo-cyclohexyl)-acetic acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 eq.) and 4-dimethylaminopyridine (catalytic amount) in DMF. After stirring at room temperature for approximately 10 min., the reaction mixture was cooled in an ice-bath and diethylamine (1.5 eq.) was added. The resulting mixture was stirred at room temperature for 5 hours with TLC monitoring. The solvent was removed by evaporation. The residue was diluted with EtOAc and washed with H2O twice. The aqueous then was extracted with EtOAc and the organic layer was dried over Na2SO4. The desired intermediate N,N-diethyl-2-oxo-2-(4-oxo-cyclohexyl)-acetamide was obtained after purification through a combiflash chromatography system using a silica gel cartridge and CH2Cl2/MeOH gradient eluent, which further condensed with 3-hydroxybenzaldehyde (2.5 eq.) by following the same procedure described above to get the desired product as a yellow solid ESI MS m/z: 406.51 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ: 7.54 (s. 2H, benzylidene CH═), 7.25 (t, 2H, J=7.8 Hz, aromatic ring H), 6.93-6.89 (m, 4H, aromatic ring H), 6.81-6.78 (m, 2H, aromatic ring H), 3.23 (q, 4H, J=7.2 Hz, —NCH2CH3), 2.95 (m, 4H, 4-oxo-cyclohexyl-H-2, 6), 2.54 (m, 1H, cyclohexyl-H-1), 0.94 (m, 6H, —NCH2CH3).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCCCN1C=[N+](C)C=C1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Ni+2]>[CH2:1]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccccc1
Reactant: C=CCCCCCC
Agent: [Ni+2]
Agent: CCCCn1cc[n+](C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCc1ccccc1
Temperature: 60 °C

Procedure:
Nickel(II) bis-triflimide (0.06 g, 0.1 mmol) was dissolved in [bmim] [NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser. Benzene (3.90 g, 50 mmol) and oct-1-ene (1.12 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by gas chromatographic analysis as in previous examples. The oct-1-ene peak disappeared and three isomers of octylbenzene were formed (70%, 20:26:54 2- to 3- to 4-isomer ratio) as well as octene dimer (30%). The less dense product phase was decanted from the ionic/catalyst phase and purified by Kugelrohr distillation. The ionic liquid and catalyst were prepared for reuse by heating at 60° C. under vacuum for 1 hour. The ionic liquid and catalyst were used for further reactions of benzene with oct-1-ene without loss of activity. This is an alkylation of benzene with an alkene using a metal bis-triflimide catalyst. Benzene and oct-1-ene react in the presence of 1% nickel(II) bis-triflimide in [bmim] [NTf2] to form three isomers of octyl benzene and a small amount of hexadecene (unknown isomeric distribution). This reaction shown below:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH2:11]O)[CH3:2].O=S(Cl)[Cl:15]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:15][CH2:11][C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(CC)c1CO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a mixture of (2,6-diethylphenyl)methanol (1.83 g, 11.1 mmol), toluene (20 mL) and DMF (6 drops) was added SOCl2 (2.1 g, 1.6 eq). The resulting solution was stirred at RT (1 h). After evaporating to dryness, the residue was taken up in heptane (˜50 mL) and washed with water (˜5 mL), dried (Na2SO4), filtered and evaporated to give 1.97 g (yield of 97%) of title product. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, 6H), 2.79 (q, 2H), 4.70 (s, 2H), 7.09 (d, 2H), 7.20 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[CH3:11].NOS(O)(=O)=O.CO.[N:20]1C=CC=[CH:22][CH:21]=1>COC(OC)(N(C)C)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][N:20]=[C:21]([CH3:22])[N:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: c1ccncc1
Reactant: Cc1cc(C(N)=S)ccc1Br
Agent: COC(C)(OC)N(C)C
Agent: NOS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1nsc(-c2ccc(Br)c(C)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromo-3-methylbenzenecarbothioamide (1.20 g) in dimethylacetamide dimethyl acetal (2 ml) and dichloromethane (30 ml) was stirred under nitrogen at room temperature for 7 h. The solvent was evaporated in vacuo to give a dark brown oil to which was added hydroxylamine-O-sulphonic acid (0.88 g), methanol (20 ml) and pyridine (0.83 ml) and the mixture stirred at room temperature under nitrogen for 16 h. After evaporation, aqueous potassium carbonate was added and the mixture was extracted with dichloromethane. The combined extracts were dried and evaporated to give a brown residue which was purified by column chromatography on silica eluting with hexane:ethyl acetate (4:1) to give the title compound as an orange solid (0.8 g). T.l.c.hexane:ethyl acetate (4:1), Rf=0.52
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (350 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (196 mg), potassium carbonate (260 mg) and N,N-dimethylformamide (4 ml) was stirred at 50° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (400 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To an oven dried 250 mL round bottom flask containing 5.0 g (25.73 mmol) 5-tert-butyl-2-methoxy-benzene-1,3-diamine, 150 mL DCM was added. The reaction mixture was cooled to 0° C. after which triethylamine (5.0 mL, 36.0 mmol) was added followed by the drop wise addition of methylsulfonyl chloride (1.99 mL, 25.7 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature stirring for an additional 2 h. The reaction mixture was poured over saturated solution of sodium bicarbonate (100 mL) and the layers separated. The aqueous layer was washed twice more with 50 mL dichloromethane and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum to afford a crude oil that was purified by flash chromatography (silica gel, 1:1 EtOAc:Hex) to yield 6.1 g of the desired product (87%). Calculated mass=272. Observed mass=273
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.C1(C)C=CC=CC=1.Cl>O>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.254 part), zinc amalgam (0.56 part), toluene (1 volume part), 35% hydrochloric acid (0.5 volume part) and a small proportion of water were refluxed for 5 hours. The toluene layer was separated and the water layer was extracted with diethyl ether. The toluene layer was combined with the ethereal layer, washed with water and dried. The solvents were then distilled off under reduced pressure and the residue was recrystallized from ligroine. The foregoing procedure provided 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formula II-2 wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.14 part) as colorless powdery crystals melting at 62.5°-66° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(#N)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.O>[O:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:2]3[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]4[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:27][C:28]=2[S:41]([CH3:44])(=[O:42])=[O:43])[CH2:40][CH2:39]1
Reactant: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)Nc1nc(-c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)cc2ncn(C)c(=O)c12
Temperature: 140 °C

Procedure:
7-Chloro-5-(isopropylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (60 mg, 0.24 mmol), crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(methylsulfonyl)-N-(2-morpholinoethyl)benzenamine (240 mg, ˜0.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and Na2CO3 (102 mg, 0.96 mol) in a mixed solvent of acetonitrile (4 mL) and H2O (4 mL) were added to a 20 mL microwave tube and sealed. The tube was then heated in a Microwave Reactor at 140° C. for 10 minutes. The solvent was removed and the crude product purified by silica column using 7% MeOH in DCM to give the final product as a pale solid. ESI-MS m/z 501.2 (MH+); 1H NMR (DMSO-d6) δ 8.71 (d, J=7.2 Hz, 1H), 8.46 (d, J=2.4 HZ, 1H), 8.40 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.77 (t, J=4.8 Hz, 1H), 3.59 (m, 4H), 3.42 (s, 3H), 3.33 (m, 4H), 3.20 (s, 3H), 2.62 (m, 2H), 2.44 (s, 3H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-].[Na+].[O-:22][CH2:23][CH3:24].[Na+]>>[CH2:23]([O:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: CC[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5.0 g), aqueous sodium hydroxide (5N, 80 ml) and industrial methylated spirit (10 ml) was boiled under reflux for 160 hours. Reaction was incomplete. The hot reaction mixture was filtered and the residue extracted with hot dimethylformamide (40 ml). The extract was evaporated to give a crude product. A mixture of this crude product and ethanolic sodium ethoxide (0.13 g sodium in 110 ml absolute ethanol) was boiled under reflux for 50 hours. The hot reaction mixture was filtered and the filtrate cooled in ice. The precipitate was collected and purified by flash chromatography on Kieselgel 60 using dichloromethane:industrial methylated spirit 9:1 as the eluent. The purified product was recrystallised from industrial methylated spirit to give the novel compound 7-ethoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 214°-217°.
Reaction SMILES: C(N1C(C(O)=O)CSC1(C)C)(=[O:8])C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:8]
Reactant: CC1(C)SCC(C(=O)O)N1C(=O)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 48 g. (181 mmole) of 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxylic acid, prepared by the procedure described by Example 1, in 1.5 l. of tetrahydrofuran were added 27.8 g. (181 mmole) of 1-hydroxybenzotriazole followed by 37.4 g. (181 mmole) of dicyclohexylcarbodiimide. The mixture was stirred for 30 minutes at room temperature. The reaction mixture developed into a thick slurry resulting from the precipitation of dicyclohexylurea. To the heavy slurry was added 63 g. (181 mmole) of benzyl D-4-benzyloxyphenylglycinate and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was filtered to remove the dicyclohexylurea, the filtrate evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and finally with water. The washed solution was dried, treated with carbon, and evaporated to dryness under reduced pressure to yield 107 g. (99% yield) of N-[α-(benzyl D-4-benzyloxyphenylacetate]- 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31]C(NC(=O)CC2C=CC=CC=2)=S)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15](NCCCOC(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.N[C@@H](CC)C[OH:47].NC1C=CC(OC2C3C(=CC(OC)=C(C(N[C@@H](CC)CO)=O)C=3)N=CC=2)=C(F)C=1>>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:25][CH3:26])=[C:12]([C:15]([OH:47])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC[C@H](N)CO
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCCOC(C)C
Agent: CC[C@@H](CO)NC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Yield: 81 %

Procedure:
Similar to the synthesis of compound 1, from compound 39c (300 mg), DMTMM•n-hydrate (329 mg), and (S)-2-aminobutan-1-ol (113 μL), compound 41a was yielded (297 mg, yield: 81%).
Reaction SMILES: FC(F)(F)C(O)=[O:4].S(=O)(=O)(O)O.[NH2:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:15]=1[C:16]#[N:17].[OH-].[NH4+]>O>[NH2:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:15]=1[C:16]([NH2:17])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(N)c(C#N)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc(N)c(C(N)=O)c(OC)c1
Temperature: 75 °C
Yield: 40.5 %

Procedure:
Trifluoroacetic acid (6.52 g, 4.4 mL) was charged to a flask equipped with a magnetic stirring bar and thermocouple. Sulfuric acid (96%, 9.2 g, 5 mL) was charged to the flask. In small portions 2-amino-4,6-dimethoxybenzonitrile (1.01 g, ˜76% pure) was charged to the mixed acid solution in the flask. A condenser was added and the solution was heated at 75° C. for 17 h. After the dark mixture had cooled to room temperature it was charged to water (9.79 g) cooled in a large ice bath while maintaining the reaction temperature below 10° C. Concentrated ammonium hydroxide (19.37 g) was added dropwise to the cooled solution (reaction temperature kept below 15° C.). The solution was then extracted two times with dichloromethane. The organic extracts were dried over MgSO4 and evaporated to yield the desired product (0.45 g) as a light brown solid.