Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.Br[C:19]1[N:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]([CH2:28][CH2:29][CH2:30][CH3:31])=[N:21][C:20]=1[C:32]#[N:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)CC>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[N:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]([CH2:28][CH2:29][CH2:30][CH3:31])=[N:21][C:20]=1[C:32]#[N:33]
Reactant: CCCCc1nc(C#N)c(Br)n1CC(C)C
Reactant: Nc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCCCc1nc(C#N)c(-c2ccccc2N)n1CC(C)C
Temperature: 100 °C
Yield: 843.4 %

Procedure:
Palladium (II) acetate (5.0 mg, 0.022 mmol), triphenylphosphine (17 mg, 0.067 mmol), water (2.6 mL), n-propanol (13 mL), and aqueous sodium carbonate (4.4 mL of 2 M) were added to 2-aminophenylboronic acid (1.11 g, 8.13 mmol) and 5-bromo-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (2.10 g, 1.00 mmol). The reaction was placed under a nitrogen atmosphere and heated at 100° C. for 15 hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional palladium (II) acetate (5.0 mg in 1 mL toluene) and triphenylphosphine (17 mg) were added. The reaction was heated at 100° C. for an additional 23.5 hours, and an analysis by LC/MS indicated the presence of starting material. Additional palladium (II) acetate (5.0 mg in 1 mL toluene), 2-aminophenylboronic acid (0.500 g), and aqueous sodium carbonate (2.2 mL of 2 M) were added, and the reaction was heated at reflux for an additional four hours and allowed to cool to room temperature. The reaction mixture was filtered to remove solid, and the filtrate was partitioned between 2M aqueous sodium carbonate and dichloromethane. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic fractions were dried over magnesium sulfate, treated with decolorizing carbon, filtered, and concentrated under reduced pressure to provide 2.5 g of 5-(2-aminophenyl)-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as a brown solid. The solid was recrystallized from a mixture hexanes (30 mL) and tert-butyl methyl ether (20 mL) after hot filtration to provide 1.51 g of product. A portion (0.48 g) was recrystallized from a mixture of hexanes (6 mL) and tert-butyl methyl ether (6 mL) to provide 5-(2-aminophenyl)-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[OH:10][CH2:9][C:3]1([CH3:2])[CH2:8][CH2:7][N:6]([C:12]2[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=2)[CH2:5][CH2:4]1
Reactant: CC1(CO)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(CO)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 25 °C

Procedure:
(4-Methylpiperidin-4-yl)methanol hydrochloride (2.09 g, 12.63 mmol), (2-chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and triethylamine (1.8 mL, 12.630 mmol) in ethanol (15 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to r.t. and concentrated in vacuo to give the title compound as an orange semi-solid. This material was used without any further purification. HPLC-MS: MH+ m/z 252.2, RT 0.34 minutes.
Reaction SMILES: [C:1]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(OCC)=[O:2].[BH4-].[Na+].O>C1COCC1>[OH:2][CH2:1][C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
3.5 grams (15 mmol) of 3-carboethoxy-β-carboline were suspended in 300 ml THF, 2.7 grams (75 mmol) sodium borohydride were added and the mixture was stirred at room temperature for 12 hours. The mixture was then cooled, 50 ml water were added and the resulting mixture was stirred overnight. The solvent was evaporated under reduced pressure and water (300 ml) was again added. The aqueous suspension was extracted with dichloromethane, followed by ethylacetate, the organic extracts were combined, and the solvent was evaporated under reduced pressure. The remaining residue was purified by column chromatography on silica gel, using and a 9:1 mixture of ethylacetate and methanol as eluent, to give 3-(hydroxymethyl)-β-carboline (2.5 grams, 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][N:30]1[CH2:31][C:27]([F:35])([F:26])[CH2:28][C@H:29]1[C:32]([OH:34])=[O:33])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CN2CC(F)(F)C[C@H]2C(=O)O)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.049 g, 0.11 mmol) and (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid (0.044 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4Cl solution and brine. The organic layer was separated and dried over Na2SO4. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 2) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.COCCOC.[F:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([S:49]([CH3:52])(=[O:51])=[O:50])[C:35]=1[CH2:53][OH:54].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=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].O>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])([CH3:19])[CH3:18])=[CH:6][CH:7]=2)[CH:37]=[C:36]([S:49]([CH3:52])(=[O:51])=[O:50])[C:35]=1[CH2:53][OH:54]
Reactant: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2F)n1
Reactant: CC1(C)OB(c2cc(F)c(CO)c(S(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2F)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a 50 mL round bottom flask was added 2-(1-(4-bromophenyl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (380 mg, 911 μmol), DME (25 mL) and H2O (6 mL). The solution was sparged with N2 for 10 min prior to addition of (2-fluoro-6-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (360 mg, 1.09 mmol), potassium carbonate (380 mg, 2.73 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (74 mg, 91 μmol). The reaction mixture was allowed to stir at 80° C. for 2 h. The cooled reaction solution was diluted with EtOAc (30 mL) and filtered through a Celite padded Buchner funnel. The filtrate was washed with aq NH4Cl (150 mL×2). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage SP-1, 25 g SiO2 column, gradient elution from 5% EtOAc to 100% EtOAc) to afford the title compound (100 mg, 20% yield). 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J=2 Hz, 1H), 7.51 (dd, J1=2 Hz, J2=10 Hz, 1H), 7.29 (d, J=9 2H), 7.08-7.16 (mult, 1H), 6.85-6.92 (mult, 3H), 6.77-6.84 (mult, 2H), 6.65 (s, 1H), 5.09 (d, J=6 Hz, 2H), 3.35 (s, 1H), 3.30 (2, 3H), 3.02 (t, J=6 Hz, 1H), 1.72 (s, 6H), 1.62 (s, 6H); 19F NMR (400 MHz, CDCl3) δ−112.1, −113.5 ppm; LCMS (ES) m/z=541.3 [M+H]+, 563.2 [M+Na]+.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21][CH2:22][CH2:23][CH2:24]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:24][CH2:23][CH2:22][S:21][CH3:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSCCCO
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (2.4 g) synthesized in Example A82(3) was dissolved in tetrahydrofuran (50 mL), and 3-(methylthio)propanol (1.0 mL), tributylphosphine (4.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (4.7 g) were added to the solution under ice-cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hr. Hexane (50 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.1 g, 95%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[OH:28])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH:31]1(Br)[CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:28][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:17])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: BrC1CCC1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2O)Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.17 h

Procedure:
A solution of 2-[(1-hydroxynaphthalene-2-carbonyl)amino]indan-2-carboxylic acid ethyl ester (289) (560 mg, 1.5 mmol) in dry DMF is treated with NaH oil dispersion (60%, 100 mg, 2.25 mmol, 1.5 eq) and stirred for 10 min. The cyclobutyl bromide (405 mg, 3 mmol, 2 eq) is added and the reaction heated and stirred in the microwave at 150° C. for 3 hours. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (75 mL) and washed with water (2×30 mL) and brine (30 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (200 g silica gel, 10% EtOAc in heptane) to give white solid. (290 mg, 45%)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[N:6]=1)[CH2:2][CH3:3].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)C1C=CC=CC=1.C(O)(=O)C>O>[CH:17](=[N:10][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[NH:9][N:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1
Reactant: CCCNc1nc(N)n[nH]1
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Solvent: O
Product: CCCNc1nc(N=Cc2ccccc2)n[nH]1

Procedure:
A 5-liter flask equipped with a reflux condenser, thermometer, and mechanical stirrer was charged with 251.8 g (1.75 mole) of N5-Propyl-1H-[1,2,4]triazole-3,5-diamine, 1.75 liter of toluene, 203.4 g (1.92 mole) of benzaldehyde and 5.2 g (0.087 mole) of acetic acid and then heated to reflux for 1˜3 hours. During the reaction, water was formed as by-product and removed azeotropically. After checking the end of the reaction by LC (peak area of N5-Propyl-1H-[1,2,4]triazole-3,5-diamine is less than 1%), the mixture was cooled down and gave the crude N3-Benzylidene-N5-propyl-1H-[1,2,4]triazole-3,5-diamine suspension solution, which was used for the next stage without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[N:10]3[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=[C:9]3[C:6]2=[N:7][CH:8]=1)[CH3:2].Cl.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(N(CC)CC)C.Cl>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[NH:10][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[C:5]([CH:4]=1)[C:11]([N:23]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH3:22])=[O:12])[CH3:2]
Reactant: CCc1cnc2c(c1)C(=O)N1C(=O)C(C)(C(C)C)N=C21
Reactant: CNCCCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)N(C)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 7-ethyl-2-isopropyl-2-methyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione (5.47 g, 20.19 mmol) in anhydrous N,N-dimethylformamide is treated successively with 4-(methylamino)butyric acid hydrochloride (3.29 g, 21.2 mmol) and triethylamine (4.29 g, 42.39 mmol). The resulting mixture is stirred at room temperature under nitrogen for 2.5 hours. After this period, the reaction mixture is diluted with water, acidified with concentrated hydrochloric acid and extracted with ether. The organic extract is dried over magnesium sulfate, vacuum filtered through diatomaceous earth and concentrated in vacuo to give the title product as a white solid, mp 42°-49° C. (dec.).
Reaction SMILES: [C:1]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([F:32])[CH:18]=1)[C:5]1[CH:6]=[C:7]([O:12]C(=O)C)[CH:8]=[CH:9][C:10]=1Br)(=[O:3])[CH3:2].C1(C)C(C)=CC=CC=1.C([Sn](CCCC)(CCCC)[C:46]1[S:47][C:48]2[CH:54]=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=1)CCC.C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[S:47]1[C:48]2[CH:54]=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=[C:46]1[C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][C:5]=1[N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([F:32])[CH:18]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A mixture of acetic acid 3-{acetyl-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-4-bromophenyl ester (50 mg) and dichlorobis(triphenylphosphine)palladium (II) (7 mg), xylene (1 ml) and 2-tributylstannylbenzothiazole (84 mg) was refluxed for 1.5 hours. The reaction mixture was cooled at room temperature, methanol (2 ml), water (1 ml) and potassium carbonate (50 mg) was added thereto, and the solution was vigourously stirred for 15 minutes at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, then dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.CN(C)C(=O)C.C(Cl)([Cl:20])=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([Cl:20])=[O:11])=[C:6]([CH3:8])[N:7]=1
Reactant: COc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1nc(C)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.4 g (0.06 mole) of 2-methoxy-4-methylthiazole-5carboxylic acid were suspended in 150 ml of tetrahydrofuran, followed by the addition of 0.02 g of N,N-dimethyl-acetamide. Under heating and reflux, phosgene was blown at a rate of 1.1 l/hr for 4.5 hours (0.23 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.8 g of 2-methoxy-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.2% and 93.9%, respectively.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27](O)=[O:28])([CH3:23])[CH3:22]>>[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27]([N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:11]([S:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH2:18]1)=[O:28])([CH3:23])[CH3:22]
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(c2)CNCC3)CC1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (CA [741674-53-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 536.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[S:7][C:6](=[S:8])[N:5]=[N:4]1.C(=O)(O)[O-].[Na+].[Na].C(O[CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:38])[CH:24]2[NH:28][C:29](=[O:37])[CH2:30][C:31]2[S:32][C:33](=[O:36])[S:34][CH:35]=2)[C:21]=1[C:39]([OH:41])=[O:40])(=O)C.C.Cl>O.C(OCC)(=O)C>[C:39]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:20]=1[CH2:19][S:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)[CH:24]([NH:28][C:29](=[O:37])[CH2:30][C:31]1[S:32][C:33](=[O:36])[S:34][CH:35]=1)[C:23]2=[O:38])([OH:41])=[O:40]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: COC1N=NC(=S)S1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 50 °C
Yield: 10.3 %

Procedure:
5-Methoxy-2-thioxo-1,3,4-thiadiazoline (4.43 g.) and sodium bicarbonate (2.27 g.) in water (20 cc.) are added to the sodium salt of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (12.2 g.) in a buffer (100 cc.) of pH 6.5. The mixture is heated under a nitrogen atmosphere to 50° C., for 5 hours. It is allowed to cool and treated with decolourising charcoal. Ethyl acetate (100 cc.) is added and the mixture is brought to pH 2.5 by adding 5 N hydrochloric acid while stirring. The organic phase is separated off and the aqueous phase is again extracted with ethyl acetate (160 cc.). The combined organic extracts are dried over sodium sulphate, treated with decolourising charcoal and then concentrated to dryness under reduced pressure (20 mm.Hg). A residue (11.5 g.) is obtained, and is triturated with acetonitrile (8 cc.) and isopropyl ether (8 cc.). A solid (2.4 g.) is filtered off and recrystallised from acetonitrile (375 cc.) and isopropyl ether (400 cc.) to give 2-carboxy-3-[(5-methoxy-1,3,4-thiadiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (1.52 g.) m.p. 208° C.
Reaction SMILES: C([O:9][C:10]1[C:11]([OH:37])=[N:12][C:13]([C:20]23[N:26]([C:27](OCC4C=CC=CC=4)=O)[CH:23]([CH2:24][CH2:25]2)[CH2:22][CH2:21]3)=[N:14][C:15]=1[C:16]([O:18]C)=O)(=O)C1C=CC=CC=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1.[BH3-]C#N.[Na+].C(O[Na])(C)=O.C=O>CO.[Pd]>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:16]([C:15]2[C:10]([OH:9])=[C:11]([OH:37])[N:12]=[C:13]([C:20]34[N:26]([CH3:27])[CH:23]([CH2:22][CH2:21]3)[CH2:24][CH2:25]4)[N:14]=2)=[O:18])=[CH:41][CH:40]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C23CCC(CC2)N3C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: [Pd]
Agent: C=O
Agent: CC(=O)O[Na]
Solvent: CO
Product: CN1C2CCC1(c1nc(O)c(O)c(C(=O)NCc3ccc(F)cc3)n1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl 1-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (C-39) in methanol was hydrogenated under H2 atmosphere in presence of Pd/C 10% (10% w/w) at room temperature for 2 hours. After filtration and evaporation, the crude was dissolved in MeOH and p-fluorobenzylamine (3.5 eq.) added. After being refluxed overnight, the residue was washed with Et2O/EP. The solid was dissolved in MeOH and NaCNBH3 (1.4 eq.), AcONa (1.6 eq.), HCHO 37% (1 eq.) were added. The reaction mixture was stirred at room temperature overnight. The product was purified by preparative HPLC (C18, gradient CH3CN/H2O+0.01% TFA) to obtain the title compound (C-40) as trifluoro acetate salt.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[Cl:46][C:47]1[N:51]2[C:52]([CH2:57][C:58]3[CH:59]=[CH:60][C:61]([F:65])=[C:62]([NH3+:64])[CH:63]=3)=[CH:53][NH:54][C:55](=[O:56])[C:50]2=[CH:49][C:48]=1[Cl:66]>CN(C1C=CN=CC=1)C.CN(C=O)C.O.CC#N>[Cl:46][C:47]1[N:51]2[C:52]([CH2:57][C:58]3[CH:59]=[CH:60][C:61]([F:65])=[C:62]([NH:64][C:12]([CH:10]4[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]4)=[O:14])[CH:63]=3)=[CH:53][NH:54][C:55](=[O:56])[C:50]2=[CH:49][C:48]=1[Cl:66]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: [NH3+]c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-Boc-Azetidine-3-carboxilic acid (1.35 eq), HATU (1.35 eq) and DMAP (1.35 eq) in DMF (0.1 M) was stirred at RT for 20 min and then Example 14, N2 (1 eq) was added. The mixture was stirred overnight at RT and the product was isolated by purification by prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were evaporated to afford the desired compound. 1H NMR (300 MHz, DMSO-d6) δ: 10.89 (1H, d, J=5.6 Hz), 9.80 (1H, s), 7.78-7.69 (1H, m), 7.23-7.14 (2H, m), 7.00-6.91 (1H, m), 6.52 (1H, d, J=5.8 Hz), 4.31 (2H, s), 4.00-3.85 (3H, m), 3.62-3.49 (1H, m), 1.38 (9H, s). MS (ES) C23H23Cl2FN4O4 requires: 508, found: 509 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][N:14]=1.[OH-].[Na+]>C(O)(=O)C.ClCCl.O>[CH3:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][N+:14]=1[O-:9]
Reactant: Cc1nsc2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c2cccnc2s[n+]1[O-]
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of m-chloroperbenzoic acid (160 mmol) in acetic acid (200 mL) was added dropwise to a solution of 3-methylisothiazolo[5,4-b]pyridine (107 mmol) in dichloromethane (200 mL). The reaction mixture was maintained for 6 h at 25° C. The reaction mixture was diluted with water (100 mL), the pH was adjusted to 8 with 10% sodium hydroxide, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide 3-methylisothiazolo[5,4-b]pyridine-N-oxide in 62% yield as a yellow solid.