Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[CH:20]([NH:34][C:35](=[O:65])[C:36](=[N:62][O:63][CH3:64])[C:37]1[N:38]=[C:39]([NH:42]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:40][CH:41]=1)[C:19]2=[O:66])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.O>[NH2:42][C:39]1[S:40][CH:41]=[C:37]([C:36](=[N:62][O:63][CH3:64])[C:35]([NH:34][CH:20]2[C:19](=[O:66])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH2:25][C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27])=[C:17]3[C:15]([OH:16])=[O:14])=[O:65])[N:38]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CC(=O)c3ccccc3)CSC12)c1csc(N)n1
Temperature: 45 °C
Yield: 36.3 %

Procedure:
The syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4yl)-acetamido]-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.7 g) is dissolved in formic acid (55 cc) at 20° C. Distilled water (11 cc) is added and the mixture is heated for 15 minutes at 45° C. The mixture is cooled to 20° C., diluted with water (44 cc) and filtered. The filtrate is concentrated to dryness under reduced pressure (5 mm Hg; 0.67 kPa) at 20° C. The residue is taken up in ethanol (3×50 cc), the solvent being evaporated off each time under reduced pressure (5 mm Hg; 0.67 kPa) at 20° C. in order to remove the water and the formic acid. The final residue is taken up in a saturated solution of sodium bicarbonate (50 cc) and the aqueous phase is washed with ethyl acetate (50 cc) and acidified to pH 3 with 1N hydrochloric acid, whilst stirring, in the presence of ethyl acetate (100 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.54 g) in the form of a beige solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:11][CH:12]=1)(=O)=O.[OH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:23][C:22]([F:25])([F:24])[C:19]1[N:17]2[N:18]=[C:13]([N:10]3[CH2:11][CH:12]=[C:7]([C:33]4[CH:34]=[C:29]([OH:28])[CH:30]=[CH:31][CH:32]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: O=S(=O)(OC1=CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1)C(F)(F)F
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(C2=CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 72 %

Procedure:
Obtained in 72% yield by an analogous procedure to Example 605, starting from 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate and 3-hydroxyphenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:13]=1[NH2:27]>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nc(Cl)c(N)c(Nc2ccc(Cl)cc2)n1
Solvent: c1ccncc1
Product: Cc1nc(Cl)c(NC(=O)c2ccccc2F)c(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-Fluorobenzoyl chloride (93 μl, 0.78 mmol) was added to 6-chloro-N4-(4-chlorophenyl)-2-methylpyrimidine-4,5-diamine I-(7A-80)a (173 mg) and pyridine (1 ml) and stirred at room temperature for 7 h. The reaction was incomplete at this time so an additional 1.5 equivalents of 2-fluorobenzoyl chloride was added to the reaction mixture and continued stirring overnight at room temperature. The reaction was extracted from saturated NaHCO3 solution into ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness to afford the desired crude product I-(7A-80)b (0.25 g): +ESI MS (M+1) 391.2.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][CH:24]=3)[CH:21]=2)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3[I:1])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3nccc3cn2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cn3ncc(I)c3cn2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
N-iodosuccinimide (13 mg, 0.06 mmol) was added in one portion to a stirred solution of 6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrazine (11 mg, 0.05 mmol) in dry DMF (0.5 ml) at RT under N2. After 30 minutes, a further portion of N-iodosuccinimide (13 mg, 0.06 mmol) in DMF (0.2 mmol) was added. After a further 30 minutes at RT the mixture was heated to 50° C. for 90 minutes. After cooling to RT, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated NaHCO3 (1:1, 1 ml). The mixture was stirred at RT for 1 hour then partitioned between CH2Cl2/H2O. The mixture was passed through a phase separating cartridge. The organic layer was evaporated to give the title compound (13 mg, solid). 1H NMR (400 MHz, CDCl3): 9.01 (1H, d), 8.69 (1H, d), 8.05 (1H, s), 8.00-7.90 (2H, m), 7.24-7.14 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>O1CCOCC1.CCOC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCC(O)CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCC(O)CO)nc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-1,2-propanediol (4.93 g, 54.1 mmol) and 6-chloronicotinonitrile (1.50 g, 10.8 mmol) was prepared in anhydrous dioxane (20 mL), and then stirred at RT for hours and 80° C. for additional hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with a half saturated solution of brine (2×50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (2×50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by trituration in hot MTBE (10 mL) and filtration, the title compound was obtained as a white powder (970 mg, 46%). UPLC/MS, M+(ESI): 193.9, M−(ESI): 192.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([OH:19])[C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[CH:5][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([O:19][CH2:30][CH2:31][CH3:32])[C:17]=3[N:18]=2)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 37.4 %

Procedure:
5.9 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyloxazolo[5,4-d]pyrimidin-7-ol were dissolved in 150 ml of N,N-dimethylformamide, and 7.7 g of potassium carbonate and then 2.7 g of 1-bromopropane were added. The solution was stirred at 60° C. for 5 h and then, after cooling, poured into 150 ml of water. The precipitate was filtered off with suction. The regioisomer mixture obtained was purified by silica gel chromatography (50 g silicon dioxide solute cartridge, heptane/ethyl acetate 9/1). In addition to 1.4 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-6-propyl-6H-oxazolo[5,4-d]pyrimidin-7-one (LC/MS (Method LC1): Rt=1.43 min; m/z=360.13 [M+H]+), 2.5 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6](=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([O:1][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH:3]=2)[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: Fc1ccc(Br)nc1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cn3)c2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of tert-butyl-4-(3-hydroxybenzylidene)piperidine-1-carboxylate (0.500 g; Example 57, Step 3), 2-bromo5-fluoropyridine (0.456 g, 1.50 equiv), cesium carbonate (1.13 g, 2.01 equiv), and tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.058 g, 0.090 equiv) in toluene (9 mL, 0.2 M) was heated to 100° C. in a Biotage Personal microwave for 10 minutes. The reaction mixture was filtered through Celite, and the Celite was washed with dichloromethane. The filtrate was concentrated and purified on 60 g silica gel using a gradient eluent consisting of 0-10% ethyl acetate/dichloromethane over 60 minutes to give the title compound as a white solid. 0.274 g, 41% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (9H, s), 2.31 (2H, t, J=5.8 Hz), 2.45 (2H, t, J=5.4 Hz), 3.39 (2H, t, J=5.9 Hz), 3.49 (2H, t, J=5.9), 6.33 (1H, s), 6.85-6.98 (3H, m), 7.02 (1H, d, J=7.6 Hz), 7.33 (1H, t, J=7.8 Hz), 7.40-7.47 (1H, m), 8.03 (1H, d, J=3.1 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=1[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=4[CH3:40])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CSc1ccc(Br)c(C)c1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (150 mg), 1-bromo-2-methyl-4-methylsulfanyl-benzene (60 mg), in N,N-dimethylformamide (3 mL) a 2 M aqueous Na2CO3 solution (0.29 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (19 mg) is added. The resulting mixture is stirred for 6 h at 90° C. After cooling to room temperature, water and methanol are added and the aqueous phase is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by HPLC on reversed phase (MeOH/H2O/TFA). Yield: 56 mg (56% of theory); LC (method 2): tR=1.70 min; Mass spectrum (ESI+): m/z=426 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].CC1C=CC=C(C)C=1NC(=O)CN1CCNCC1>>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:29][C:28]1=[O:33]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Agent: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Product: Cc1nc2cc(OCC(O)CN3CCN(CC(=O)Nc4c(C)cccc4C)C(=O)C3)ccc2s1

Procedure:
Compound 64 was prepared in the manner of compound 7 substituting compound 33 for compound 6 and compound 32 for compound 5 in part D of compound 7: Mass Spectrum (MH+)=483.3
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[S:9][C:8]=1[C:23]#[N:24])=[O:6].[OH-:28].[Na+].Cl>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[S:9][C:8]=1[C:23]([NH2:24])=[O:28])=[O:6]
Reactant: [OH-]
Reactant: Cc1cccc(C(=O)c2c(C#N)sc3c2ccc(=O)n3-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(=O)c2c(C(N)=O)sc3c2ccc(=O)n3-c2ccccc2)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of Example 5 (127 mg, 0.34 mmol) and 0.25M sodium hydroxide(aq) (1.36 ml, 0.34 mmol) was heated to reflux in EtOH (20 ml) for 45 minutes. The solution was cooled to room temperature, 2M HCl(aq) (100 ml) added and the aqueous extracted with DCM (2×100 ml). The combined DCM extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (0-10% EtOAc in DCM) to give the title compound as a white solid (125 mg, 95%). δH (CDCl3) 7.70 (1H, br s), 7.59-7.32 (8H, m), 7.05 (1H, d, J 9.7 Hz), 6.44 (1H, d, J 9.7 Hz), 2.37 (3H, s). LCMS (ES+) RT 3.00 minutes, 389 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:33]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:34])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)N4CCCCC4)[nH]c3cc21
Yield: 15 %

Procedure:
Piperidine-1-carboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and piperidine-1-carbonyl chloride (63 mg, 0.43 mmol). 30 mg (15%) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]1[P:23]([O:27][CH3:28])([O:25][CH3:26])=[O:24])=[O:5])[CH3:2].CCCCCC.C([Li])CCC.C(=O)=O.CC(C)=O.I[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[O:17][CH2:18][C:19]([CH3:21])([CH3:22])[N:20]=3)=[CH:13][CH:14]=2)[C:9]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:51][CH:50]=2)=[CH:8][CH:7]1[P:23]([O:25][CH3:26])([O:27][CH3:28])=[O:24])=[O:5])[CH3:2]
Reactant: ICc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)N1c2ccc(C3=NC(C)(C)CO3)cc2C=CC1P(=O)(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1c2ccc(C3=NC(C)(C)CO3)cc2C(Cc2ccc(-c3ccccc3)cc2)=CC1P(=O)(OC)OC
Reaction time: 1 h
Yield: 56.2 %

Procedure:
1-Ethoxycarbonyl-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-dimethoxyphosphoryl-1,2-dihydroquinoline (934 mg) was dissolved in THF (10 ml), and a 1.6 M n-butyllithiumhexane solution (1.8 ml) was added under cooling with dry ice-acetone. The mixture was stirred for 1 hr at the same temperature. 4-(Iodomethyl)biphenyl (740 mg, 2.52 mmol) was added under cooling with dry ice-acetone, and the mixture was stirred at −20° C. for 1 hr and at 0° C. for 1 hr. Then, water was added, and the mixture was stirred for 0.5 hr at room temperature and extracted three times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate, ethyl acetate/methanol=20/1) to give the objective compound (738 mg) as a yellow powder.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)=[N:7][N:6]=1)(=O)=O.CS(C1SC(C2C=C3C(=CC=2)C=NC=C3)=NN=1)=O.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH2:44]>CCOC(C)=O>[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)=[N:7][N:6]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnccc3c2)s1
Reactant: NCc1ccco1
Agent: CS(=O)c1nnc(-c2ccc3cnccc3c2)s1
Solvent: CCOC(C)=O
Product: c1coc(CNc2nnc(-c3ccc4cnccc4c3)s2)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A stirred mixture of 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)isoquinoline and 6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)isoquinoline (44 mg, 0.16 mmol) and furan-2-ylmethanamine (78 mg, 0.8 mmol) (commercially available from Acros Organics (Order Number 11980)) was heated at 80-100° C. for 3 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc and washed with 2M aqueous Na2CO3 solution and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with gradients of EtOAc in hexanes) to provide N-(furan-2-ylmethyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine as an amphorous solid (32 mg, 65%). LCMS (M+H) 309.3 calc for C16H13N4OS 309.1. 1H NMR (300 MHz, DMSO-d6): δ ppm 9.34 (s, 1H), 8.54 (m, 2H), 8.29 (s, 1H), 8.17 (m, 2H), 7.92 (d, J=5.8 Hz, 1H), 7.64 (s, 1H), 6.43 (m, 2H), 4.58 (d, J=5.2 Hz, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C@@H:16]([OH:27])[C@@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C@@H:16]([O:27][CH2:3][C:2]([CH3:7])=[CH2:1])[C@@H:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@@H](O)[C@H](C)OCc2ccccc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]([C@H](C)OCc1ccccc1)[C@@H](Cc1ccc(C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 150.3 %

Procedure:
To a 250 mL round bottom flask were added (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-hydroxy-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (11.2 g, 23 mmol) and anhydrous THF (145 mL). The solution was sparged with N2 for 5 min and then tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3; 2.10 g, 2.3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (dppf; 2.55 g, 4.59 mmol) were added, and the resulting dark solution was sparged with N2 for an additional 5 minutes. The reaction mixture was warmed to 55° C. under N2 and treated with a solution of tert-butyl (2-methylallyl)carbonate (7.9 g, 45.9 mmol) in THF (5 mL). The dark mixture was stirred at 55° C. for 1 h and then cooled to room temperature. The reaction mixture was filtered through paper, rinsing with CH2Cl2, and the filtrate was evaporated to give a dark oil. The oil was partially purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (9.36 g) as a yellow oil that is contaminated with dibenzylideneacetone (dba): 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 10H), 7.02 (d, J=7.8 Hz, 2H), 6.87 (m, 2H), 5.06 (m, 1H), 4.91 (s, 1H), 4.77 (ddd, J=11.7, 9.3, 4.7 Hz, 1H), 4.64 (d, J=11.9 Hz, 1H), 4.31 (d, J=11.9 Hz, 1H), 4.16 (s, 2H), 3.96 (m, 1H), 3.74 (dd, J=9.2, 7.1 Hz, 1H), 3.62 (p, J=6.1 Hz, 1H), 3.41 (m, 2H), 2.85 (m, 2H), 2.70 (dd, J=13.7, 3.5 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 1.49 (dd, J=13.7, 10.6 Hz, 1H), 1.34 (d, J=6.1 Hz, 3H); ESIMS m/z 565 ([M+Na]+).
Reaction SMILES: C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC.[CH3:22][C@@H:23]([CH2:29][CH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[OH:34][C:32]([CH3:33])([CH3:35])[CH2:31][CH2:30][CH2:29][C@H:23]([CH3:22])[CH2:24][CH2:25][CH2:26][CH:27]=[O:28]
Reactant: C[C@H](CCCCO)CCCC(C)(C)O
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@H](CCCC=O)CCCC(C)(C)O
Yield: 68.3 %

Procedure:
5.68 g of 4-methylmorpholine N-oxide (monohydrate) (NMO) and 31.5 g of molecular sieves (powder, 4A) in 200 ml of abs. CH2Cl2 were stirred for 0.25 h at ambient temperature. 500 mg of tetrapropylammonium perrhutenate (TPAP) was added, before a solution of 4.59 g of (R)-5,9-dimethyl-decane-1,9-diol in 20 ml of abs. CH2Cl2 was added within 1 h. 15 minutes later, the reaction mixture was filtered and the solvents removed i.V. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 3.103 g of (S)-9-hydroxy-5,9-dimethyl-decanal as colorless oil, 98.7% pure according to GC.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:22]=[CH:21][C:12]2[N:13]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[NH:15][C:11]=2[CH:10]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(O)(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[NH:15][C:11]=3[CH:10]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.8 ml of triethylamine are added dropwise, with stirring, to 2.07 g of methyl 5-hydroxybenzimidazole-2-carbamate and 1.94 g of 4-fluorobenzenesulfonyl chloride at about 10° C. The mixture is then stirred at room temperature for 2 h, 100 ml of 2N acetic acid are added while cooling, and the resulting precipitate is filtered off with suction, washed with water and dried. Melting point 236° C., decomposition, from dimethylformamide/methanol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]1[N:23]([CH3:34])[C:24](=[O:33])[C:25]([F:32])=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[F:32][C:25]1[C:24](=[O:33])[N:23]([CH3:34])[C:22]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([S:9][CH3:10])=[CH:8][C:2]=2[F:1])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(=O)c1cc(F)c(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-fluoro-4-(methylthio)aniline (0.236 g, 1.50 mmol) in THF (10 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (3.42 ml, 3.42 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. after the addition was complete. Methyl 2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.300 g, 1.37 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by the addition of 1 M HCl until the pH of the reaction mixture was 5, and then diluted with EtOAc and saturated NaCl. The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave pure desired product (0.359 g, 75%) as a white solid.