Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=O)=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:38])[NH:15][N:14]=1.[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][N:41]=3)(=[O:26])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:38])[NH:15][N:14]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (From Step 5, Example 293; 126 mg, 0.222 mmol), pyrimidin-4-amine (31.7 mg, 0.334 mmol), and THF (1.11 mL). The resulting solution was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (489 μl, 0.489 mmol) was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was quenched with 1 mL of MeOH and concentrated. Purification was done on OJ-H column, with 20% methanol and 0.2% diethylamine. Since the product contained some DEA, it was purified further by mass directed LC purification with TFA to afford 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-N-(pyrimidin-4-yl)-3,4-dihydrophthalazine-6-sulfonamide (23 mg, 21.7% yield). m/z (ESI) 478.0 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4]1.O=S(Cl)Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C@:23]([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1>ClCCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:31][C:7]([CH:3]2[CH2:4][CH2:5][CH2:6]2)=[O:9])([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-trifluoromethylcyclobutyl carboxylic acid (22.7 mg, 0.135 mmol) in DCE (1 mL) was added SOCl2 (16 mg, 0.135 mmol) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool down to room temperature and TEA was added (31 μL, 0.23 mmol), followed by the addition of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (20 mg, 0.045 mmol). The reaction was stirred at room temperature for 18 h, concentrated and the residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide (5.2 mg, 22% yield). LCMS: RT=2.14 min [M+H] 525.2 (LCMS Method 2.); NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1H, s; 8.13 ppm, 1H, s; 7.68 ppm, 1H, m; 7.11 ppm, 6H, m; 6.87 ppm, 1H, m; 6.57 ppm, 2H, m; 5.87 ppm, 1H, t, J=53 Hz; 4.45 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.51 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.09 ppm, 1H, m; 2.20 ppm, 4H, m; 1.94 ppm, 2H, m.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][O:25][CH3:26])[CH:22]=3)[S:17][C:10]=12.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]=[C:40]=[S:41])=[O:38]>>[F:1][C:2]1[CH:3]=[C:4]([NH:27][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[S:41])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][O:25][CH3:26])[CH:22]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: COCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: COCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1

Procedure:
Following the procedure described above for the compound 90 (scheme 17) but replacing the amine 89 with the amine 95 and using 2-(2-methoxyphenyl)acetyl isothiocyanate instead of 2-phenylacetyl isothiocyanate, title compound 96 was obtained as a beige solid (6 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.57 (1H, s), 11.77 (1H, s), 8.53 (1H, d, J=5.48 Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s), 7.91 (1H, s), 7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98 (1H, d, J=8.22 Hz), 6.91 (1H, d, J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz), 4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s), 3.65 (2H, t, J=4.89 Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC=CCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC=CCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A mixture of p-nitrobenzenesulfonic acid (20 g), phosphorous pentoxide (50 g) and 1,2-dichloroethylene (100 ml) is heated at reflux for 4 days. The hot supernatant is decanted from the gummy residue and allowed to cool to room temperature. The resulting crystalline precipitate of p-nitrobenzenesulfonic anhydride (1.5 g) is collected, washed with anhydrous diethylether, and dried under vacuum. The gummy residue is twice more refluxed overnight with 100 ml portions of dichloroethylene and worked up as above to provide additional p-nitrobenzenesulfonic anhydride (4.0 g): mp 171°-172°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:55])[C:22]([C:30]4[N:31]=[C:32]([NH:35]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:33][CH:34]=4)=[N:23][O:24][CH2:25][CH2:26][N:27]=[N+:28]=[N-:29])[C:18](=[O:56])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(O)=O>C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:55])[C:22]([C:30]4[N:31]=[C:32]([NH2:35])[S:33][CH:34]=4)=[N:23][O:24][CH2:25][CH2:26][N:27]=[N+:28]=[N-:29])[C:18](=[O:56])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.336 g of the product of Step A and 7 ml of formic acid were stirred at 50° C. for 15 minutes and was vacuum filtered to remove triphenylcarbinol. The filtrate was evaporated to dryness and the residue was taken up in water. After efflorescence, the mixture was vacuum filtered to obtain 0.77 g of raw product which was dissolved in minimum of aqueous 10% sodium bicarbonate solution. 0.77 g of activated carbon were added thereto and the mixture was vacuum filtered. Formic acid was added to the filtrate to adjust the pH to 2 and the mixture was vacuum filtered to obtain 0.171 g of syn isomer of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:13][N:12]=3)=[CH:5][CH:4]=1>CO.[Pd]>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]2)=[CH:13][N:12]=3)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.38 mmol) was dissolved in methanol (10 ml) and added Pd/C (5%) (283 mg). This mixture was stirred under H2 pressure (6.5 kg) for 12 h. Combined methanol fractions were evaporated on rotavapour to obtain the crude. Crude was purified on combiflash using a gradient mixture of EtOAc and Petether (1:9) as eluent to afford the titled compound (35 mg) as a white solid. M. P.: 184-188° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.40 (d, J 8.1, 2H), 8.27 (d, J 2, 1H), 7.93 (d, J 2, 1H), 7.81 (d, J 8.3, 2H), 4.31 (d, J 13.5, 2H), 2.91-2.81 (m, 3H), 1.91 (d, J 12.9, 2H), 1.78-1.62 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[S:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[S:13]1
Reactant: O=c1c2ccncc2sn1CCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=c1c2ccncc2sn1CCCCO
Yield: 100.4 %

Procedure:
A solution of 1 g of 2-(4-(2-tetrahydropyranyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred overnight at ambient temperature and concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate, washed with 4 mL of saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum overnight gave 0.73 g (78%) of 2-(4-hydroxybutyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil: 1H NMR (400 MHz, CDCl3): 9.28 (s, 1H), 9.15 (d, J=5 Hz, 1H), 7.98 (d, J=5Hz, 1H), 3.86 (t, J=7.5 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.36 (br s, 1H), 1.98 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=[CH:13][CH:12]=1.C(B1OB(C=C)OB(C=C)O1)=C.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.O>[CH3:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([CH:12]=[CH2:13])[N:3]=1
Reactant: c1ccncc1
Reactant: COc1nc(Br)cnc1N
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cnc(N)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-bromo-3-methoxypyrazin-2-amine (800 mg, 3.92 mmol, 1 eq.; Jiang, B. et al. Bioorg. Med. Chem. (2001), 9, 1149-1154.), trivinylboroxine pyridine-complex (944 mg, 3.92 mmol, 1.0 eq), tetrakis(triphenylphosphin)palladium(0) (45 mg, 0.04 mmol, 0.01 eq) and potassium carbonate (542 mg, 3.92 mmol, 1.0 eq) in 40 mL dimethoxyethane/water (3/1) was stirred at room temperature for 10 min and then heated to reflux temperature for 3 hours. The reaction mixture was hydrolysed with 100 mL of water and extracted with ethyl acetate. The resulting organic phase was washed with brine, dried with sodium sulphate and concentrated in vacuo. The crude mixture was purified via MPLC (column: Snap cartridge, eluent: hexane→hexane/ethyl acetate 1/1) to deliver 495 mg (78%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2Br)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:68][C:69]1[CH:70]=[C:71]([S:75]([NH2:78])(=[O:77])=[O:76])[CH:72]=[CH:73][CH:74]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[NH:78][S:75]([C:71]2[CH:72]=[CH:73][CH:74]=[C:69]([Cl:68])[CH:70]=2)(=[O:77])=[O:76])[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Br)ccnc21
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(NS(=O)(=O)c3cccc(Cl)c3)ccnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
A mixture of 3,4-dibromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrrolo[2,3-b]pyridine (D3) (1.020 g, 2.51 mmol), xantphos (0.218 g, 0.377 mmol), palladium(II) acetate (0.042 g, 0.188 mmol), cesium carbonate (1.636 g, 5.02 mmol) and 3-chlorobenzenesulfonamide (0.602 g, 3.14 mmol) in 1,4-dioxane (15 mL) was stirred at 100° C. for ca. 3 hours. The mixture was evaporated to dryness and the residues partitioned between water (15 mL) and ethyl acetate (40 mL). The aqueous phase was separated and extracted with additional ethyl acetate (15 mL). The organic extracts were combined, washed with brine (10 mL), dried with MgSO4 and evaporated to dryness. The residue was purified through silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to give the title compound (407.4 mg). LCMS (A): m/z (M−H)− 514/516, C19H23BrClN3O3SSi requires 515/517 (acidic).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 1-(piperidin-4-yl)urea hydrochloride (83 mg, 0.580 mmol), and N, N-diisopropylethylamine (112 mg, 0.870 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59.4 mg, 45%). Decomposition was observed at 225.4° C. 1H NMR (DMSO-d6) δ: 10.81 (s, 1H), 7.92 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.23 (s, 1H), 6.11 (s, 1H), 6.06 (br. s., 1H), 4.26 (d, J=12.9 Hz, 2H), 3.63 (t, J=9.6 Hz, 1H), 3.17 (t, J=11.0 Hz, 2H), 2.31 (s, 3H), 1.88 (dd, J=13.0, 2.9 Hz, 2H), 1.40-1.53 (m, 2H), 1.39 (s, 6H); ESI-MS: m/z 452.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH3:17]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Yield: 69.6 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.34 g (1.3 mmol) 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After ionic exchange purification, 0.273 g (70% of yield) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27](Cl)[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN1C(=O)N(C)CCC1>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: OCC#CCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCO
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To a suspension of 675 mg of NaH in 45 ml of DMF and 5 ml of DMPU was added 4.85 g of 2-butyne-1,4-diol. The mixture was stirred at room temperature until evolution of gas had ceased. Then 1.5 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide was added and the resulting mixture was heated to 95° C. and stirred for 5 days. Eventually, the mixture was pourred into 150 ml of 10% aqueous citric acid and extracted three times with 150 ml of ethyl acetate. The organic layers were washed with water and brine, dried over MgSO4 and evaporated. The resulting residue was purified by column chromatography on silicagel eluting with hexane:ethyl acetate 1:1 to give 265 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a beige foam along with 1.13 g of the starting material 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide. LC-MS: tR=5.39 min, [M+1]+=583.41, [M−1]−=581.35.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[CH:14][N:13]=1>O.CO>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[C:15]([CH3:19])=[CH:14][N:13]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1124.2 %

Procedure:
Sodium hydroxide (2.38 g, 5.9 mmol) was dissolved in water (10 mL), 4-aminothiophenol (6.77 g, 5 4 mmol) was added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for 30 minutes. 2,4-Dichloro-5-methylpyrimidine (7.05 g, 4 3 mmol) was slowly added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for a further 1 hour during which time a precipitate formed. This precipitate was isolated by filtration, washed with minimum ice cold diethyl ether and dried under vacuum to give 4-[(2-chloro-5-methylpyrimidin-4-yl)thio]aniline (8.49 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[N:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[N:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1cccnn1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccnn1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridazin-3-yl-methylamine (example 4.11).
Reaction SMILES: [CH2:1]([S:3][C:4]1[O:5][C:6]2[C:14]([C@H:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C@H:16]3[OH:22])=[C:13]([O:23]C)[CH:12]=[C:11]([O:25]C)[C:7]=2[C:8](=[O:10])[CH:9]=1)[CH3:2].B(Br)(Br)Br>ClCCCl>[CH2:1]([S:3][C:4]1[O:5][C:6]2[C:14]([C@H:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C@H:16]3[OH:22])=[C:13]([OH:23])[CH:12]=[C:11]([OH:25])[C:7]=2[C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCSc1cc(=O)c2c(OC)cc(OC)c([C@H]3CCN(C)C[C@H]3O)c2o1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: CCSc1cc(=O)c2c(O)cc(O)c([C@H]3CCN(C)C[C@H]3O)c2o1
Temperature: 90 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of the title A compound (cis-(-)-2-(ethylthio)-8-(3-hydroxy-1-methyl-4-piperidinyl)-5,7-dimethoxy-4H-1-benzopyran-4-one: 180.5 mg, 0.476 mmol) in 1,2-dichloroethane (3 mL) was added a solution of BBr3 (2.5 mL of 2M solution in 1,2-dichloroethane). The mixture was stirred at 90° C. or 3 hours and cooled to room temperature. It was quenched by MeOH (5 mL) and concentrated. The residue was re-dissolved in MeOH (10 mL) and neutralized by aqueous NaHCO3 solution. The resulting solution was purified by HPLC (YMC OD S-10 30×500 mm; 45% B; flow rate 49 mL/minute; UV 254 nm). Those fractions containing the desired product were pooled, concentrated and lyophilized to afford the title compound (162 mg, 70%) as solid, mp 104° C. [α]D =-19.0° (MeOH, c 0.52).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[NH2:22][C:23]1[C:27]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:24]=1.C(N(C(C)C)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:31]([O:30][C:29]([NH:28][C:27]1[C:23]([NH:22][C:17]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:20]=2)=[O:19])=[N:24][N:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:26]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 60 °C

Procedure:
A solution of 4-({[(pyridin-3-ylmethoxy)carbonyl]amino}methyl)benzoic acid (0.1 g, 0.35 mmol), tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (0.096 g, 0.35 mmol), and N,N-diethylisopropylamine (0.049 g, 0.35 mmol) in methylene chloride (5 mL) was treated with BOP (0.23 g, 0.52 mmol) and heated to 60° C. for 1 hour. The reaction was loaded directly onto a silica column and purified by flash chromatography (0-3% methanol/methylene chloride) to give pyridin-3-ylmethyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate as a white solid. 1H NMR (CD3OD) δ 8.57 (s, 1H), 8.48 (d, J=4.99 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=7.92 Hz, 2H), 7.87 (d, J=7.92 Hz, 1H), 7.72 (d, J=7.92 Hz, 2H), 7.44 (m, 5H), 7.27 (t, J=7.33 Hz, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18].Cl>O1CCCC1.ClCCl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([N:9]=[CH:8][C:7](=[O:18])[N:6]2[CH2:5][CH2:4][CH:3]=[O:2])=[CH:11][CH:12]=1
Reactant: COc1ccc2ncc(=O)n(CCC(OC)OC)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(CCC=O)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
1-(3,3-Dimethoxypropyl)-7-methoxyquinoxalin-2(1H)-one (300 mg, 1.08 mmol) was dissolved in tetrahydrofuran (3 ml). 1N Hydrochloric acid (3 ml) was added to this solution and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with dichloromethane and stirred, and the organic layer was then separated. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and then the solvent was removed under reduced pressure to yield 236 mg (94%) of the title compound in the form of a light brown solid.