Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:19])=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:19][C:11]1[CH:10]=[CH:9][C:8]([C:22]2[N:26]3[N:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:13][C:12]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CC1(C)COB(c2ccc(F)c(-n3ccnc3)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
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: COCCOC
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-n1ccnc1
Yield: 13.2 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-imidazole (344 mg, 1.67 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.446 g, 1.67 mmol), 2 M Na2CO3 (1.67 ml) and tetrakis(triphenylphosphine)palladium(0) (0.096 g) in 1,2-dimethoxyethane (6 ml). The crude residue was purified by flash chromatography (silica gel, 3% MeOH(CH2Cl2) and triturated with Et2O to yield the title compound (77 mg, 13%): 1H NMR (360 MHz, CDCl3) δ 7.29 (1H, s), 7.35 (1H, d, J 1.4 Hz), 7.50 (1H, t, J 9.1 Hz), 7.92 (1H, s), 8.04-8.08 (1H, m), 8.30 (1H, dd, J 7.0, 2.1 Hz), 8.64 (1H, s), 8.84 (1H, s); MS (ES+) m/z 349 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH2:14]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:2]([CH2:3][OH:4])[C:5]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Yield: 88.9 %

Procedure:
D-serine (10.5 g, 0.1 mol) was stirred with potassium carbonate (69 g, 0.5 mol), benzyl bromide (64.8 g, 0.375 mol) and water (10 mL) in acetonitrile (250 mL) at 55° C. for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20% ethyl acetate in hexanes to give benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (33.36 g, 88%) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): (ppm) 7.20-7.44 (m, 15H), 5.27 (q, 2H), 3.91 (d, 2H), 3.80 (m, 2H), 3.67 (d, 2H), 3.63 (m, 1H) and 2.52 (dd, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:45][CH3:46].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.ClCCl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:44]=[CH:43][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:45][CH3:46])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CCCS(C)(=O)=O)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(CCCS(C)(=O)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of 0.08 g (0.25 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.112 g (0.30 mmole) of 4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide and 0.072 g (0.38 mmole) of p-toluenesulfonic acid monohydrate in 3 mL of isopropanol was stirred in a sealed tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate solution, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide (I-76) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-])=O)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=C(NCC1CCN(c2ccncc2)CC1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NC(=O)NCC1CCN(c2ccncc2)CC1
Yield: 99.6 %

Procedure:
A solution of 2-[1-(4-pyridyl)piperidin-4-ylmethylaminocarbonyl]amino-nitrobenzene (1.02 g, 2.87 mmol) in ethanol was hydrogenated at atmospheric pressure over 5% palladium-on-carbon. After completion (16-20 h), the mixture was filtered through diatomaceous earth, using hot ethyl acetate to wash the filter cake. Concentration of the filtrate in vacuo yielded 930 mg (99%) of the title compound.
Reaction SMILES: NCCCCCCNC(OC[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCCCNC(=O)OCc1ccccc1
Reactant: NCCCCCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Product: NCCCCCCNc1ccccc1
Yield: 100 %

Procedure:
To prepare 1-amino-6-phenylmethoxycarbonylamino-hexane (23), an equimolar mixture (0.01 mol) of 1,6-diaminohexane and benzaldehyde in 25 mL of methylene chloride was stirred for 5 hr in the presence of 1.5 g of anhydrous magnesium sulfate at room temperature. After removing the drying agent by filtration the filtrate was evaporated to dryness under reduced pressure to give 2 g (100% yield) of crude 1-amino-6-phenylamino-hexane 22 as a colorless oil; NMR(CDCl3) 1.1-1.9(m, 10H, hexane CH2 -2,-3,-4,-5, NH2); 2.6(m, 2H, CH2 -1); 3.51(m, 2H, hexane CH2 -6); 7.1-7.8 (m, 5H, aromatic); 8.16(s, 1H, imine CH). To a mixture of 2 g (0.01 mol) of 22 and 1.4 mL (0.01 mol) of triethylamine in 20 mL of methylene chloride. Then 1.78 g (0.01 mol) of benzylchloroformate was added dropwise at -5° C. The resulting mixture was stirred for 0.5 hr at 0° C. and for 2 hr at room temperature then diluted to 50 mL with methylene chloride and washed with water (20 ml), 2% sodium bicarbonate (20 ml), water and saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of solvent under reduced pressure the residue was dissolved in 5 mL of ethanol and 10 mL of 2N hydrochloric acid was added. The resulting mixture was stirred for 6 hr at room temperature then evaporated to dryness under reduced pressure. The residue was diluted to 50 mL with water and washed with ethyl ether (2×15 ml). The water phase was evaporated under reduced pressure and the product 23 was purified by crystallization from a small portion of water with a yield of 42%; mp 175°-178° C.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=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+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]2=[N:10]1
Reactant: Fc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Reactant: CC(=O)Nc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Temperature: 150 °C
Yield: 8.1 %

Procedure:
A mixture of 4-bromo-2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (320 mg, 0.89 mmol), N-(6-aminopyrimidin-4-yl)-acetamide (152 mg, 1.0 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (52 mg, 0.089 mmol) and cesium carbonate (580 mg, 1.78 mmol) in dioxane (10 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 1 h. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80-100% ethyl acetate in cyclohexane) to afford an off-white solid. This was re-purified by HPLC [gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)], to afford the title compound as a white solid (31 mg, 10% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.65-10.61 (m, 2H), 9.26 (d, J=2.6 Hz, 1H), 9.08 (d, J=1.1 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 7.92 (d, J=3.4 Hz, 1H), 7.83-7.81 (m, 2H), 7.74 (dd, J=9.1, 7.3 Hz, 1H), 2.14 (s, 3H). LCMS (Method B): RT=3.20 min, m/z: 432 [M+H+].
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([C:32]([NH:34][CH2:35][C:36](=O)[CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][CH3:40])=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20][N:21]([CH3:23])[CH:22]=2)=[CH:14][CH:13]=1)(=[O:8])[CH3:7]>C1(C)C(C)=CC=CC=1>[C:27]([O:26][C:25](=[O:31])[NH:24][C:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([NH:9][C:6](=[O:8])[CH3:7])[C:32]3[NH:34][CH:35]=[C:36]([CH2:37][C:38]([CH3:41])([CH3:42])[CH2:39][CH3:40])[N:5]=3)=[CH:13][CH:14]=2)=[CH:22][N:21]([CH3:23])[N:20]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cn(C)nc3NC(=O)OC(C)(C)C)cc2)NC(C)=O)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.17 g, 15.2 mmol) was added to an ambient temperature solution of tert-butyl [4-(4-{2-(acetylamino)-3-[(4,4-dimethyl-2-oxohexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (160 mg, 0.30 mmol) in xylene (5 mL). After stirring at 150° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 509.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:11]=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.O>C(O)C.[Fe]>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:11]=[N:12][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:14][CH:15]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
A solution of 3-(4-cyclopropyl-piperazin-1-yl)-6-(3-nitro-phenyl)-pyridazine (3.60 g, 11 mmol) in ethanol (18 mL) was added to water (30 mL) and powdered Fe (1.86 g, 33 mmol). The mixture was stirred for 3 h at 80° C. The resulting mixture was filtered and the filtrate was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give 2.32 g (71%) of 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.C(O)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:7])([OH:13])[OH:10]
Reactant: CCOP(=O)(CCCNO)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=P(O)(O)CCCNO
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of diethyl 3-(N-hydroxyamino)propylphosphonate (12.9 g.), acetic acid (65 ml.) and 1 N hydrochloric acid (130 ml.) was heated to reflux with stirring for 8 hours and then was concentrated under reduced pressure to remove off acetic acid. The concentrate was decolorized by treating with an activated charcoal and evaporated to dryness under reduced pressure to give an oily residue (9.5 g.), which was dissolved in water (30 ml.) and adjusted to pH 4 with sodium bicarbonate (ca. 4.2 g.) to give crystals of 3-(N-hydroxyamino)propylphosphonic acid (4.80 g.), m.p. 160°-163.5° C. (decomp.). An additional crystals of the same object compound (0.91 g.) was recovered from the mother liquor after standing overnight at ambient temperature (m.p. 159°-163° C. (decomp.)). The I.R. and N.M.R. spectra of these crystals were superimposable with those of the authentic specimen (m.p. 160°-166° C. (decomp.)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.[Cl:14][S:15](O[Si](C)(C)C)(=[O:17])=[O:16].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: CC(C)c1cn2ccc(Br)cc2n1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
7-Bromo-2-isopropylimidazo[1,2-a]pyridine (1.00 g, 4.18 mmol) obtained in step 1 of Example 28 was dissolved in 1,2-dichloroethane (10 mL). Under ice-cooled condition, trimethylsilyl chlorosulfonate (1.20 mL, 8.36 mmol) was added, and the mixture was stirred at 90° C. for 3 hours. Under ice-cooled condition, triethylamine (1.17 mL, 8.36 mmol) and phosphoryl chloride (0.779 mL, 8.36 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile. After adding a sodium hydrogen carbonate aqueous solution, the precipitated solid was collected by filteration to give 7-bromo-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.31 g, yield 93%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OCC)=[O:15])[N+:10]([O-:19])=[C:9]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:8]=[C:9]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:10]3[O:19][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Nc1cc(N2CCCCC2)nc(NC(=O)OCC)[n+]1[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cc(N2CCCCC2)nc2nc(=O)on12

Procedure:
4.5 G. of diethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide are treated under an argon atmosphere with 60 ml. of toluene and the mixture is heated to reflux for 12 hours. After cooling the mixture, the precipitate is filtered off and recrystallized from ether, there being obtained pure ethyl 5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 209°-210° C. (decomposition).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:4]([C:3]1[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:8][N:9]=[CH:10][C:2]=1[O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=1)(=[O:5])[NH2:6]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cncc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
31 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.083 mmol, 1. eq.) and 17 mg of tert-butyl (3-hydroxyphenyl)carbamate (0.083 mmol, 1 eq.) were dissolved in 1 ml of DMF, then 81 mg of cesium carbonate (0.248 mmol, 3 eq.) were added. The resulting mixture was stirred at room temperature for 18 hours. Since the reaction was not complete, the mixture was stirred for another 3 days at 50° C. bath temperature. The mixture was then partitioned between aq. NH4Cl solution (10 ml) and dichloromethane (10 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane (10 ml each). The combined organic layers were washed with brine (20 ml), dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 17 mg (0.03 mmol, 30%) of the analytically pure target compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@H:6]([C:8]1[CH:12]=[CH:11][O:10][N:9]=1)[OH:7])=[N+:2]=[N-:3].F[C:14]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17].[H-].[Na+]>>[N:1]([CH2:4][CH2:5][C@@H:6]([O:7][C:14]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17])[C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC[C@@H](O)c1ccon1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN=[N+]=[N-])c1ccon1
Yield: 78.4 %

Procedure:
The product from step (a) (0.1 g) and 2,5-difluoro-4-chloro-benzonitrile (0.18 g) and sodium hydride (60% dispersion in oil, 0.035 g) were subjected to the procedure described in Example 90(a) to afford the product as a gum (0.15 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:15][N:14]=2)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2]1.Br[C:29]1[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[C:8]([O:7][C:6]([N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:13]1[CH:18]=[C:17]([C:29]2[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=2)[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(=O)c1coc(Br)n1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1coc(-c2ccnc(N(CC3CC3)C(=O)OC(C)(C)C)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (48.3 g), ethyl 2-bromo-1,3-oxazole-4-carboxylate (25.8 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (4.79 g), potassium carbonate (32.4 g) and DME (489 mL)/water (98 mL) was stirred at 80° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (33.3 g).
Reaction SMILES: ClC1C=C(C=CC=1)N.N[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1OC)[C:13]([NH:15]C1C=CC(F)=C(F)C=1)=[O:14]>>[C:13]([NH2:15])(=[O:14])[C:12]1[CH:24]=[CH:25][CH:26]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Solvent: Nc1cccc(Cl)c1
Product: NC(=O)c1ccccc1
Yield: 5 %

Procedure:
The title compound was synthesized as in Example 1 using 3-chloroaniline (2.0 mL, 18.9 mmol), CSI (2.0 mL, 23.0 mmol), and 3-amino-N-(3,4difluoro-phenyl)-4-methoxy-benzamide (1.39 g, 5.0 mmol) to give 0.030 g of benzamide, 3-[[[[[(3-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-. Microanalysis: C21H17ClF2N4O5S; calculated: C=49.37; H=3.35; N=10.97. found: C=48.97; H=3.11; N=10.78. MS: M++1=511 Da. Mp 193-196° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(=O)[NH2:2].N1C=CC=CC=1.O=S(Cl)Cl>>[C:1]([CH:4]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])#[N:2]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C#N)C1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1-Benzyl 4-ethyl 2-carbamoylpiperidine-1,4-dicarboxylate (2.4 g, 7.18 mmol) was dissolved in pyridine (50 mL, 618.21 mmol). The mixture was cooled on an ice bath and SOCl2 (3.14 mL, 43.07 mmol) was added dropwise and left overnight at room temperature. The reaction mixture was evaporated and partitioned between diluted HCl and DCM. The aqueous layer was extracted with DCM and the combined organic layer was washed with water, dried over Na2SO4 and evaporated. Crude 1-benzyl 4-ethyl 2-cyanopiperidine-1,4-dicarboxylate (2.25 g, 99%) was isolated. 1H NMR (400 MHz, dmso) δ 1.21 (t, 3H), 1.54-1.66 (m, 1H), 1.98-2.12 (m, 2H), 2.29-2.37 (m, 1H), 2.83-2.91 (m, 1H), 3.04-3.16 (m, 1H), 3.83-3.91 (m, 1H), 4.02-4.18 (m, 2H), 5.13 (s, 2H), 5.25-5.31 (m, 1H), 7.28-7.40 (m, 5H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][N:40]=1)CCC>>[S:37]1[CH:38]=[CH:39][N:40]=[C:36]1[C:2]1[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Product: FC(F)(F)c1cc(-c2nccs2)c2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1

Procedure:
The reaction of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (148 mg, 0.3 mmol, Example 7) with 2-tributylstannylthiazole (Matrix Scientific) under the conditions of Example 35 gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 499 (M+1).