Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(-c3ccc(=O)[nH]n3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(=Cc2ccc(F)c([N+](=O)[O-])c2)c2ccccc21

Procedure:
A stirred solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (20 g, 0.083 mol) and 4-fluoro-3-nitrobenzaldehyde (13.97 g, 0.083 mol) in tetrahydrofuran (120 ml) was cooled to 15° C. and triethylamine (11.5 ml, 0.083 mol) was added dropwise at <25° C. The mixture thickened at this point, so further tetrahydrofuran (50 ml) was added to aid stirring. The mixture was stirred at ambient temperature for 65 hours and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo, the residue was triturated with water (30 ml) and the resulting solid was collected by filtration. The two crops of solid were combined and suspended in water (120 ml). The mixture was stirred at ambient temperature for 30 minutes and the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-fluoro-3-nitrobenzylidene)-3H-isobenzofuran-1-one, still slightly wet with water, which was used directly in the next stage.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C@@:9]([C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])([CH2:12][CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C[C@H]1C[C@@H](OC(=O)C(=O)CC)[C@H](C(C)(C2C=CC=CC=2)C)CC1.[CH3:45][N:46]([CH:48](N(C)C)N(C)C)[CH3:47]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C@@:9]([C:14](=[O:20])[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])([CH2:12][CH3:13])[C:10]=1/[CH:11]=[CH:45]/[N:46]([CH3:48])[CH3:47])=[O:5])[CH3:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCOC(=O)C1=C(C)[C@@](CC)(C(=O)N(CC)CC)OC1=O
Agent: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(/C=C/N(C)C)[C@@](CC)(C(=O)N(CC)CC)OC1=O

Procedure:
According to the procedure described in Example 6 1.22 0 g of compound (23) as obtained from example 17 (4.103 mmol) in 7.3 mL dimethyl formamide were treated with 7.55 mL tris(dimethylamino)methane (42.26 mmol, 10.3 eq) yielding the crude product as an orange oil (1.463 mg, 101% by weight).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.C1C(=O)N(Br)C(=O)C1.[CH3:44][C@H:45]1[O:50][C@@H:49]([CH3:51])[CH2:48][N:47]([C:52](=[S:54])[NH2:53])[CH2:46]1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:54][C:52]([N:47]3[CH2:48][C@H:49]([CH3:51])[O:50][C@H:45]([CH3:44])[CH2:46]3)=[N:53][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(C(N)=S)C[C@H](C)O1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (1.5 g, 3.40 mmol) was added DMA (10 mL) and NBS (0.61 g, 3427 mmol). After stirring at rt for 10 min, (2R,6S)-2,6-dimethyl-4-morpholinecarbothioamide (0.800 g, 4.59 mmol) was added and stirring continued for 2 h. Water was added and the solid was collected by filtration and dried over two days to afford the title compound of Step A (1.80 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.49-7.63 (m, 3H), 7.45 (t, J=7.6 Hz, 1H), 7.39 (t, J=6.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.46 (d, J=5.3 Hz, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.66 (br. s., 1H), 2.94 (s, 2H), 2.78 (s, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 597 [M+H]+.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N(I)C(=O)C1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[N:6]1[C:5]2[CH:9]=[CH:10][CH:2]=[CH:3][C:4]=2[NH:8][CH:7]=1
Reactant: Cc1ccc2[nH]cnc2c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1I
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 5-methyl-1H-benzoimidazole (132 mg, 1.0 mmol) and NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat. NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 78 (30%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J=8.4 Hz), 2.59 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C8H7IN2, 259.0 (M+H), found 259.2.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[N:21]=3)=[CH:15][CH:14]=2)[C:4]1=[O:37])[CH3:2].[ClH:38]>CCO>[ClH:38].[ClH:38].[NH:21]1[C:22]2[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=2[N:24]=[C:20]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][C:10]([CH3:12])=[C:11]3[N:3]([CH2:1][CH3:2])[C:4]2=[O:37])=[CH:14][CH:15]=1
Reactant: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2nccc(C)c21
Agent: Cl
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2nccc(C)c21
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.090 g) and 2N HCl in EtOH (5.0 mL) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.040 g).
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][N:27]([S:35]([CH3:38])(=[O:37])=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][N:27]([C:28]1[CH:29]=[CH:30][C:31]([NH:34]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:32][CH:33]=1)[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[N:7]1.B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC>[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2([NH2:12])[CH2:2][CH2:1]2)=[N:7]1
Reactant: Cn1ccc(C#N)n1
Reactant: CC[Mg]Br
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: Cn1ccc(C2(N)CC2)n1
Reaction time: 0.17 h

Procedure:
Ethyl magnesium bromide (2.5 mol, 1 M in ether) was added at −78° C. to a solution of a 1-methyl-1H-pyrazole-3-carbonitrile (0.5 g, 1 mmol) and Ti(Oi-Pr)4 (1.1 mmol) in Et2O (5 mL). The yellow solution was stirred for 10 min. After the solution was warmed to ambient temperature (1 h), BF3.OEt2 (2 mmol) was added. After the mixture was stirred for 1 h, 1 N HCl and ether were added. NaOH (10%) was added to the resulting two clear phases and the mixture was extracted with ether. The combined ether layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Et2O). 1H NMR (400 MHz, CDCl3): δ 0.94-1.05 (m, 4H), 2.32 (s, 2H), 3.83 (s, 3H), 5.92 (d, 1H), 7.23-7.24 (d, 1H). LCMS: (ES+) m/z observed 137.7.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[O:9][CH:8]([CH2:10]Cl)[CH2:7][O:6]1.[CH3:23][O-:24].[Na+].[I-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[O:9][CH:8]([CH2:10][O:24][CH3:23])[CH2:7][O:6]1
Reactant: C[O-]
Reactant: ClCC1COC(Cc2ccc(Cl)cc2Cl)(c2cccnc2)O1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCC1COC(Cc2ccc(Cl)cc2Cl)(c2cccnc2)O1
Temperature: 25 °C

Procedure:
6.0 g of 3-[2-(2,4-dichlorobenzyl)-4-chloromethyl-1,3-dioxolan-2-yl] pyridine, 1.8 g of sodium methylate and a catalytically acting amount of sodium iodide are stirred in 50 ml of dimethyl sulfoxide for 20 h at an internal temperature of +120° C. After cooling to RT, the reaction mixture is poured into 400 ml of water, and extracted twice with 120 ml of ethyl acetate each time. The organic phases are combined, washed with 150 ml of water, dried over sodium sulfate, treated with active charcoal and filtered, and the solvent is evaporated off. The oily residue is purified by chromatography on silica gel with ether. The compound is obtained as colourless oil; nD22.5 :1.4774.
Reaction SMILES: [CH3:1][CH2:2][NH+:3]([CH2:6][CH2:7][N:8]1[N:20]=[C:19]2[C:10]3[C:11]([S:16][C:17]4[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:18]=42)=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]1=3)[CH2:4][CH3:5].CS([O-])(=O)=O.CCN(CCN1N=C2C3C(SC4C=C(Cl)C=CC=42)=C(CO)C=CC1=3)CC.FC(F)(F)C(O)=O>O>[CH3:5][CH2:4][N:3]([CH2:6][CH2:7][N:8]1[N:20]=[C:19]2[C:10]3[C:11]([S:16][C:17]4[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]1=3)[CH2:2][CH3:1]
Reactant: CC[NH+](CC)CCn1nc2c3c(c(C)ccc31)Sc1cc(Cl)ccc1-2
Agent: CCN(CC)CCn1nc2c3c(c(CO)ccc31)Sc1cc(Cl)ccc1-2
Agent: CS(=O)(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the compounds according to Example Ia-3 and Ia-4 (cis-trans mixture) (300 mg), trifluoroacetic acid (10 ml) and water (10 ml) is stirred at room temperature for 24 hours and concentrated. The solid residue is washed with hot cyclohexane.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1cc(C)nc(Nc2cc(Cl)nnc2C(N)=O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Temperature: 130 °C
Yield: 19.6 %

Procedure:
To a solution of 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (140 mg, 504 μmol) in NMP (2.52 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (216 mg, 1.01 mmol) and the mixture heated at 130° C. for 72 h. The reaction mixture was cooled and diluted with ethyl acetate and brine. The organic phase was washed with brine (2×) and water (1×), then the organic phase was concentrated in vacuo then purified by chromatography (silica, 40-100% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (75 mg, 98.8 μmol, 20%) as an orange solid. MS (EI/CI) m/z: 456.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](N)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].N([O-])=[O:19].[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([OH:19])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: O=N[O-]
Reactant: Cc1ccnc(N)c1Oc1cc(Cl)cc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-amine (600 mg, 1.913 mmol) in 5% aqueous H2SO4 (10 mL) was added a solution of sodium nitrite (198 mg, 2.87 mmol) in water (1 mL). The suspension was stirred in an ice bath for 30 minutes, after which it was added to a solution of 5% aqueous H2SO4 (10 mL), and the mixture was warmed to 100° C. and maintained at 100° C. for 1.5 hours. After this time, the mixture was cooled to 0° C. and treated with additional sodium nitrite (60 mg, 0.86 mmol) and then heated at 100° C. for 20 minutes. After this time, the mixture was cooled to 25° C., the resulting solid was collected by filtration, washed with water (10 mL), and dried under high vacuum to give the title compound. HRMS (M+1)=313.9577.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18](OC2C=CC([N+]([O-])=O)=CC=2)=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3.[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:39])[C:37]=1[NH2:38].[H-].[Na+].CCOC(C)=O>C1COCC1.CCCCC>[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:39])[C:37]=1[NH:38][C:18]([C:7]1[C:8]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[O:10][C:9]=2[C:4]([O:3][CH:2]([F:30])[F:1])=[CH:5][CH:6]=1)=[O:19]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Reaction time: 8 h

Procedure:
4-Nitrophenyl 7-difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate (250 mg) and 3,5-Dichloro-4-aminopyridine (129 mg) was dissolved under argon in dry THF, 5 mL. Sodium hydride (50% suspension in oil), 40 mg, was added, and the mixture left stirring overnight. Aqueous work up with EtOAc and chromatography in a gradient from 0 to 60% EtOAc in pentane afforded the title compound. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.57 (s, 2H), 7.63 (d, J=9.0 Hz, 1H), 6.86 (d, J=9.1 Hz, 1H), 6.73 (t, J=72 Hz, 1H), 3.03-2.81 (m, 4H), 2.49-2.29 (m, 4H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: NCC(N)=O
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=3[O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2cccnc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 3-hydroxypyridine as in Example 45 to afford 0.044 g (31%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C29H24NO5F3 524.1685, found 524.1680.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][CH2:13]Cl)[N:8]([OH:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]3[CH2:11][CH2:12][CH2:13][O:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: O=C1c2cc(Cl)ccc2OC(CCCCl)N1O
Agent: [NH4+]
Agent: [OH-]
Product: O=C1c2cc(Cl)ccc2OC2CCCON12

Procedure:
A mixture of 10 g. of crude 6-chloro-2-(3-chloropropyl)-2,3-dihydro-3-hydroxy-4H-1,3-benzoxazin-4-one prepared in the manner hereinbefore described and 50 ml. of 15 percent aqueous solution of ammonium hydroxide was stirred for 5 hours at room temperature and then filtered and washed with water. The crude product (6 g.) was recrystallized from 45 ml. of ethanol yielding 3.8 g., m-p. 148°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11]C(=O)C.[I:16]I>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(Cl)cc1NC(C)=O
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)c1cc(I)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0 g in 80 mL of dry chloroform) and 2.5 g silver trifluoromethanesulfonate was added iodine (2.87 g in 40 mL chloroform) and the mixture stirred at room temperature. After 5 hours, the mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. Purification of the resulting oil by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (2.26 g).
Reaction SMILES: [F:1][C:2]([F:32])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([O:30][CH3:31])=[CH:23]2)[C:3]([NH:5][NH:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:9][N:8]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)C.C(N(C(C)C)CC)(C)C.ClC(Cl)(Cl)C#N>CO>[F:1][C:2]([F:32])([C:3]1[N:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:11]=[C:12]([F:13])[C:7]2=[N:6][N:5]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([O:30][CH3:31])=[CH:23]2
Reactant: COc1cnc2ccc(C(F)(F)C(=O)NNc3ncc(-c4cnn(C)c4)cc3F)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(-c5cnn(C)c5)cn34)cc2c1
Yield: 43.5 %

Procedure:
A sealable microwave vial was charged with 2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 509 μmol) and polymer supported triphenylphosphine (2.3 mmol/g, 221 mg, 509 μmol). The flask was sealed and dichloroethane (4 mL) was added followed by diisopropylethylamine (89 μl, 509 μmol) and 2,2,2-trichloroacetonitrile (127 μl, 1271 μmol). The resulting mixture was irradiated in a microwave (Biotage Initiator) at 150° C. for 40 min. The reaction mixture was filtered and the filter cake was washed with CH2Cl2 (15 mL) and MeOH (10 mL). The filtrate was concentrated in vacuo and the resulting crude residue was purified by MPLC using 100% CH2Cl2 to 98:2 CH2Cl2: MeOH to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline (94 mg, 44% yield) as a tan amorphous solid. LRMS (ESI) m/z calcd for C21H16F3N6O (M+H) 425.1. found 425.4.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][O:22][CH3:23])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].[H-].[Na+].[I-].[Na+]>>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[C:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: COCCn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O

Procedure:
The method described in Example 1254 was used to treat 1-(4-chlorobutyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.1 g, 3.3 mmol) with methanesulfonamide pretreated with sodium hydride in the presence of sodium iodide. The crude was purified by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 600 mg of N-{4-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]butyl}methanesulfonamide as white crystals, mp 159-161° C.