Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][NH:21][C@H:22]1[CH2:27][NH:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:20][N:21]1[C:2](=[O:4])[N:26]2[CH2:27][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 125 %

Procedure:
Triphosgene (21.3 g, 72 mmol) was added in portions to a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL) at 0° C. After stirring at 20° C. overnight, the reaction mixture was washed with H3PO4 (10%), sat. NaHCO3 and saturated NaCl. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50%) as a yellow solid. 1H NMR (400 Mz, CDCl3): δ 7.43-7.36 (m, 5H), 5.06 (d, J=11.4 Hz, 1H), 4.90 (d, J=11.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.32-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.93 (d, J=11.9 Hz, 1H), 2.14-2.05 (m, 2H), 2.05-2.00 (m, 1H), 1.71-1.63 (m, 1H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:54]([C:51]3[CH:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][CH:50]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: COc1ccc(N)cc1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(OC)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 62 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (5.0 g, 7.83 mmol) and p-anisidine (1.93 g, 15.65 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 62%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (80 mg, 0.11 mmol) gave the title compound (50 mg, 74%) as white crystals.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(O)(=O)C>[CH3:1][S:2][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:20])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: COC(=O)C(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 99.5 %

Procedure:
Methyl α-methylthio(p-aminophenyl)acetate (760 mg) and 533 mg of phthalic anhydride were dissolved in 8 ml of acetic acid, and the solution was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of an aqueous solution of sodium bicarbonate was added. The mixture was extracted once with 20 ml of methylene chloride, and then twice with 10 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.222 g of methyl α-methylthio(p-phthalimidophenyl)acetate as colorless crystals in a yield of 99.5%.
Reaction SMILES: C(=O)(O)N.[F:5][C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:19])O)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])[N:28]=[CH:27][N:26]=[C:25]2[O:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]([NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:38]([O:37][C:25]3[C:24]4[C:29](=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:28]=[CH:27][N:26]=3)[CH:39]=2)=[O:19])[CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(O)Nc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Agent: NC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(F)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used reacting 3-fluoro-4-(trifluoromethyl)phenylcarbamate carbamate as described in Example 150 (135 mg, 0.45 mmol) with amine 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 126 mg of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea. 1H (DMSO-d6) 9.50 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.70 (m, 2H), 7.60 (s, 2H), 7.35 (m, 2H), 7.30 (m, 2H), 7.00 (m, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.84 (m, 2H), 3.40 (s, 3H). LCMS (ESI) m/z 547 (M+H)
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[C:27]([C:37](O)=[O:38])[CH:28]=[C:29]([Cl:36])[CH:30]=4)[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[C:27]([C:37]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:38])[CH:28]=[C:29]([Cl:36])[CH:30]=4)[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(C)(=O)=O)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (314 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (69 mg, 40%) as a white solid: LC/MS m/e calcd for C29H33ClN2O3S (M+H)+: 526.11, observed: 525.1.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[N+:9]([O-:12])(O)=[O:10].[CH:13]12[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:23]1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=1>C(Cl)Cl>[N+:9]([C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:23]3)[C:19]=2[CH:18]=1)([O-:12])=[O:10]
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to −78° C. and treated with 1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.5 g, 13.7 mmol) in CH2Cl2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was stirred at −78° C. for 30 minutes then warmed to 0° C. for 1 hour. The reaction mixture was poured into a vigorously stirred ice (100 g). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×30 ml). The organic layer was combined and washed with H2O (3×30 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (20 mL) and H2O (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4.2 g). Chromatography yielded pure product as a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanes Rf 0.23). 1H NMR (400 MHz, CDCl3 8.12 (br d, J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43–3.35 (m, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS m/e 300 (M+).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1

Procedure:
4-(5-Chloro-1-methyl-1H-imidazol-4-yl)benzonitrile (1 g), 4-chlorobenzenethiol (797 mg), and 1.3 ml of triethylamine in 20 mL of DMF were heated in a microwave tube at 180° C. for 90 min. The reaction mixture was purified by reverse phase HPLC with MS detector to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.21 (d, 2H), 7.83 (s, 1H), 7.66 (d, 2H), 7.45 (d, 2H), 6.98 (d, 2H), 3.63 (s, 3H). LCMS: [M+1]=326.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[CH3:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1B(O)O>COCCOC.C(OCC)(=O)C>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]4[C@H:6]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]34)[CH:10]=2)=[C:27]([CH3:26])[CH:32]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A (80 mg, 0.18 mmol) in 25 mL of DME (10 mL) was added 2-methyl-4-methoxyphenyl boronic acid (45 mg, 0.27 mmol) and TEA (0.26 mL, 1.8 mmol). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(dppf)2 (15 mg, 0.1 mmol) and the mixture was stirred at 85° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with sat'd aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford (35 mg, 45% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 7.13 (d, 1H, J=8.1 Hz), 6.97 (s, 1H), 6.75 (m, 3H), 3.83 (s, 3H), 3.79 (m, 1H), 3.65 (m, 2H), 3.52 (m, 3H), 3.21 (m, 2H), 3.01 (m, 2H), 2.24 (s, 3H), 1.97 (m, 2H), 1.60 (m, 2H), 1.21 (s, 9H). LRMS (ES+): 467 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[OH:16])=[CH:5][CH:4]=[N:3]1.Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=[N:3]1
Reactant: BrCc1ccccn1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCc1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
A mixture of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (100 mg, 0.46 mmol), 2-bromomethylpyridine hydrobromide salt (140 mg, 0.55 mmol) and potassium carbonate (158 mg, 1.15 mmol) in DMSO (4 mL) was stirred at 100° C. overnight. The crude was purified by HPLC to provide the title compound as a brown solid (158 mg, 81%). Exact mass calculated for C16H14N4O3 310.1. found 311.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][C:31]#[N:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Yield: 92.1 %

Procedure:
A mixture 9-benzyl-6-methyl-9H-carbazol-4-ol (1.4172 g, 0.0049 mol), potassium carbonate (0.8184 g, 0.0059 mol), bromoacetonitrile (0.75mL, 0.011 mol) and DMF (18 mL) is stirred at room temperature for 3 h. The mixture is then partitioned between water and dichloromethane and the combined organic layers are dried over sodium sulfate and concentrated to a residue. Water is added to the residue and solids precipitated. The solids are collected by filtration and washed with water, followed by a little hexane, and then vacuum dried at room temperature. The solids are chromatographed on silica gel (150 mL) using dichloromethane (100%) to give 1.4723 g (91%) of the title compound. An aliquot is recrystallized from ethyl acetate/hexane, chromatographed on silica gel (50 mL) using ethyl acetate/hexane (20/80) and then recrystallized again from ethyl acetate/dichloromethane/hexane; mp 188-188.25° C.; MS (ESI+) for C22H18N2O m/z 327.2 (M+H)+; IR (drift) 1497, 1467, 1447, 1365, 1340, 1305, 1264, 1237, 1152, 1126, 1053, 799, 781, 754, 711 cm−; 1H NMR (CDCl3) δ2.54, 5.06, 5.49, 6.73, 7.10, 7.25, 7.36, 8.10. Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.62; H, 5.68; N, 8.55.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CS(C)=O>[CH2:3]([C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCI
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC(CCCC)(C(=O)OCC)C(=O)OCC
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A mixture of sodium hydride (50% w/w suspension in mineral oil, 2.40 g, 50.0 mmol) in dimethylsulfoxide (50 mL) was cooled to 5° C., and a solution of diethyl butylmalonate (10.0 mL, 45.5 mmol) in dimethylsulfoxide (10 mL) was added dropwise with vigorous stirring. After 4 hours, the solution was treated with iodooctane (8.20 mL, 44.3 mmol), and the solution was stirred an additional 12 hours. It was poured into water (400 mL), and extracted with ethyl acetate (2×500 mL). The extracts were washed in sequence with water (3×400 mL), then saturated brine (400 mL). The extracts were then combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting oil was separated by flash chromatography (3:97 ethyl acetate-hexane) to afford the product, diethyl butyl-octylmalonate, as an oil (13.7 g, 41.7 mmol, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30](=[O:39])[NH:31][C:32]2[CH:37]=[C:36](Cl)[N:35]=[CH:34][N:33]=2)[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30](=[O:39])[NH:31][C:32]2[CH:37]=[C:36]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[O:9][CH3:10])[N:35]=[CH:34][N:33]=2)[CH2:25]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(OC)c1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Temperature: 90 °C
Yield: 76.3 %

Procedure:
To a solution of 2,6-dimethoxyphenyl boronic acid (0.60 g, 3.3 mmol) in a mixture of dimethoxyethane/water (8 ml, 3:1), 3-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (0.82 g, 2.2 mmol) was added followed by tetrakis(triphenylphospine) palladium(0) (0.15 g, 0.13 mmol) and saturated solution of potassium carbonate (2 ml). The reaction mixture was heated at 90° C. for 2 h, then it was cooled to room temperature and filtered through a celite bed which was washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography, using hexane/ethyl acetate (4:1) as eluent, to provide 0.80 g (yield: 53%) of 3-[6-(2,6-dimethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30]C)=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO>CC#N>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(C)cc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2cc(C)cnc2O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (70 mg, 0.15 mmol) in CH3CN (3 mL) was added TMSI (44 uL, 0.30 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was re-partitioned between EtOAc and H2O, washed with NaHSO3 (2×), brine, dried over MgSO4 and evaporated to dryness to yield a white solid. The crude material was further purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (62 mg, 91%). H NMR (400 MHz, MeOD) 7.81 (s, 2H), 7.65 (s, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.25 (dd, J=1.7, 8.3 Hz, 1H), 7.17-7.14 (m, 2H), 2.29 (s, 3H), 2.03 (s, 3H), 1.57 (dd, J=4.0, 7.0 Hz, 2H), 1.15 (dd, J=4.0, 7.0 Hz, 2H). Retention time: 1.42 min; ESI-MS m/z calc. 439.4. found 440.5 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20](Br)Br)([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[Ca+2].O>C(O)C>[CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20]=[O:24])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1c(C(Br)Br)c(-c2ccc(F)cc2)c2cccnc21
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2cccnc21

Procedure:
1 g of the product of step 1, above, in 35 ml of 100% ethanol is mixed with 0.4g of calcium carbonate (powdered) and 15 ml of water. The mixture is refluxed for about 4 hours, then cooled, quenched with water and extracted with ethyl acetate. The extracts are dried and then evaporated to dryness to yield a dark amber gum, which is chromatographed on prep. plates, using petroleum ether/ether (85/15) and the largest (second of three) major band eluted with ethyl acetate to obtain the title product of this example as yellow solids, mp 95°-101°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:8][OH:9])[NH2:7].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C>O1CCOCC1.B(F)(F)F.C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[O:9][N:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=NO)c1ccco1
Agent: C
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3ccco3)no2)cc1
Yield: 74.6 %

Procedure:
To a solution of 2-furanamidoxime (12.6 g, 0.1 mole) and p-nitrobenzoyl chloride (18.1 g, 0.1 mole) in 500 ml of dry dioxane, 1 ml of BF3 -ethyl ether is added and the mixture is heated to reflux for 16 hours. Evaporation of the solvent in vacuo gives a light brown solid. It is decolorized with Darco (CHCl3) and crystallized from ethanol-acetonitrile to give 19.2 g (75%) of product, m.p. 168°-170° .
Reaction SMILES: [H-].[Na+].[C:3]([OH:5])#N.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH2:6]([O:5][CH2:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of 1.1 g of sodium hydride (21 mmole, 50% oil dispersion) in 25 ml of dry DMF at 0° C. was added a solution of 3.34 g of Example 1 Part G cyanoalcohol (20 mmole) in 10 ml of DMF over a period of 10 minutes. After stirring for an additional b 15 minutes, 3.6 g of benzyl bromide was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. and 3 hours at 25° C. then quenched with a saturated ammonium chloride solution, and diluted with ether. The organic layer was washed with brine. The combined aqueous layer was re-extracted with ether. The combined organic layer was dried over anhydrous MgSO4 and concentrated to leave an oil. The crude oil was chromatographed on a silica gel column, eluting with 10-20% ethyl acetate in hexanes to give 4.43 g of the title A benzyl ether.