Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)cc(C)c1C
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc[nH]c2=O)c1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (105 mg, 0.25 mmol) in CH3CN (5.0 mL) was added TMSI (71.7 μL, 0.50 mmol) drop wise. The reaction was stirred at 55° C. for 1 hour. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (82 mg, 81%). ESI-MS m/z calc. 401.5. found 402.5 (M+1)+. Retention time 1.18 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].[OH-].[K+].[C:11]1([C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:20][CH2:21]Br)[C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:23]1([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]#[N:19])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1CCNCC1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.1 %

Procedure:
To 1.96 parts of piperidine is added 1.91 parts of potassium iodide and 25 parts deionized water under a nitrogen atmosphere. The mixture is gently warmed and 1.65 parts of potassium hydroxide and 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile are added. The temperature is raised to reflux and maintained thereat for 4.5 hours. After cooling to room temperature, the reaction mixture is extracted three times with 14 part portions of ethyl ether. The ether extracts are combined, and extracted four times with 25 parts by volume portions of a dilute acetic acid solution. The acid extracts are combined, neutralized to about pH 10 with 50% sodium hydroxide solution, and extracted again with ethyl ether. The ether extracts are combined, washed twice with 50 parts by volume portions of a saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent is removed under reduced pressure to afford, as an off-white solid, in 86.1% yield, 2,2-diphenyl-4-piperidinobutyronitrile. This compound melts at 74° - 77° C., and is represented by the following structural formula. ##STR16##
Reaction SMILES: [I:1][C:2]1[C:19]([OH:20])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:2]1[C:19]([OH:20])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1CNCCc2nc(O)c(I)cc21

Procedure:
To a solution of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol hydrobromide (1.76 g, 6.79 mmol) in DCM (50 ml) and DMF (10 ml) was added Et3N (2.90 ml, 20.7 mmol) and TFAA (1.00 ml, 6.90 mmol). The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and parted between sat. aq. NaHCO3 and EtOAc. The organic phase was dried, concentrated in vacuo and purified by column chromatography to yield 1.46 g (77%) of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (DMSO-d6) δ 11.43 (br s, 1H), 7.30 (m, 1H), 6.18 (m, 1H), 3.95-3.42 (m, 4H), 3.06-2.96 (m, 2H), 2.95-2.87 (m, 1H), 1.12 (2× d, 3H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.36 g, 4.96 mmol) and NIS (1.12 g, 4.96 mmol) in TFA (2 ml) and AcOH (36 ml) was stirred at room temperature for 16 h. Evaporation of TFA and AcOH followed by chromatographic purification of the resulting residue gave 1.95 g (98%) of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 4.17-3.41 (m, 4H), 3.20-2.94 (m, 3H), 1.26 (2× d, 3H) ppm. A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (50.0 mg, 125 μmol) and K2CO3 (17.3 mg, 125 μmol) in MeOH (10 ml) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 20.2 mg (53%) of 3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.90 (s, 1H), 3.09-2.80 (m, 7H), 1.28 (d, 3H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]([O:29][Si](C)(C)C)[C:27]#N)[CH:23]=[CH:24][CH:25]=1.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1CI)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@@H:42]1[CH2:27][C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)=[O:29])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Reactant: C[Si](C)(C)OC(C#N)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(=O)c1cccc(Cl)c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
Diisopropylamine (764 uL, 5.4 mmol) was dissolved in THF (15 mL) under nitrogen and cooled to −70° C. Then a 1.6 M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) was added and stirring at −70° C. was continued for 15 min. Then a solution of (3-chloro-phenyl)-trimethylsilanyloxy-acetonitrile (1.18 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 30 min, producing a yellow color. Then a solution of (S)-2-iodomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.53 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 5 h and then allowed to warm up to 20° C. and stirred overnight. The mixture was extracted with AcOEt, 1 M citric acid, and 50% NaCl. The crude product was purified by flash chromatography on silica gel with a heptane/AcOEt gradient 0-15%. One obtained 500 mg (31%) of a yellow oil. MS: m/z=224 [M+].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=[N:7]2)[CH2:2]1.Br[C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO>[O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH:10]=[C:9]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)[CH:8]=[N:7]2)[CH2:2]1
Reactant: Nc1ncc(Br)cn1
Reactant: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCOC3)c2)cn1
Temperature: 100 °C

Procedure:
To a solution of 1-(Tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.42 mmol) in 1,4-dioxane (3 mL) was added EtOH (1 mL) and water (0.4 mL). The following reagents were added successively: 5-bromopyrimidin-2-amine (75 mg, 0.43 mmol), potassium carbonate (180 mg, 1.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (20 mg, 0.02 mmol). The vessel was purged several times with N2 and heated to 100° C. for 4 h. The reaction mixture was filtered through a pad of Celite, concentrated, and purified by chromatography on silica gel (40 g column, 0-15% MeOH/methylene chloride) to afford the desired product. LCMS: (M+H)=232.0.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55]>>[CH3:1][N:2]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: O=C(CCl)N1CCOCC1
Product: CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 364.5 %

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 102 mg 4-(2-chloroacetyl)-morpholine were reacted in the same manner as in Example 746, to give 0.43 g 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methyl-(2-morpholin-4-yl-2-oxoethyl)amide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 63 mg of the title compound as orange crystals.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]1[C:21]2[N:20]3[CH:22]=[CH:23][N:24]=[C:19]3[C:18](=[O:25])[NH:17][C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)=[O:7])(C)(C)C.CS(C)=O.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O>[C:6]([CH2:8][CH:9]1[C:21]2[N:20]3[CH:22]=[CH:23][N:24]=[C:19]3[C:18](=[O:25])[NH:17][C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 107 h
Yield: 42 %

Procedure:
A mixture of 1 g of 10-(tert-butoxycarbonyl-methyl)-5H,10H-imidazo[l,2-a]indeno[1,2-e]pyrazin-4-one, 5 ml of dimethyl sulphoxide and 25 ml of 3N hydrochloric acid in ethyl ether is stirred, under cover of argon, for 107 hours at a temperature in the region of 20° C. After concentration under reduced pressure, the residue is crystallized from 30 ml of acetone. The solid obtained is treated with 50 ml of water and 7 ml of saturated sodium hydrogen carbonate solution; three extractions with dichloromethane (3×50 ml) are performed on this mixture, the aqueous phase is filtered and the aqueous solution is acidified with 8 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried at 80° C. under vacuum (1 mmHg; 0.13 kPa) to give 0.35 g of 10-(carboxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one in the form of a greenish solid melting above 260° C. (Analysis, % calculated C: 64.05, H: 3.94, N: 14.94, O: 17.06, % found C: 63.7, H: 3.2, N: 14.9).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]1([F:28])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](=C)[C:20](=O)[CH2:21][C:22](OC)=O)=[CH:18][C:12]=2[O:11]1>CO>[F:28][C:10]1([F:9])[O:14][C:13]2[CH:15]=[CH:16][C:17]([CH:19]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:8])[NH:1][C:21]([CH3:22])=[C:20]3[C:4]([O:6][CH3:7])=[O:5])=[CH:18][C:12]=2[O:11]1
Reactant: C=C(C(=O)CC(=O)OC)c1ccc2c(c1)OC(F)(F)O2
Reactant: COC(=O)/C=C(/C)N
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)OC(F)(F)O2

Procedure:
20 mmol of methyl β-aminocrotonate and 20 mmol of crude methyl (2,2-difluoro-1,3-benzodioxol-5-yl)-methylene-acetoacetate are heated under reflux in 30 ml of methanol for 12 hours, the methanol is evaporated off and the residue is chromatographed on silica gel with chloroform. The evaporated product fraction is taken up in a little methylene chloride and the mixture is foamed to a glass by rapid evacuation.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[Cl:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.18 g, 0.65 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.017 g, 0.72 mmol) was added. The reaction was allowed to stir for 15 minutes at rt. 4,7-Dichloro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.33 mmol) was added and the reaction was heated to 140° C. for 5 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude solid was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane, followed by further purification by preparative reverse phase HPLC to afford 1-(7-chloro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=544.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, d, J=2.3 Hz), 7.90 (1H, d, J=9.0 Hz), 7.54-7.65 (3H, m), 7.35-7.42 (2H, m), 7.11 (1H, d, J=8.2 Hz), 6.30 (1H, dd, J=8.2, 2.3 Hz), 5.57 (1H, d, J=2.3 Hz), 4.06 (1H, d, J=9.4 Hz), 3.80-3.92 (3H, m), 3.56-3.63 (4H, m), 3.40-3.54 (2H, m), 2.83-2.89 (4H, m), 2.06 (3H, d, J=1.6 Hz), 1.88-2.03 (2H, m), 1.81-1.87 (1H, m), 1.66 (1H, dt, J=13.4, 1.1 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:25][C:24]([O:23][CH3:22])=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of 3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 10.7 mmol) in DMF (40 mL) was added Bromo-acetic acid methyl ester (1.01 mL, 10.7 mmol) and K2CO3 (1.48 g, 10.7 mmol). The resultant suspension was stirred at 70° C. overnight. The reaction mixture was diluted with water and ethyl ether. The organic extract was dried over MgSO4, filtered and concentrated to provide the desired product as an oil. The crude product was purified on SiO2 and concentrated to provide the desired product as an oil (3.5 g, 87%). LCMS (retention time=2.96, ES+383)
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C(=[N:27][CH:28]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:27][CH:28]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
According to the method described in the document (J. Am. Chem. Soc., (2003), 125, 5139-5151), a 1 M citric acid aqueous solution (52 mL) was added to a THF (52 mL) solution of tert-butyl 2-[(diphenylmethylene)amino]-3-[4-(trifluoromethoxy)phenyl]propanoate (2.44 g, 5.21 mmol) prepared in Reference Example 1 (1a). The mixture was stirred at room temperature for 4 hours. The reaction solution (mainly THF) was evaporated, neutralized with a sodium bicarbonate aqueous solution, and then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 94:6, 3:7, and 1:9, V/V) to give 1.5 g of the title compound (colorless oil, yield: 95%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Br.O1CC[CH2:25][CH2:24]1>CCOCC>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH3:25])([OH:18])[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl(4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 Methylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45]([OH:47])=[O:46])O1>O1CCOCC1.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:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=3)[C:45]([OH:47])=[O:46])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 98.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (100 mg, 0.26 mmol) in dioxane (9 mL)/water (3 mL) were added potassium carbonate (217 mg, 1.57 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (65 mg, 0.39 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (120 mg, 98%). LC-MS m/z 469 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH3:22]
Reactant: COC(=O)c1cc2cc(OC)ccc2cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc2cc(OC)ccc2cc1/N=C/N(C)C
Temperature: 25 °C

Procedure:
A suspension of 1.2 g (5.2 mmol) of methyl 3-amino-7-methoxy-2-naphthoate in 30 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours. The mixture is cooled to room temperature. The resulting precipitate is collected by filtration and washed with ether. After drying in vacuo, this yields 1.28 g (85.9%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate as a light yellow solid, mp 160–162° C.,
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].C(O)(=O)C.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:31]1([CH2:34][NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:33][CH2:32]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 378.6 %

Procedure:
cis-N-(2-Amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) (200 mg, 0.05 mmol) was dissolved in 10 mL methanol. Acetic acid (0.156 mg, 2.6 mmol) and cyclopropanecarboxaldehyde (73 mg, 1 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (221 mg, 1 mmol) was added at stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Crystallization with diisopropylether and a small amount of dichloromethane yielded cis-N-[2-(cyclopropylmethyl-amino)-cyclohexyl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide as a white solid (83 mg, 36%), MS: m/e=439.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]([CH3:11])[CH:10]=1)=[N:6][CH:5]=[N:4]2.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:9]([CH3:11])=[N:8][C:7]2[N:3]([N:4]=[CH:5][N:6]=2)[C:2]=1[OH:1]
Reactant: Cc1cc(O)n2ncnc2n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2ncnn2c(O)c1Br
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of 4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene (15.0 g, 0.1 mol) in acetic acid (100 ml) was treated dropwise at 20° C. with a solution of bromine (16.172 g, 0.102 mol) in acetic acid (20 ml). As the reaction progressed, the suspended crystals dissolved and new crystals of brominated product were formed. After about 2 hours, the reaction mixture was poured into water (250 ml) and crystals were collected by filtration. The crude product was purified by first converting into its sodium salt by dissolving 22 g in one liter of hot aqueous 0.2N sodium carbonate and then slowly acidifying with dilute hydrochloric acid. The unchanged starting material was converted into a soluble salt by addition of excess of triethylamine. Crystals were then collected and recrystallized from hot water to give 19 g (82%) of Compound TAI-4 as white needles, m.p.=269° C.