Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])=[N:13][N:12]=1>O.C1COCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccn4)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccn4)o3)cc2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Lithium hydroxide monohydrate (60 mg) in water (2 mL) was added to a stirred suspension of methyl {trans-4-[4-({[5-(pyridin-2-ylamino)-1,3,4-oxadiazol-2-yl]carbonyl}amino)phenyl]cyclohexyl}acetate (Example 105, 309 mg) in THF (7 mL). After 16 hours the solution was heated to 40° C. and stirred for a further 5 hours then allowed to cool to ambient temperature. The THF was removed in vacuo and the residue was acidified with 2M HCl. The precipitate was filtered off, washed with ether, warm DCM and warm ether then dried overnight. The resultant solid was purified by HPLC using a gradient of 5-25% MeCN in water with 1% ammonia as the eluent to give the title compound (119 mg) as a solid; 1H NMR δ 10.80 (1H, bs), 10.91 (1H, s), 8.31 (1H, d), 7.86 (2H, m), 7.69 (2H, d), 7.23 (2H, d), 7.05 (1H, m), 2.45 (1H+DMSO, m), 2.14 (2H, d), 1.82 (5H, m), 1.47 (2H, m), 1.13 (2H, m); MS m/e MH+ 422.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
In an alternative procedure a solution of 4-fluorobenzaldehyde O-methyloxime (0.82 g, 5.35 mmol) in acetic acid ( 8 ml ) was treated at 10° C. with sodium cyanoborohydride (0.67 g, 10.7 mmol) added in small portions over 10 min and the resulting solution was stirred at 25° C. for 18 h. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water and the pH was adjusted to 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with ether and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution hexane-ethyl acetate, 8:2) and distilled in vacuo to give 0.62 g (75% yield) of the title amine as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].CC(C)=[O:18].[Mn]([O-])(=O)(=O)=O.[K+].C(O)(C)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([OH:18])=[O:6]
Reactant: CC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Temperature: 50 °C

Procedure:
2,3-Dimethoxy-6-nitrobenzaldehyde (40.0 g, 0.19 mole) was treated with acetone (275 mL) and warmed to 50° C. A solution of potassium permanganate in water (60 g/L) was added slowly at 50°-70° C. over a period of 16-20 hours until thin layer chromatographic analysis revealed complete absence of the starting material. Isopropanol (7.5 mL) was then added and the mixture was heated an additional hour. The precipitated manganese dioxide was removed by filtration and the filter cake was washed with 3% aqueous potassium hydroxide (ca 175-200 mL). The combined filtrates were acidified with hydrochloric acid and the precipitate was collected by filtration and dried in vacuo. The crude product was recrystallized from acetone to give the pure material, 28.3 g (67%), mp 187°-189° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:34])[NH:16][C:17]2[C:18](=[O:33])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:20](=[O:24])[NH:21][C:22]=2[NH2:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:47]1([CH2:50]Br)[CH2:49][CH2:48]1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15](=[O:34])[NH:16][C:17]2[C:18](=[O:33])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:20](=[O:24])[N:21]([CH2:50][CH:47]3[CH2:49][CH2:48]3)[C:22]=2[NH2:23])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester in N,N-dimethylformamide (2.5 g, 5.17 mmol) at 25° C. under argon was treated with potassium carbonate (6.43 g, 46.53 mmol) followed by cyclopropyl methyl bromide (752 mg, 7.76 mmol). The suspension was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with a solution of water (100 mL) and a 1.0N aqueous hydrochloric acid solution (31 mL). The resulting suspension was diluted with chloroform and neutralized with a 1.0N aqueous hydrochloric acid solution. The layers were separated. The aqueous layer was extracted with chloroform. The organics layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 97/3 methylene chloride/methanol) afforded (4-{[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (1.45 g, 52%) as an orange foam; EI-HRMS m/e calculated for C28H32FN5O5 (M+) 537.2387. found 537.2387.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:33])[N:6]([C:30](=[O:32])[CH3:31])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:27][C:26]4[C:22](=[N:23][N:24]([CH3:28])[CH:25]=4)[CH2:21]3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)[CH3:3].[I-].[Na+].[C:36]([O:40][P:41]([O-:48])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([O:40][P:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][CH:2]([O:4][C:5](=[O:33])[N:6]([C:30](=[O:32])[CH3:31])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:27][C:26]4[C:22](=[N:23][N:24]([CH3:28])[CH:25]=4)[CH2:21]3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)[CH3:3])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 65 °C
Yield: 76.5 %

Procedure:
To a solution of 2b (75 mg, 0.16 mmol) in THF (1.5 mL) was added sodium iodide (66 mg, 0.44 mmol) and the tetrabutylammonium salt of di-tert-butylphosphate (200 mg, 0.04 mmol). The reaction mixture was heated at 65° C. for 48 h, concentrated in vacuo, dissolved in DMSO, filtered, and purified directly by HPLC (C-18 column, 30-100% gradient elution, MeCN:H2O). Fractions containing product were lyophilized to give 20 mg (20%) of the title compound as a 1:1 mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 7.44-7.39 (m, 1H), 7.17-7.14 (m, 1H), 6.90-6.85 (m, 1H), 6.45-6.38 (m, 1H), 4.85-4.75 (m, 1H), 4.48-4.46 (m, 4H), 4.25-4.08 (m, 2H), 3.95-3.77 (m, 2H), 3.85 (s, 3H), 2.47-2.48 (m, 3H), 1.56-1.54 (m, 3H), 1.41-1.40 (m, 18H). MS 654 (M+1)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCC1(O)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCOCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (16.6 g, 79.0 mmol) in dichloromethane (250 mL) and triethylamine (14.3 mL, 102.7 mmol) was cooled to 4° C. A solution of 4-aminomethyltetrahydropyran-4-ol (11.4 g, 86.9 mmol) in dichloromethane (70 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to stir at ambient temperature over the weekend and then it was concentrated under reduced pressure. The residue was stirred with water (300 mL). The resulting solid was isolated by filtration, rinsed with water, and dried in a vacuum oven at 50° C. for 4 hours to provide 22.53 g of 4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol.
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>O1CCOCC1>[C:2]12([NH:12][S:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
1-Adamantanamine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 30.3% yield and used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:32][C:31]5[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(CN2CCn3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)c1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-methoxybenzyl chloride, to give the desired product as a white solid (74%).
Reaction SMILES: C([S:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[SH:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)C(C)SC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)C(C)S
Temperature: -15 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Under nitrogen atmosphere, a mixture of 40.00 g (0.192 mol) of ethyl 3-acetylthio-2-methylbutyrate and 800 ml of ethanol was cooled to −15° C., 72.01 g (0.212 mol, 1.1 Eq) of a 20% solution of sodium ethoxide in ethanol was added dropwise thereto over 1 hour, and the mixture was stirred for 3 hours. The reaction mixture was neutralized with 15.00 g of acetic acid, and then ethanol was evaporated off under reduced pressure. After addition of an aqueous sodium chloride solution to the residue, extraction with diethyl ether was performed. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and brine (twice). The solvent in the organic layer was evaporated off, and vacuum distillation (35 to 36° C./2 torr) was performed to give 17.63 g of the objective compound (GC purity: 99.3%, yield: 56.1%, diastereomer ratio: 80.6/19.4).
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[CH:17][CH:16]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(=O)OC(c1ccccc1)c1ccc(Cl)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a stirred solution of (6-chloropyridin-3-yl)(phenyl)methyl acetate (0.52 g, 2.0 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (2.0 mL, 9.8 mmol) in anhydrous dichloromethane (10 mL) was added titanium tetrachloride solution (1M in toluene, 4.4 mL, 4.4 mmol) dropwise at 0° C. under argon. After stirring at 0° C. for 48 hrs (refrigerator) and room temperature for 5 hours, the mixture was poured into a saturated aqueous sodium bicarbonate solution (40 mL) maintained at 0° C. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.48 g, 1.6 mmol, 80% yield) as a colorless liquid. MS found: (M+H)+=304.25.
Reaction SMILES: O[CH:2]1[C:6]2[S:7][CH2:8][CH2:9][S:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[N:20]1([C:26]([CH:28]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[C:4](=[O:11])[C:5]3[S:10][CH2:9][CH2:8][S:7][C:6]=3[CH:2]2[CH2:28][C:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[CH:13][CH:14]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Reactant: COc1ccc(N2C(=O)C3=C(SCCS3)C2O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(SCCS3)C2CC(=O)N2CCCCC2)cc1
Yield: 71.5 %

Procedure:
2,3,6,7-Tetrahydro-7-hydroxy-6-(4-methoxyphenyl)-5H-1,4-dithiino[2,3-C]pyrrol-5-one (1.48 g) and piperidinocarbonylmethylenetriphenylphosphorane (3.4 g) were dissolved in toluene (30 ml) under heating, and the solution was refluxed for 12 hours. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (methylene chloride:ethyl acetate=10:1). The thus-obtained crude crystals were recrystallized from ethyl acetate-ether to give crystals (1.45 g) of 2,3,6,7-tetrahydro-6-(4-methoxyphenyl)-7-piperidinocarbonylmethyl-5H-1,4-dithiino[2,3-C]pyrrol-5-one, melting at 163°-164° C. and 183°-185° C. (double melting).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])O[C:11](C)(C)[O:12][C:13]=1[CH3:14].C=[N:19][C:20]([CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])[N:19]([C:20]([CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH3:21])[CH2:11][O:12][C:13]=1[CH3:14]
Reactant: CC1=C(c2ccccc2F)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1cccc(Cl)c1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cccc(Cl)c2)CO1
Yield: 83.2 %

Procedure:
Xylene (2 ml ) was added to a mixture of 5-(2-fluorophenyl)-2,2 ,6-trimethyl-2H,4H-1,3-dioxin-4-one (compound of Example 1 ) (0.71 g) and N-methylene-1-methyl1-(3-chlorophenyl)ethylamine (compound of Example 3) (0.6 g), and the resulting mixture was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: NCCCN1CCOCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCCN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-morpholin-4-ylpropyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 1.0 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 1.6 mmol of 3-morpholin-4-yl-propylamine. LC/MS [4.66 min; 485 (M+1)]
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[O:37]1[CH2:38][CH2:39][N:34]([CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:35][CH2:36]1
Reactant: C1COCCN1
Reactant: CCC(Br)CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1)N1CCOCC1
Yield: 53.7 %

Procedure:
A solution of (2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid amide (Example 24; prepared as described in Reaction Scheme 1; 0.20 g, 0.44 mmol), Et3N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7 mmol) in CH2Cl2 (2 mL) was stirred at rt for 18 h. The reaction was then concentrated to give a crude white wax which was purified by flash chromatography (SiO2, 85% EtOAc/5% hexanes/10% MeOH) to afford the title compound (112 mg) as a white solid in 54% yield. MS (ESI), (M+H)+ 474.4; 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (br s, 1H) 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (br s, 4H), 2.27 (m, 2H) 1.15-1.62 (m, 9H), 0.80 (d, 6H, J=6.0).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].S(=O)(=O)(O)O.[F:12][C:13]1[CH:27]=[CH:26][C:16]([CH:17](O)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:26][CH:27]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: OCCCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCCCCl)c2ccc(F)cc2)cc1
Yield: 75 %

Procedure:
A mixture of 4-chloro-1-butanol (6.51 g, 60 mmol), 1 mL of concentrated sulfuric acid and 4,4′-difluorobenzhydrol (2.2 g, 10 mmol) in 50 mL of toluene was heated at reflux for 12 h. The reaction mixture was cooled, washed successively with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. The resultant brown oil was purified on a silica gel column. Elution with 2% ethyl acetate/hexane afforded 2.33 g (7.5 mmol, 75%) of the product as a colorless oil. 1H NMR (CDCl3): δ 1.71-1.80 (2H, m), 1.84-1.93 (2H, m), 3.43 (2H, t, J=6.0), 3.52 (2H, t, J=6.4), 5.30 (1H, s) 6.95-7.02 (4H, m), 7.24-7.29 (4H, m)
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:42][CH3:43])[C:7]([NH:30][CH:31]2[CH2:34][N:33]([C:35](OC(C)(C)C)=[O:36])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].F[C:45](F)(F)[C:46](O)=O>ClCCl>[C:35]([N:33]1[CH2:34][CH:31]([NH:30][C:7]2[N:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)[CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5][C:6]=2[CH2:42][CH3:43])[CH2:32]1)(=[O:36])[CH:45]=[CH2:46]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1NC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)N1CC(Nc2nc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)c(C(N)=O)nc2CC)C1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 3-{[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}azetidine-1-carboxylate (130 mg), and dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0° C., followed by stirring for 2 hours. The solvent was evaporated, and subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To a mixture of the obtained residue and chloroform (4 mL) were added diisopropylethylamine (140 μL) and acryloyl chloride (40 μL) under ice-cooling, followed by stirring at room temperature for 8 hours. The reactant was subjected to liquid separation by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-[(1-acryloylazetidin-3-yl)amino]-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (18 mg).