Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ncccc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20 mL sealed tube was placed 2-chloro-3-(trifluoromethyl)pyridine (500 mg, 2.76 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.705 g, 5.52 mmol, 2.00 equiv), PCy3 (216.4 mg, 0.77 mmol, 0.28 equiv), Pd2(dba)3 (304.7 mg, 0.33 mmol, 0.12 equiv), NaOt-Bu (828 mg, 8.28 mmol, 3.00 equiv), dioxane (8 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (10:1). This resulted in 449.3 mg (46%) of tert-butyl 4-(3-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:21]([O:20][C:18]([C:13]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A solution of diisopropylamine (1.0 mL, 7.7 mmol) in 20 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under argon. n-Butyl lithium in hexanes (2.5 M, 3.6 mL, 7.7 mmol) was added all at once and the mixture was stirred for 0.5 hour and transferred to a precooled (−30° C.) solution of 1.0 g (7.0 mmol) of ethyl cyclopentane carboxylate in 10 mL of THF. After a further 45 min, benzyl bromide (0.92 mL, 7.7 mmol) was added and the mixture was allowed to warm to room temperature over night. The resulting mixture was concentrated, and the residue was taken up in 70 mL of ether, washed with water, 1 N HCl, water, saturated brine and was dried (MgSO4). The residue obtained after filtration and evaporation was purified by flash chromatography over 100 g of silica gel, eluting with 3% ethyl acetate-hexane to give 1-benzylcyclopentane carboxylic acid ethyl ester (0.80 g, 45%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl.ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(CCCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound (2.50 g), which had been obtained in (1), in anhydrous dichloromethane (25 ml), trifluoroacetic acid (15 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 15 minutes and at room temperature for 15 minutes. The reaction mixture was diluted with 1,2-dichioroethane and concentrated by evaporation under reduced pressure. The residue was washed successively with hexane and diethyl ether by decantation and then the solvent was distilled off, whereby crude (3S)-3-[4-[2,3,-di(4-nitrobenzyloxycarbonyl)guanidino]butanoylamino]pyrrolidine trifluoroacetate (2.55 g) was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [N:1]([C@@H:4]([CH3:19])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]=[CH:15][C:13]3=2)[CH:8]=[N:7]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>C1COCC1>[CH3:19][C@H:4]([NH2:1])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]=[CH:15][C:13]3=2)[CH:8]=[N:7]1
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C=CCO3)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ncc2ccc3c(c21)C=CCO3
Temperature: 25 °C

Procedure:
To a solution of the product from Example 8, Step B (0.10 g, 0.39 mmol) in dry THF (20 ml) at 0° C. was added a solution of lithium aluminum hydride (0.39 mL, 1.56 mmol of a 1 M solution in THF) and the mixture was allowed to warm to room temperature (1 h) with stirring. Aqueous potassium hydroxide (2 M, 0.02 mL) was added to the reaction mixture and the solids that formed were removed by filtration. The filtrate was evaporated to a yellow oil (0.05 g, 56%): LC/MS (+APCI) m/z 230. Analysis. Calculated for C13H15N3O.0.17H2O: C, 67.26; H, 6.60; N, 18.10. Found: C, 67.35; H, 6.45; N, 17.76.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH-].[Na+].[CH3:8][O:9][CH2:10][CH2:11][NH2:12]>ClCCl.O>[Cl:1][CH2:2][C:3]([NH:12][CH2:11][CH2:10][O:9][CH3:8])=[O:4]
Reactant: COCCN
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)CCl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4 g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20 g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-oooled condenser, was placed 35.7 g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1 g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDCl,) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=O)[CH:3]=1.[OH-].[NH4+:15]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:15])=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 4,5,6-trichloropyridine-2-carboxylate (15 g, 62.4 mmol) was suspended in concentrated aqueous ammonium hydroxide (80 mL) and methanol (150 mL). After stirring for 4 hours at 25° C., the methanol was removed and the aqueous suspension was filtered. The filter cake was washed with water and dried to provide 4,5,6-trichloropyridine-2-carboxamide (13 g, 56.9 mmol), mp 169-170° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][OH:26])[C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][O:26][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2c(s1)CCCC2CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1nc2c(s1)CCCC2COS(=O)(=O)c1ccc(C)cc1

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. The product is an undistillable oil which is used crude for the subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:4]
Reactant: O=C(Nc1ccccc1C(O)C(F)(F)F)c1ccco1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: O=C(Nc1ccccc1C(=O)C(F)(F)F)c1ccco1
Reaction time: 18 h

Procedure:
To a solution of N-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]furan-2-carboxamide from Step 3 (336 mg, 1.18 mmol) and methylene chloride (31 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxyl-3(1H)-one (2.00 g, 4.72 mmol), followed by tert-butanol (3.1 mL) under an argon atmosphere at 23° C. After 18 h, sat'd NaHCO3 (31 mL) was added followed by solid sodium thiosulfate (5.20 g, 32.9 mmol). After 1 h at 23° C., the organic layer was separated from the aqueous. The aqueous layer was extracted with ether (2×100 mL), and the combined organics were washed with sat'd NaHCO3:sat'd Na2S2O3 (3×80 mL) and brine (1×80 mL), and dried (MgSO4). After concentration in vacuo, the crude residue was purified by flash chromatography (ethyl acetate:hexane 1:3) which afforded (312 mg) as a yellow gum: 1H NMR (CDCl3) δ 6.60 (m), 7.20-7.35 (m), 7.67 (br s), 7.75 (m), 8.03 (m), 9.01 (d, J=6 Hz), 11.93 (brs); 13C NMR (CDCl3) 112.5, 114.6, 115.4, 116.1, 118.4, 121.2, 122.4 (q, J=280 Hz), 122.8, 131.8, 131.9, 137.6, 143.1, 145.2, 156.7. MS (EI) 283 (M+), 258, 256, 214. IR (neat) 1674 cm−1. Anal. Calc'd. for C13H8NO3F3: C, 55.13; H, 2.85; N, 4.95. Found: C, 51.01; H, 2.66; N, 4.52.
Reaction SMILES: CN([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=O)C(=O)OC1C=CC=CC=1.NC1C=[C:36]2[C:41](=CC=1)[N:40]([CH2:44]CN(C)C(=O)OC1C=CC=CC=1)[C:39](=O)[CH2:38]C2>C(O)C.C([O-])(O)=O.[Na+]>[CH3:44][N:40]1[CH2:41][CH2:36][CH:15]([N:14]2[CH2:13][CH2:12][CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:21]=[CH:22][C:23]2=3)[CH2:38][CH2:39]1
Reactant: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Reactant: CN(CCN1C(=O)CCc2cc(N)ccc21)C(=O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(N2CCCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of compound 8 (321.6 mg, 1.24 mmol) in dry ethanol (10 mL) was treated with compound 6 (707 mg, 2.48 mmol) at room temperature. The reaction mixture was stirred for 16 hours at room temperature then diluted with saturated NaHCO3 solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4) and concentrated to give a brown residue. The crude product was purified by column chromatography on silica gel (MeOH:CH2Cl2, 2:98 followed by 2 N NH3 in MeOH:CH2Cl2, 4:96 to 5:95) to give compound 39 (374.6 mg, 81.9%) as a yellow residue. 1H-NMR (DMSO-d6) δ 1.56-1.79 (m, 9H), 1.97 (t, 2H, J=10.5 Hz), 2.16 (s, 3H), 2.65 (brs, 2H), 2.80 (d, 2H, J=10.2 Hz), 2.91 (brs, 2H), 3.12 (m, 1H), 6.30 (brs, 2H), 6.59 (m, 2H), 6.89 (d, 1H, J=8.9 Hz), 7.07 (t, 1H, J=4.5 Hz), 7.57 (d, 1H, J=5.1), 7.70 (d, 1H, J=3.5 Hz); ESI-MS (m/z, %) 369 (MH+, 35), 272 (100). ESI-HRMS calculated for C21H29N4S (MH+), calculated: 369.2101; observed: 369.2107; HPLC-purity: 97.31% by area.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH3:16])[CH:7]=[C:6]([CH2:17][S:18]([CH3:20])=[O:19])[N:5]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>[Br-].C([N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC)CCCCCCC.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[Cl:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH3:16])[CH:7]=[C:6]([C:17]2([S:18]([CH3:20])=[O:19])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:5]=1
Reactant: BrCCOCCBr
Reactant: C[C@@H]1COCCN1c1cc(CS(C)=O)nc(Cl)n1
Agent: CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Br-]
Product: C[C@@H]1COCCN1c1cc(C2(S(C)=O)CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
Sodium hydroxide (50% w/w) (20.04 ml, 379.60 mmol) was added to (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.2 g, 7.59 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.79 ml, 30.37 mmol) and tetraoctylammonium bromide (0.415 g, 0.76 mmol) in methyl THF (20.05 ml). The resulting mixture was stirred at RT for 90 minutes. The reaction mixture was diluted with methyl THF (50 mL), and washed sequentially with water (50 ml) and saturated brine (5 ml). The organic layer was dried over MgSO4, filtered and then evaporated onto silica (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (1.360 g, 50%); 1H NMR (400 MHz, DMSO-d6) 1.84-1.96 (1H, m), 2.02 (1H, td), 2.09 (3H, d), 2.27-2.45 (2H, m), 3.14 (1H, d), 3.10-3.26 (3H, m), 3.24 (1H, d), 3.33-3.41 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H, d), 3.78-3.87 (1H, m), 3.87-3.97 (2H, m), 4.07 (1H, d), 4.32-4.48 (1H, m), 6.76 (1H, s); m/z: (ES+) MH+, 360.11 and 362.06. b) Iodobenzene diacetate (0.788 g, 2.45 mmol) was added to (3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (0.88 g, 2.45 mmol), magnesium oxide (0.394 g, 9.78 mmol), 2,2,2-trifluoroacetamide (0.553 g, 4.89 mmol) and rhodium(II) acetate dimer (0.027 g, 0.06 mmol) in DCM (20 ml). The resulting suspension was stirred at RT for 18 hours. The reaction mixture was filtered through Celite and then concentrated in vacuo onto silica (50 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to afford N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (1.018 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.34 (3H, dd), 2.49 (1H, td), 2.63 (2H, ddd), 2.75-2.82 (1H, m), 3.26 (3H, d), 3.29-3.41 (3H, m), 3.49 (1H, s), 3.51-3.60 (1H, m), 3.63-3.73 (1H, m), 3.80 (1H, d), 3.98-4.11 (4H, m), 6.68 (1H, d); m/z: (ES-) M-H−, 469.04 and 471.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])(O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC(O)(Cc1ccncc1)c1ccc(F)cc1
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1

Procedure:
Oxidation of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanediol according to the oxalyl chloride method of Swern [J. Org. Chem., 44, p 4148, 1979)] gave the titled dione following extractive workup and recyrstallization from hexanes m.p. 85-86.5° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1ccc(C#C[Si](C)(C)C)cc1
Yield: 87.1 %

Procedure:
To 15.0 g (75.4 mmol) of 1-n-propyl-4-bromobenzene were added 8.8 g (89.8 mmol) of trimethylsilylacetylene and 100 ml of triethylamine (NEt3), and the reaction system was purged with argon. Next were added 81 mg (0.4 mmol) of copper (I) iodide (CuI), 324 mg (1.2 mmol) of triphenylphosphine, and 162 mg of dichlorobistriphenylphosphine palladium (II) [PdCl2(PPh3)2] to the reaction system, and the mixture was subjected to reaction for 24 hours with heating and refluxing. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. After the resultant water-insoluble oil was extracted with hexane, the hexane phase was washed with water. By removing hexane from the hexane phase, 14.2 g (65.7 mmol) of 1-(4-n-propylphenyl)-2-trimethylsilylacetylene was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.Cl.[NH:14]1[CH2:17][CH:16]([C:18]2[C:23]([Cl:24])=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O.CC#N>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:14]1[CH2:17][CH:16]([C:18]2[C:23]([Cl:24])=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:15]1)=[O:12]
Reactant: Clc1nccnc1C1CNC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 1H-benzoimidazole-2-carboxylic acid (19) (100 mg, 0.47 mmol), 2-azetidin-3-yl-3-chloro-pyrazine hydrochloride (8) (96 mg, 0.47 mmol), HATU (540 mg, 1.3 mmol) and Et3N (101 mg, 1 mmol) in dry DCM (10 mL) was stirred at RT overnight. Then the mixture reaction was poured into saturated aqueous Na2CO3 and extracted with DCM (50 mL×3), the organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude compound which was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) and followed by reverse phase prep. HPLC (10% to 80% water/MeCN) to afford pure (1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (84) (50 mg, 0.16 mmol, yield 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[F:29].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[CH2:20]([O:19][C:17]([N:15]1[CH2:16][C:11]2[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[C:3]([F:29])[CH:4]=3)=[N:13][C:12]=2[CH2:14]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)cc1F
Yield: 22 %

Procedure:
Method as described for example 85 using (S)-ethyl 2-(4-amino-3-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 19) and ethyl isocyanate as starting materials. The solvent was removed in vacuo and the residue purified by prep HPLC (high pH) yielding the title compound (10 mg, 0.021 mmol, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][C:5]1[C:10]([Cl:11])=[CH:9][N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:28][CH3:29])[N:6]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45].CO>C(Cl)Cl.C(Cl)(Cl)Cl>[C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:7]3[N:6]=[C:5]([O:4][C:3]4[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=4[NH:1][C:43](=[O:46])[CH:44]=[CH2:45])[C:10]([Cl:11])=[CH:9][N:8]=3)=[C:14]([O:28][CH3:29])[CH:15]=2)[CH2:20][CH2:21]1)(=[O:27])[CH3:26]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1ncc(Cl)c(Oc2ccccc2N)n1
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C=CC(=O)Nc1ccccc1Oc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2OC)ncc1Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-(4-(4-(2-aminophenoxy)-5-chloropyrimidin-2-ylamino)-3-methoxy phenyl)piperazin-1-yl)ethanone (75 mg, 0.16 mmol) in DCM (5 mL), DIPEA (42 mg, 0.33 mmol) and acryloyl chloride (15 mg, 0.165 mmol) were added at −78° C., and the mixture was stirred for 15 min. TLC showed completion of starting material (TLC system: 10% methanol in chloroform (Rf): 0.2). The reaction mixture was quenched with water (15 mL) and extracted with DCM (2×10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by prep-HPLC to obtain N-(2-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-chloropyrimidin-4-yloxy)phenyl) acrylamide as a yellow solid. (Yield: 28 mg, 33.7%). MS: m/z 523.2 (ES+, M+H). 1HNMR (DMSO-d6) δ 9.54 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.99 (br s, 1H), 7.25 (m, 4H), 6.56 (s, 1H), 6.50 (d, 1H, J=10.4 Hz), 6.22 (br s, 1H), 6.127 (s, 1H), 5.70 (dd, 1H, J=2.0, 10.4 Hz), 3.73 (s, 3H), 3.57 (m, 4H), 3.06 (br t, 2), 3.00 (br t, 2H), 2.03 (s, 3H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 90 °C

Procedure:
To a solution of 6,6-dimethyl-5,7-dioxaspiro[2.5]-octane-4,8-dione (Aldrich, 51 mg, 0.3 mmol) in DMF (0.5 mL) at room temperature was added 4-fluoroaniline (Aldrich, 33 mg, 0.3 mmol). The reaction mixture was heated at 90° C. for 2 h, cooled to room temperature, and used directly in the next step.