Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:4][C:5](=[O:18])[NH:6][C:7]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[ClH:19].Cl.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:19].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:7]2[NH:6][C:5](=[O:18])[NH:4][C:3]=2[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCN(c3ccccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6.2 g of 4-(bromomethyl)-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 5.0 g of 1-(2-methylphenyl)piperazine dihydrochloride and 5.4 g of potassium carbonate in 100 ml of ethanol is stirred at room temperature for 24 hours. Water is added to the reaction mixture and the precipitate which forms is separated by filtration. The solid is then suspended in 2-propanol, 1 equivalent of hydrochloric acid is added, and the resulting solid is separated and recrystallized from 2-propanol/water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2H-imidazol-2-one hydrochloride melting at about 223°-225° C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of methyl ({[2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazol-4-yl]carbonyl}amino)acetate (Preparation 99) (158 mg, 0.32 mmol) in 1,4-dioxan (5 ml) was treated with sodium hydroxide solution (1M) (470 □1,0.47 mmol). The mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted in water and washed with ethyl acetate. The aqueous layer was acidified with solid citric acid and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound (61 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C.N1C=CC=CC=1>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:20](=[O:21])[CH2:19][Cl:18])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 828.4 %

Procedure:
To a suspension of the HCl salt of 2-amino-6(5H)-phenanthridinone (100 mg, 0.04 mmol) in DMF (5 mL), pyridine (0.5 mL) was added, followed by the addition of chloroacetyl chloride (0.2 mL, 0.002 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 to 2 hrs. It was then poured over crushed ice, and the solid obtained was washed thoroughly with cold water. The solid was then dried under vacuum to give N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-choroacetamide (95 mg, 84%).
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[C:15](=[CH:17][CH:18]=1)[OH:16].Cl>C(OCC)(=O)C.O.CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][CH:2]([F:6])[F:7])=[C:14]([OH:19])[CH:13]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Cl)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1cc(Cl)ccc1OC(F)F
Temperature: 125 °C
Yield: 19.4 %

Procedure:
723 mg (5.0 mmol) of sodium chlorodifluoroacetate, 220 mg (5.5 mmol) of sodium hydroxide and 838 mg (5.5 mmol) of 4-chlorocatechol were successively added to a mixture of 7.0 mL of N,N-dimethylformamide and 0.1 mL of water under argon atmosphere with stirring. The mixture was slowly heated to 125° C. and allowed to react at this temperature for 1.0 h. The reaction was stopped and cooled to room temperature. To the reaction solution was added 10 mL of 1.0 mol/L hydrochloric acid until the solution turned acid, and then 50 mL of water and 20 mL of ethyl acetate were added. The organic layer was isolated, and the water layer was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 50 mL of water and 50 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated. The residue was purified by preparative silica gel thin layer chromatography (mobile phase: petroleum ether: ethyl acetate=4:1) to obtain 189 mg of a light yellow oil. Yield 19.4%. MS([M-H]−): 193.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.O[CH2:14][C:15](CO)(C)[C:16](=[O:18])[CH3:17].C1COCC1>C(N(CC)CC)C>[C:16]([C:15]1([CH3:14])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:18])[CH3:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)C(C)(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3-dihydroxymethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to -78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: [CH:1]1([O:7][CH:8](C)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(CO)OC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) in triethylanine (5.8 ml) and dichloromethane (250 ml) was added 4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. under nitrogen, and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine (100 ml each), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (200 g) column chromatography using a gradient elution of hexane:ethyl acetate (6:1 to 1:1) to give the title compound as a white crystalline solid (8.0 g, 80%).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15.75 h
Yield: 97.2 %

Procedure:
Ethyl difluoroacetate (3.51 g, 28.3 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.12 g, 28.3 mmol) followed by 2-acetyl-5-chlorothiophene (4.12 g, 25.6 mmol). A pink precipitate formed after 5 minutes which was dissolved by adding ether (10 mL) and THF (10 mL) to the reaction. The reaction was stirred at room temperature overnight (15.75 hours), then treated with 3N HCl (15 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a red solid (5.94 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (2.02 g, mp 72°-77° C., 33%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H), 7.57 (d, J=4.2 Hz, 1H), 7.01 (d, J=4.2 Hz, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.01 (d); M+ 238.
Reaction SMILES: ClC1N=C(NC2C=C(OC)NN=2)C(Cl)=CN=1.[Cl:17][C:18]1[C:19]([NH:34][C:35]2[CH:39]=[C:38]([O:40][CH:41](C)C)[NH:37][N:36]=2)=[N:20][C:21]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)[CH3:26])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:18]1[C:19]([NH:34][C:35]2[CH:39]=[C:38]([O:40][CH3:41])[NH:37][N:36]=2)=[N:20][C:21]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)[CH3:26])=[N:22][CH:23]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Agent: COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 144 %

Procedure:
2,5-Dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 37; 0.25 mmol, 64 mg) and (1S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.25 mmol, 34.5 mg) were dissolved in n-BuOH (0.35 M) and DIEA (0.50 mmol, 0.08 ml) was added. The reaction was stirred at 110° C. overnight. The solvent was evaporated and the remaining material was separated between EtOAc and water, washed with brine, and dried. Evaporation of the solvent gave a brown oil (131 mg). This material was purified by Gilson (10-50% acetonitrile/H2O, 15 min). The title compound was collected by evaporation of the solvent as a white solid (2.3 mg). 1H NMR (MeOD) 8.32 (d, 1H), 7.85-8.07 (m, 1H), 7.49 (ddd, 1H), 7.29-7.41 (m, 1H), 5.80 (s, 1H), 4.92-5.19 (m, 1H), 3.82 (s, 3H), 1.50 (d, 3H); m/z 364.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:55]([SH:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>O.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>[CH2:55]([S:62][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]cnc2cc(SCc3ccccc3)ccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 7-bromoquinazolin-4(3H)-one (10 g, 44.4 mmol), Xantphos (1.286 g, 2.222 mmol), and Pd2(dba)3 (1.017 g, 1.111 mmol). The flask was flushed with Ar (g), then dioxane (89 ml), benzyl mercaptan (5.52 ml, 46.7 mmol), and n,n-diisopropylethylamine (15.52 ml, 89 mmol) were added in sequence. The reaction was fitted with a reflux condenser, heated to 90° C., and stirred for one hour. The reaction was diluted with water and filtered. The solids were washed thoroughly with water, then air dried for several hours and triturated with ethyl acetate. After stirring overnight, the solids were filtered, washed with ethyl acetate, and vacuum dried over a nitrogen blanket overnight to afford 7-(benzylthio)quinazolin-4(3H)-one as a light yellow solid. (ESI) 269.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(OCC)(=O)C>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:1]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.25 g (29.5 mmol) of diethyl 3,5-pyrazoledicarboxylate (1) in 225 mL of acetone was added 11.7 g (36 mmol) of cesium carbonate, followed after 10 min by the addition of 5.3 mL (36 mmol) of t-butyl bromoacetate and the mixture was stirred overnight at room temperature. Since TLC analysis confirmed that the reaction was complete (Rf product=0.6 (7:3 hexanes:ethyl acetate)), the mixture was filtered and concentrated to give quantitatively 1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (2) as a clear oil as indicated by 1H NMR (containing a trace of t-butyl bromoacetate). (δ(300 MHz, CDCl3) 7.14 (s, 1H), 5.15 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (s, 9 H), 1.27 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H)). This material was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([C:9]1[C:10](CCCCCCCC)=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C>CCCCC(COP(OCC(CCCC)CC)(O)=O)CC.[Cu]>[CH2:9]=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:12]1([C:11](=[CH:10][CH:9]=[CH:15][CH:14]=1)[OH:16])[OH:13]
Reactant: CCCCCCCCc1ccc(O)c(O)c1CCCCCCCC
Agent: [Cu]
Agent: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Product: C=CCCCCCC
Product: Oc1ccccc1O

Procedure:
In the same way as the previous example, 100 ml of a copper solution was contacted with a 0.3M solution of dioctylpyrocatechol (100 ml) in ESCAID 100, obtained from the reaction of an excess of 1-octene with pyrocatechol.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:32]([OH:35])(=O)[CH3:33]>O1CCCC1.O>[C:13]([O:17][C:18]([NH:20][CH:21]([C:32]1([OH:35])[CH2:33][CH2:3][CH2:1][CH2:2]1)[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Reactant: CC(=O)O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
A solution of diisopropylamine (3.77 ml, 23 mmole) in 40 ml of dry tetrahydrofuran under argon was chilled to -40° C. and treated with 13 ml of a 1.71 N n-butyllithium solution (21.5 mmoles). After stirring for 20 minutes, the mixture was cooled to -78° C. and treated with a solution of N-(t-butoxycarbonyl)glycine, benzyl ester (2.65 g, 10 mmole) in 10 ml of tetrahydrofuran. The mixture became darker yellow, but remained clear. After 0.5 hours at -78° C., 0.88 ml (11.5 mmoles) of dried (4Å sieves) cyclopentanone was added and then after 15 minutes at -78° C., the mixture was warmed over 0.5 hours to -20° C., whereupon the solution darkened to a deep purple. The temperature was raised to 0° C. for 20 minutes, then 1.32 g (22 mmole) of acetic acid in 5 ml of tetrahydrofuran was added, whereupon the color was discharged, leaving a gelatinous precipitate. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane:ethyl acetate, 3:1. Evaporation of product fractions and crystallization from hexane gave, in two crops, 1.68 g of product, melting point 68°-70° C. (Rf=0.77, silica, hexane:ethyl acetate, 3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1.C(Cl)(Cl)Cl>[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=3[O:2][CH3:1])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(OC)c1

Procedure:
From 2,4-dimethoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.7° (c=0.50, CHCl3), ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:26])([F:27])[F:25])(=[O:15])=[O:16])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethoxyphenylsulfonyloxy)phenoxy]propanol (610 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (CH2Cl2) to give the title compound as a colorless oil (480 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.73 (t, J=8.2 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 6.47 (s, 1H), 4.20 (t, J=6.1 Hz, 2H), 2.87 (t, J=6.1, 2H), 2.26 (s, 3H).
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2C=CC=C[C:15]=2[N:20]([CH3:22])[CH3:21])CCCCC1.CC(C)([O-])C.[K+].BrC1[N:41]=[C:40]([CH3:42])[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=1.[F:52][C:53]([F:65])([F:64])C1C=NC2CCNCC=2C=1>C1(C)C=CC=CC=1>[CH3:42][C:40]1[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=[C:22]([N:20]2[CH2:15][CH2:14][C:9]3[C:8](=[CH:13][C:12]([C:53]([F:65])([F:64])[F:52])=[CH:11][CH:10]=3)[CH2:21]2)[N:41]=1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(C(F)(F)F)cc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (4 mg, 0.069 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (6.5 mg, 0.014 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (34 mg, 0.3 mmol), 1d (50 mg, 0.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (28 mg, 0.14 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% ethyl acetate:hexanes) to afford the tittle compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.03 (s, 9H), 2.09 (s, 3H), 2.15 (s, 2H), 2.21 (s, 3H), 3.03 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.79 (s, 2H), 6.68 (s, 1H), 8.12 (s, 1H), 8.75 (s, 1H), 9.02 (s, 1H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:36][CH2:35][CH2:34][OH:33])=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: NCCO
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine yielded N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.07 (d, 1H, J=1.2 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.43 (d, 2H, J=1.5 Hz), 7.38 (s, 1H), 7.29 (d, 1H, J=2.4 Hz), 6.98 (dd, 1H, J=2.1 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.72 (t, 2H, J=5.7 Hz), 3.53 (t, 2H, J=6.0 Hz); LCMS: ret. time: 16.21 min.; purity: 97%; MS (m/e): 466 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C=O.O.[C:30]([BH3-])#N.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][N:14]([CH3:30])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in tetrahydrofuran (2.0 mL) was treated with a 1.23M solution of formaldehyde in water (384 μL, 0.474 mmol). The resultant reaction mixture was stirred at RT for 30 min, followed by the addition of sodium cyanoborohydride (17.8 mg, 0.284 mmol). After stirring at RT for 2 h, the reaction mixture was quenched with acetic acid (0.5 mL) and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (38 mg, 92%). LCMS calculated for C20H30BrN4O2 (M+H)+: m/z=437.2, 439.2. found: 437.1, 439.1.