Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Product: COc1cc(OC)c(C2=CCN(C)CC2OC(C)=O)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2.79 g (10 mmol) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) were dissolved in 15 ml of acetic anhydride and stirred at 100° C. for 4 h. The solution was then evaporated in vacuo in a rotary evaporator and the residue was dissolved in 10 ml of water, adjusted to pH>12 with sodium hydroxide solution and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H](C2C=CC=CC=2)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>ClCCl>[CH2:34]([O:33][C:31]([N:11]1[CH2:12][C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH2:10]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Yield: 76.8 %

Procedure:
3-(S)-Tert-butyldimethylsilyloxy-4-(R)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidine (5.48 g, 13.15 mmol) was dissolved in dry dichloromethane (120 ml), and benzyl chloroformate (3.76 ml, 26.3 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After heating the reaction solution under reflux for 2 hours, dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 4.52 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:13][CH:12]([NH:19][O:18][CH2:16][CH3:17])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCON
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCONC(C)Cc1ccc(OC)c(OC)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
1-(3,4-Dimethoxyphenyl)-2-propanone (1.35 g, 7.5 mmol) was dissolved in H2O (15 ml) and a solution of O-ethylhydroxylamine hydrochloride (1 g, 10 mmol) and Na2CO3 (0.53 g, 5 mmol) in water (10 ml) was added dropwise under stirring at 10° C. The reaction was left at room temperature overnight and then extracted with diethyl ether. After evaporation of the solvent, the residue was dissolved in EtOH (20 ml) and concentrated hydrochloric acid (1 ml), then hydrogenated over PtO2 at 3,6×106 Pa (50 psi). The solvent was removed under vacuum. The residue was dissolved in 30 ml of water, the aqueous phase was made basic with NaHCO3 and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated to dryness. The crude residue was purified by flash chromatography, to afford 0.75 g of the title compound.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([O:10][CH3:11])[CH2:6]1.O([Si](C)(C)C)[K].Cl.Cl.Cl.[O:22]1[C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]4)[CH2:33][CH2:32]3)[C:25]=2[CH:24]=[CH:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:22]1[C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([NH:45][C:3](=[O:12])[CH2:4][C@H:5]5[CH2:9][CH2:8][C@H:7]([O:10][CH3:11])[CH2:6]5)[CH2:41][CH2:40]4)[CH2:33][CH2:32]3)[C:25]=2[CH:24]=[CH:23]1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)O[K]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5occc45)CC3)CC2)C1
Temperature: 25 °C

Procedure:
A mixture of racemic trans-(3-methoxy-cyclopentyl)-acetic acid methyl ester [WO 2009/019174] (70 mg, 0.41 mmol) and KOSiMe3 (88 mg, 0.69 mmol) in CH2Cl2 (1.5 ml) was stirred at room temperature over night. The solvent was evaporated and DMF (1.5 ml) was added followed by trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol), DIPEA (177 mg, 1.37 mmol) and TBTU (143 mg, 0.44 mmol). After stirring 4 h at room temperature, sat. aq. NaHCO3 sol. was added and the product was extracted with CH2Cl2. The organic layer was dried (Na2SO4), the solvent was evaporated and the crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1) to yield the title compound as a white solid (125 mg, 78%), MS (ISP) m/z=469.3 [(M+H)+].
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.O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[N:19][CH:18]=[CH:17]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In pyridine (30 ml) was dissolved 6-aminoisoquinoline (3.348 g, Synthesis, 733 (1975), and 4-toluenesulfonyl chloride (5.13 g) was added thereto, followed by stirring at room temperature overnight. Water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1=Cc2cccc(-c3ccccc3C=O)c2OCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cccc(-c3ccccc3CO)c2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.58 g) in a mixture of ethanol (5.8 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (34 mg) at 0 C. The reaction mixture was stirred for 30 minutes at ambient temperature, thereto was added 1N hydrochloric acid (2 ml), and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated n vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give a solid of ethyl 2,3-dihydro-9-(2-hydroxymethylphenyl)-1-benzoxepin-4-carboxylate (530 mg).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CN=C1>O1CCCC1>[C:7]1([C:5]2[N:6]=[C:2]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:3]([CH3:19])[C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1c(Cl)nc(-c2ccccc2)c1-c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -20 °C

Procedure:
A solution of 2-chloro-4,5-diphenyl-1-methylimidazole (1.46 g, 5.4 mmol) from Step B in tetrahydrofuran (THF) (20 mL) under nitrogen was cooled to −70° C. in a dry ice/acetone bath. n-Butyl lithium (1.6 N in hexanes, 10.2 mL, 16.3 mmol) was added via syringe. The reaction was allowed to warm to −20° C. for 2 hr. In a separate round-bottomed flask, a solution of benzyl chloroformate (CBZ-Cl) (4.3 mL, 16.3 mmol) in TBF (10 mL) was cooled to −20° C. The above imidazole reaction was added via a double-tipped needle to the solution of CBZ-Cl and after 20 min the reaction was allowed to warm to rt for 30 min. The reaction was then quenched into an aqueous sodium bicarbonate solution and was then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (5% methylene chloride and 15% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.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.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([N:56]([CH2:58][CH2:59][O:60][CH3:61])[CH3:57])=[CH:48][CH:47]=1.Cl>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:55][C:53]2[S:54][C:50]3[C:49]([N:56]([CH2:58][CH2:59][O:60][CH3:61])[CH3:57])=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[C:51]=3[N:52]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution of 79 mg (0.56 mmol) 4-fluoro-benzoic acid in 10 ml THF were added 235 mg (0.62 mmol) HATU and 0.11 ml (0.62 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 1 h. A solution of 150 mg (0.56 mmol) 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at room temperature for 16 h. The reaction mixture was then poured into 100 ml 1 M hydrochloric acid and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4-1/1 ethyl acetate/hexane) followed by trituration in hexane afforded 55 mg (25%) 4-fluoro-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide as an off-white crystalline solid. ES-MS m/e (%): 390 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[S:7])[CH3:6].[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:15]Cl>O1CCCC1>[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:15][CH2:6][C:5]([O:4][CH3:3])=[S:7]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Reactant: COC(C)=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=S)CCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
1.44 parts by weight of 80% strength sodium hydride were suspended in 25 parts by volume of absolute tetrahydrofuran, and a solution of 5.31 parts by weight of methylthioacetate in 50 parts by volume of absolute tetrahydrofuran was added a little at a time at room temperature. Stirring was continued for half an hour and a solution of 18.3 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl chloride in 50 parts by volume of absolute tetrahydrofuran was then added. The reaction mixture was then stirred under reflux for a further 3 hours, was cooled, and was concentrated under reduced pressure. The residue was taken up in ether, the solution was extracted with water, the organic phase was separated off, dried with magnesium sulfate and filtered, and the ether was evaporated. The oily residue crystallized when triturated and was recrystallized from diisopropyl ether. 16 parts by weight (73% of theory) of methyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzylthioacetate (compound No. 13) of melting point 61°-63° C. were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:19][CH:20]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoate (70 mg, 0.14 mmol) was dissolved in methanol (2 mL) and 1M lithium hydroxide (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The methanol was removed under reduced pressure and the residue was diluted with water (2 mL). Upon stirring a precipitate forms. The solution was further diluted with water (15 mL) and 1M NaOH (3 mL). The solution was extracted with ether (20 mL). The organics were washed with water (10 mL) and the aqueous layers were combined. The aqueous solution was acidified with 1M HCl to give a cloudy solution. The solution was extracted with ethyl acetate (2×15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give (+/−)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoic acid (53.1 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3, δ): 7.89 (s, 1H), 7.66-7.60 (m, 2H), 7.58 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 6.97-6.92 (m, 2H), 6.77 (t, J=6Hz, 1H), 5.29 (dd, J=9, 4.4 Hz, 1H), 3.73-3.63 (m, 2H), 2.66-2.64 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.83 (m, 1H), 1.62 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H). MS (M+1): 490.2.
Reaction SMILES: F.[Si](O[C:10]1[C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[C:21]([F:33])[CH:20]=3)[O:18][C:14]=2[C:13]([CH:34]=[CH2:35])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C1C[O:39]CC1.C(#N)C>O>[F:33][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:34]=[CH2:35])=[CH:12][C:11]([OH:39])=[CH:10][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Agent: F
Solvent: O
Solvent: CC#N
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{([tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)sily]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered off and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249–251° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=1)[O:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:44][CH:43]=1>O1CCOCC1>[NH2:41][C:37]1[N:38]=[CH:39][N:40]=[C:35]([O:34][C:33]2[CH:32]=[C:31]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:57]=[CH:56][CH:55]=2)[C:36]=1[C:42]1[CH:43]=[CH:44][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:46][CH:47]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Into a 20 mL reaction vial was added acrylic acid (0.01 ml; 0.12 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42.04 mg; 0.17 mmol), and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at rt for 1 h. 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08 mmol) was then added. The reaction mixture was stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was then purified using preparative HPLC eluting from 35-45% CH3CN in 0.1% TFA in H2O. fractions containing the desired product were combined and lyophilized overnight to afford N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide as a white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264 min. MS: m/z=425 [M+H]+, RT=2.14 min. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reactant: Nc1ccnc(N2CCOCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)n2)c2ccccc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Morpholin-4-yl-pyrimidin-4-ylamine (140 mg, 0.77 mmol) and (4-bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (228 mg, 0.77 mmol) were suspended in 5 mL toluene and Pd(OAc)2 (5 mg, 3 mol %), BINAP (24 mg, 5 mol5) and CS2CO3 (753 mg, 2031 mmol) were added. The reaction mixture was stirred at 100° C. for 24 hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 169 mg of target product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].[CH2:28]([C@@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+]>[CH2:24]([N:22]([CH2:21][C:16]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:26])[C:4]([O:27][CH2:28][C@@H:30]4[CH2:31][O:32]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:15]=1)[CH3:23])[CH3:25]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a bi-phasic mixture of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (1.74 g, 4.76 mmol) in isopropanol (100 mL) and 3M aq. NaOH (23 mL), (R)-epichlorohydrin (4.40 g, 47.6 mmol) is added. The mixture is stirred at rt for 16 h before it is concentrated to about half its volume. The remaining solution is extracted with EA, the org. extract is washed with 1M aq. NaOH followed by water. The washings are extracted back with EA. The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC (Waters XBridge Prep C18, 50×150 mm ID, 10 μm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give ethyl-{3-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methyl-benzyl}-methyl-amine as a colourless resin (950 mg). LC-MS*: tR=1.26 min; [M+1]+=422.23; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.24 (t, J=7.5 Hz, 3H), 2.14 (s, 3H), 2.36 (s, 3H), 2.41-2.48 (m, 5H), 2.69-2.78 (m, 3H), 2.86 (t, J=5.0 Hz, 1H), 3.37-3.42 (m, 1H), 3.54 (s, 2H), 3.69 (dd, J=11.0, 6.8 Hz, 1H), 4.21 (dd, J=11.3, 2.5 Hz, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38][CH2:39][CH2:40][CH:41](O)[CH3:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:38][CH2:39][CH2:40][CH:41]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17])[CH3:42]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: CC(O)CCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 68.9 %

Procedure:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (general procedure 10.2 g, 0.8 mmol) was dissolved in tetrahydrofuran (10 mL) and triphenylphosphine (0.54 g, 0.9 mmol) was added followed by 4-bromobutan-2-ol (0.14 g, 0.9 mmol) and diisopropyl azodicarboxylate (0.18 g, 0.9 mmol). The mixture was stirred for 18 hours at 23° C. The mixture was concentrated and purified via Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate in hexane) to afford 0.22 g of 1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][NH+:6]=[C:5]([CH2:9]Cl)[C:4]=1[CH3:11].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[SH:21]>>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:21][C:13]2[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]=2)[C:4]=1[CH3:11]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(Cl)cc[nH+]c1CCl
Agent: [Cl-]
Product: Cc1c(Cl)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
For example, 4-chloro-2-chloromethyl-3-methylpyridinium chloride could be reacted with 1H-benzimidazole-2-thiol according to the procedure described under Example 12 to give 2-[(4-chloro-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole. Conversion of this product with, for instance, 1,1-dideuterio-3-methoxy-1-propanol or 1,1-dideuterio-2,2,2-trifluoroethanol following the protocol described under Example 14 would then give rise to formation of 2-[(4-(1,1-dideuterio-3-methoxyprop-1-oxy)-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole and 2-[(4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole, respectively. Finally, oxidation of these compounds according to the procedure used in Example 46 would provide rac-2-[(4-(1,1-dideuterio-3-methoxypropan-1-oxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole and rac-2-[(4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, respectively.