Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[CH2:23]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([NH:33][CH2:34][C:35]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol) in CH2Cl2 (80 mL) was treated with Et3N (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol). After the reaction mixture was stirred at room temperature for 15 h, 2 N aqueous NaOH solution (100 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired 4-[{(N-(Benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (6.27 g, 94%) as an amorphous solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1.Cl.[OH-].[Na+]>C(O)C.[Fe]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[NH2:14]
Reactant: O=[N+]([O-])c1cccc(OCc2ccco2)c1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(OCc2ccco2)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
830 mg (3.8 mmol) of 3-(furan-2-ylmethyl oxy)nitrobenzene was dissolved in 10 mL of ethanol. 1.1 g (19.70 mmol) of iron and 1 mL of 1N hydrochloric acid (1.0 mmol) were added thereto and heated under reflux for 2 hours. After cooling the reaction solution to room temperature, 1.5 mL of 1N sodium hydroxide was added dropwise, and filtration through celite was carried out. The filtrate was condensed, and ethyl acetate and water were added to the filtrate to separate the solution into organic layer and aqueous layer. The organic layer was separated, washed with a saturated sodium chloride solution, and dried over magnesium sulfate. Thereafter, filtration was carried out, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give 3-(furan-2-ylmethoxy)aniline (yield: 86%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH:4]([CH2:7][C:8](OC)=[O:9])[CH2:3]1.[BH4-].[Li+]>O1CCCC1.[Cl-].[Na+]>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][NH:6][C:2](=[O:1])[CH2:3]1
Reactant: COC(=O)CC1CNC(=O)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC(CCO)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg Methyl 2-(5-oxopyrrolidine-3-yl)acetate (I.26) was placed in tetrahydrofuran and 30 mg lithium borohydride was added and the mixture stirred at ambient temperature overnight. The suspension was diluted with saturated sodium chloride solution and extracted with ethyl acetate (×3). The water phase was freeze dried.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](SC)=[N:13][CH2:14][Si](C)(C)C)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:26]=[C:25]([Cl:35])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:30][C:29]([C:27]3[CH:26]=[C:25]([Cl:35])[CH:24]=[C:23]([Cl:22])[CH:28]=3)([C:31]([F:32])([F:34])[F:33])[CH2:14][N:13]=2)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(COC(C)=O)c(Br)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Yield: 93.2 %

Procedure:
Under argon atmosphere, a mixed solution of 2-bromo-4-[(methylsulfanyl){[(trimethysilyl)methyl]imino}methyl]benzyl acetate (0.90 g) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.56 g) in THF was cooled to −5° C. to be stirred, and a solution of tetrabutylammonium fluoride (0.56 ml, of 1.0 M in THF) was added thereto gradually. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl acetate (1.1 g).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.O>C1COCC1>[C:1]([O:5][C:14]([CH:11]1[CH2:13][CH2:12]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butanol (9.4 mL, 100 mmol) in 50 mL of anhydrous THF is added under nitrogen during several minutes n-butyl lithium (69 mL, 110 mmol, 1.6 M solution in hexane). After 30 min, the resulting solution is treated by the drop wise addition of a THF solution (40 mL) of cyclopropanecarbonyl chloride (10 mL, 110 mmol). The reaction mixture is further stirred at reflux for 1 h, cooled to 0° C. by an ice bath, and slowly hydrolyzed by the addition of water. The aqueous layer is extracted twice with ether and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by vacuum distillation (bp=70° C., 76 mmHg) to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:11]([O:10][C:8](=[O:9])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Br:23])=[CH:17][CH:16]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])([CH3:13])([CH3:14])[CH3:12]
Reactant: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
p-Tolyl-malonic acid di-tert-butyl ester (5.695 g, 16.6 mmol) was dissolved in 80 ml of CCl4. To the solution was added N-bromosuccinimide (3.309 g, 16.6 mmol, 1 equivalents) and benzoyl peroxide (220 mg), the reaction mixture was refluxed under argon overnight; the reaction mixture was then cooled to room temperature, and the precipitate that had formed was filtered and washed with hexanes. The combined organic portions was dried, and the residue obtained was purified by chromatography to give (4-bromomethylphenyl)-malonic acid di-tert-butyl ester 4.2559 g (59.50% yield) as white solid. 1H NMR (CDCl3) δ: 7.379 (4H, s), 4.493 (2H, s), 4.435 (1H, s), 1.473 (18H, s) ppm. FABMS (+Ve), m/z 387 [MH+, 81Br], 385 [MH+, 79Br], 331 [MH+−C4H8, 81Br], 329 [MH+−C4H8, 79Br], 275 [MH+−2C4H8, 81Br], 273 [MH+−2C4H8, 79Br]. Anal. calcd. for C18H25BrO4: C, 56.1; H, 6.5; Br, 20.7. Found: C, 55.52; H, 6.38; Br, 21.85.
Reaction SMILES: C1(S(C2C=CC(Cl)=C([N+:16]([O-])=O)C=2)=O)C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]>>[NH2:16][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Product: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
The procedure described in Example 1 is followed, except that as a starting material instead of phenyl-(4-chloro-3-nitrophenyl) sulfoxide a corresponding amount of 4-(4-chloro-3-nitrophenyl-sulfinyl)-biphenyl is employed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=2[C:21](OC)=[O:22])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=2[CH2:21][OH:22])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)=C(CO)C1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl 4-(4-chlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P29, 1.85 g) in diethylether (37.04 mL) at −20° C., LiAlH4 1M solution in diethylether (3.68 mL) was added dropwise and the resulting mixture was stirred at −20° C. for 20 min. A solution of HCl 2% in water (4.44 mL), diethylether and water were added and the organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure to obtain the title compound (1.487 g).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13]Cl)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.CC(CC)=O>C1C=CC=CC=1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][O:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH:26]([CH3:28])[CH3:27])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: ClCc1nc(Cc2ccccc2)no1
Solvent: CCC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C(COCc1nc(Cc2ccccc2)no1)c1ccc(Cl)cc1

Procedure:
First, 2.1 grams (0.01 mole) of the intermediate of Example I, 2.3 grams (0.011 mole) of 2-(4-chlorophenyl)3-methyl butyric acid, 1.0 grams (0.01 mole) of triethylamine, and 100 milliliters of methylethylketone were combined and heated under reflux for 2 hours. The mixture was then cooled and poured into 200 milliliters of benzene. The benzene mixture was then washed in turn with 100 milliliters of H2O, 100 milliliters of 5% K2CO3 solution, and 100 milliliters of H2O. The benzene phase was then dried with MgSO4 and evaporated in vacuo to yield 3.0 grams (78% of theory) of the desired product. nD30 1.5210.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9]C=[CH:7][CH:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([N:26]([CH3:28])[CH3:27])([C:24]#N)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>C(OCC)C.CO.C(Cl)(Cl)Cl>[CH2:11]([N:18]1[CH2:19][CH2:20][C:21]([C:24]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)([N:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CN(C)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 160 %

Procedure:
A little iodine was added to a mixture of 34.5 g (3.5 eq.) magnesium and 100 ml dry diethyl ether, followed over a period of 10 min by 10 g (0.15 eq.) bromobenzene, and the mixture was stirred for a further 10 min. Once the reaction had started, 183 g (2.85 eq.) bromobenzene dissolved in 500 ml diethyl ether were added dropwise over a period of 2 h and the mixture was stirred for a further 15 min. 100 g (1 eq.) 1-benzyl-4-(dimethylamino)piperidine-4-carbonitrile dissolved in 900 ml diethyl ether were added over a period of 2 h to the Grignard reagent prepared in the preceding step and the mixture was then heated for 12 h at 80° C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, extracted with ethyl acetate (3×300 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 1% MeOH/CHCl3). 30 g (35%) of product were obtained in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([OH:43])=O)=[N:39][CH:40]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:40]=[N:39][C:38]([C:41]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:43])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:20]
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 5-{((2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}pyridine-2-carboxylic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:13]([OH:19])=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1ccc(O)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(O)c(-c2ccc(Br)cc2)n1
Yield: 22.8 %

Procedure:
A solution of 4-bromobenzeneboronic acid (2.0 g) in ethanol (10 ml) was added over a period of 15 minutes to a stirred mixture of 6-iodo-2-picolin-5-ol (2.35 g), saturated aqueous sodium carbonate solution (5.0 ml), tetrakis(triphenylphosphine)palladium [0] (280 mg) and toluene (10 ml) under an atmosphere of argon. The mixture was stirred at reflux for 6 hours. The mixture was evaporated and the residue was treated with water (20 ml). The mixture was filtered and the yellow solid collected was purified by flash column chromatography on alumina (1CN Biomedicals Alumina N32-63) using 50% n-pentane/ethyl. acetate as eluent to give 2-(4-bromophenyl)-3-hydroxy-6-methylpyridine (600 mg), m.p. 196°-199° C.; NMR: 2.42(3H,s), 7.09(1H,d), 7.25(1H,d), 7.62(2H,d), 8.02(2H,d), 9.98(1H,s); m/z 264 & 266 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12](=[N:19]S(C3C=CC(C)=CC=3)(=O)=O)[N:13]([CH2:15][C:16]([NH2:18])=O)[CH:14]=2)=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH2:18])[N:19]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(=NS(=O)(=O)c3ccc(C)cc3)n(CC(N)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc3nc(N)cn3c2)cc1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a suspension of 2-[5-[(4-methoxybenzyl)oxy]-2-{[(4-methylphenyl)sulfonyl]imino}pyridin-1(2H)-yl]acetamide (20.8 g, 47.1 mmol) in tetrahydrofuran (200 mL) was added trifluoroacetic acid anhydride (49.5 g, 235.5 mmol) at 0° C., and the mixture was stirred for 1 hr. Methanol (100 mL) was added to the reaction mixture, 8N aqueous sodium hydroxide solution was added until pH reached 12 to 13, and the mixture was stirred at room temperature for 3 hr. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (8.6 g, 68%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[CH2:34])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1COCC1.C(O)(=O)C.C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CC)c2s1
Temperature: 60 °C
Reaction time: 96 h
Yield: 70.1 %

Procedure:
1-{5-[2-(3-Ethyl-ureido)-7-vinyl-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (27 mg) was dissolved in EtOH (5 mL), THF (0.5 mL) and acetic acid (0.5 mL) and 10% palladium on carbon (6 mg) and ammonium formate (168 mg) added. The flask was evacuated and purged with N2 (×2) and stirred at 60° C. for four days. The mixture was cooled to rt and filtered through a PTFE filter. The filter was rinsed with EtOH/DCM and the filtrate concentrated under reduced pressure. The residue was then taken up in EtOAc and washed with Na2CO3 (sat, aq). The aqueous layer was washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography, Biotage, 12 g Grace cartridge, DCM to 4% MeOH in DCM and the relevant fractions combined and concentrated under reduced pressure to give the desired product as a white solid (19 mg, 70%). m/z: 497 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][N:9]=[C:10]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>C(OCC)(=O)C.CN(C)C=O>[CH3:7][O:8][N:9]=[C:10]([C:16]1[N:17]=[C:18]([NH:21][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][CH:20]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1nc(C(=NOC)C(=O)OCC)cs1
Yield: 63.2 %

Procedure:
Pyridine (3 g.) was added to a solution of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (6.5 g.) in a mixture of ethyl acetate (60 ml.) and dimethylformamide (20 ml.). To the solution was dropwise added with stirring at 4° C. ethyl chloroformate (8 g.). After adding water (50 ml.) to the reaction mixture, the organic layer was separated, washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (120 g.) using a mixture of ether and petroleum ether (5:2) as an eluent to give ethyl 2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetate (syn isomer) (5.4 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1cnccn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cnccn2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a solution of 0.219 g (2.30 mmol) of aminopyrazine in THF (5 mL) at 0° C. was added 1.3 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.238 g (0.65 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (1:4) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.170 g (54% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyrazinyl)-1,3,5-triazin-2-amine: mp 271-274° C.; 1H NMR (CDCl3) δ9.59 (s, 1H), 8.42-8.33 (m, 3H), 7.92 (d, J=7.4 Hz, 1H), 7.81 (s, 1H), 7.60 (t, JHF=53.5 Hz, 1H), 7.48-7.41 (m, 2H), 3.98 (d, J=4.2 Hz, 4H), 3.85 (d, J=4.2 Hz, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.9; H, 3.8; N, 29.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g (11.1 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and 1.55 g (11.1 mmol) of benzoyl chloride were suspended in 150 mL of CH2 Cl2 and cooled to 0° C. The reaction mixture was vigorously stirred and 1.6 g (12 mmol) of AlCl3 was added in several portions over a ten minute time period. The reaction was allowed to proceed for one hour, after which 1 L of water was added to quench the reaction. The organic layer was separated and washed with 100 mL of 1N NaOH, 100 mL of brine, dried by filtration through anhydrous K2CO3, and evaporated to dryness. The crude product was crystallized twice from MeOH. This yielded 1.85 g of the title compound as white crystalline solid.