Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O:19][CH2:20][CH3:21])(=O)C>C(N(CC)CC)C>[C:20]1(=[O:19])[N:2]([CH:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:5](=[O:6])[C:4]2=[CH:3][CH:9]=[CH:10][CH:11]=[C:21]12
Reactant: CCOC(C)=O
Reactant: COC(=O)CC(N)c1ccc(C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(C)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 14 g of methyl β-amino-β-(4-methylphenyl)propionate hydrochloride, were added 200 ml of ethyl acetate and 10.2 ml of triethylamine. The mixture was stirred at room temperature for 30 minutes, then washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. To the residue, was added 8.5 g of phthalic anhydride. The mixture was stirred at 150° to 155° C. for one hour and recrystallized from an ether-n-hexane mixture to yield 15 g of methyl β-phthalimido-β-(4-methylphenyl)propionate; m.p. 97°-99° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.O=S(Cl)[Cl:12]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([Cl:12])=[O:9]
Reactant: O=C(O)Cc1cccs1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1cccs1
Temperature: 50 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 mmol) in DCM (50 mL) was added dropwise SOCl2 (0.5 mL), the mixture was heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure to give compound 2-(thiophen-2-yl)acetyl chloride, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(OC4CCCCC4)nc3)nc12

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 491 (M+Na+, 24), 469 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:19]
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
To 0.88 g (˜0.01 mole) of freshly prepared N-methylaniline (b.p. 196° C.) is added 2.0 g (˜0.01 mole) of 2-trifluoromethylbenzene-sulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is then added dropwise with stirring until the solution is slightly alkaline. The 2-trifluoromethyl-N-methylbenzene-sulfonanilide is formed as a viscous light brown liquid. It is next washed with water several times until the wash water is neutral to litmus paper, and the viscous light brown liquid is extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of light brown oil is 2.5 g (96% yield). 1H NMR (deuterioacetone): δ 7.8.2 (m, 9 ArH), 3.2 (s, 3H, N—CH3)
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Oc1ccc(I)c2cccnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12

Procedure:
A mixture of Example 201A (10.40 g, 38.4 mmol), tert-butyldimethylsilyl chloride (6.07 g, 40.3 mmol), and imidazole (5.49 g, 80.6 mmol) in DMF (75 mL) at room temperature was stirred for 16 hours, treated with water (300 mL), and extracted with diethyl ether (3×400 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:12]([Cl:13])=[C:11]([CH:14]([F:16])[F:15])[N:10]=[CH:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][C:7]1[C:12]([Cl:13])=[C:11]([CH:14]([F:16])[F:15])[N:10]=[CH:9][N:8]=1
Reactant: Oc1ncnc(C(F)F)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)c1ncnc(Cl)c1Cl

Procedure:
100 ml of POCl3 was added dropwise to a solution of 65.0 g (0.36 mol) of 4-hydroxyl-5-chloro-6-(difluoromethyl)pyrimidin in 150 mL of toluene, the mixture was refluxed for 3-5 h after addition. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove toluene and extra POCl3, and then poured into ice water. The water phase was extracted with ethyl acetate (3×50 ml), the organic phases were emerged, washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column to give 64.5 g as yellow liquid, cooled to be solid in refrigerator with yield of 90%.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[N:6]1[C:15]2[CH:14]=[CH:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[NH2:5][CH:13]1[CH2:14][C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1
Reactant: [NH4+]
Reactant: C1=Cc2ncccc2CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: NC1CCc2cccnc2C1

Procedure:
This compound was prepared from ammonium acetate (1 54 g, 20 mmol) and 5,6-dihydroquinoline (2.31 g, 10 mmol) using the method described in Example 36 and ethyl acetate instead of ether as the extracting solvent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH:31][S:36]([CH:33]2[CH2:35][CH2:34]2)(=[O:38])=[O:37])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Reaction time: 16 h
Yield: 67 %

Procedure:
1.5 g of crude tert-butyl(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}phenyl)carbamate (2.7 mmol, 1 eq.) were dissolved in 10 mL pyridine and 457 mg cyclopropyl sulfonyl chloride (3.3 mmol, 1.2 eq.) and stirring was continued at that temperature for 16 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was reextracted with DCM. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography yielding 1.19 g of the target compound (67% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:18][C:17]([CH3:20])([OH:19])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([O:25]CC)=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:16][C:17]([CH3:20])([OH:19])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(C)(O)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(O)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 0.9 g (2.9 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.54 g (4.3 mmoles) of 3-hydroxy-3-methylazetidine hydrochloride, 1 g (10.8 mmoles) of triethylamine and 10 ml of pyridine is heated under reflux for 10 hours. The product is cooled, and diluted with water. Filtering and washing yields 0.95 g (89%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-methyl-3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.38 g (1 mmole) of this ester with 1.5 ml of ethanol, and 8 ml of 0.5N sodium hydroxide under reflux for 3 hours. The mixture is cooled, filtered and acidified with acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].P(S)(OCC)(OCC)=[S:14]>O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[S:14]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCOP(=S)(S)OCC
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of methyl 4-cyanobenzoate (5.0 g, 31.0 mmol) and O,O-diethyl hydrogen dithiophosphate (10.41 g, 62 mmol) in water (100 mL) was stirred at 80° C. for 16 h under N2. The mixture was cooled to 20° C. and filtered. The precipitate was washed with water (50 mL) and dried under vacuum to give crude methyl 4-(aminocarbothioyl)benzoate (5.93 g, 98%) as a yellow powder: mp (water) 181-184° C.; 1H NMR δ 10.04 (br s, 1 H, NH2), 9.65 (br s, 1 H, NH2), 7.83-8.00 (m, 4 H, H-2, H-3, H-5, H-6), 3.88 (s, 3 H, OCH3); MS m/z 196.5 (MH+, 100%). A mixture of the crude benzoate (5.72 g, 29.2 mmol) and dichloroacetone (3.72 g, 29.3 mmol) in anhydrous DMF (50 mL) was stirred at 80° C. under N2 for 16 h. The mixture was cooled to 20° C. and poured into ice/water (400 mL) and stirred for 30 min. The precipitate was filtered, washed with water (30 mL) and dried. The residue was purified by column chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give benzoate 51 (5.40 g, 69%) as a white powder: mp (EtOAc/pet. ether) 110-111° C.; 1H NMR (CDCl3) δ 8.11 (ddd, J=8.7, 2.0, 1.6Hz, 2 H, H-2, H-6), 8.02 (ddd, J=8.7, 2.0, 1.6Hz, 2 H, H-3, H-5), 7.38 (s, 1 H, H-5′), 4.76 (s, 2 H, CH2Cl), 3.95 (s, 3 H, OCH3); MS m/z 268.6 (MH+, 100%). Anal. calcd for C12H10ClNO2S: C, 53.83; H, 3.76; N, 5.23. Found: C, 53.77; H, 3.72; N, 5.03%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[F-].[Cs+].O>CS(C)=O>[C:19]1([N:18]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
One hundred and twenty (120) ml of DMSO as a solvent was added to 10.0 g of N,N′-diphenylbenzidine (29.7 mmol), 8.38 g of p-fluoronitrobenzene (59.4 mmol), and 4.5 g of cesium fluoride (29.7 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 24 hours. Following reaction, the mixture was poured with stirring into 2500 ml of cold water to obtain crude crystals of N,N′-diphenyl-N-(4-nitrophenyl)-1,1′-biphenyl-4,4′-diamine (NTPD). Subsequently, the mixture was dried for 12 hours in a vacuum at 60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14](Br)=[N:13][CH:12]=2)=[N:7]1)[CH3:2].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([N:25]3[CH2:26][CH2:27][C:22]4([O:21][CH2:20][CH2:19][O:18]4)[CH2:23][CH2:24]3)=[N:13][CH:12]=2)=[N:7]1)[CH3:2]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOC(=O)Cn1nnc(-c2cnc(Br)s2)n1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC4(CC3)OCCO4)s2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 13 (step 1) from Intermediate 2 and 1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1)=O.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCC1>C(O)C>[C:3]1([CH:1]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:21]2=[O:29])[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2cccccc1-2
Reactant: O=C1Cc2ccccc2N1Cc1ccccc1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1C(=Cc2ccc3cccccc2-3)c2ccccc2N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1-Formylazulene (1 mmol) was dissolved in 20 mL ethanol. 223 mg 1-benzylindolin-2-one (1 mmol) and 20 mL ethanol were then added. Next, a 2 mL solution (1 mmol) containing 1M pyrrolidine and ethanol was added to react at room temperature for three days. After removal of solvent, the resulting solution was extracted by 150 mL ethyl acetate and 50 mL water. The resulting solution was extracted again by 50 mL citric acid aqueous solution and ethyl acetate. The ethyl acetate layer was collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Next, methanol was added and ultrasonically shaken at 40° C. for 1 hour. After filtration, washing by methanol, and drying, Compound 002 (315 mg, 87%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Ca+2].C(COC)OC.[C:29](Cl)(Cl)=[S:30]>O>[N:1]([C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1)=[C:29]=[S:30]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc2oc(-c3ccccn3)nc2cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2oc(-c3ccccn3)nc2cc1N=C=S
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of 5-amino-6-methyl-2-(2-pyridinyl)benzoxazole (8.7 g, 0.044 mole), calcium carbonate (4.44 g, 0.044 mole), glyme (150 ml) and water (50 ml) is cooled to 5° C in an ice-bath, and thiophosgene (5.11 g, 0.044 mole) is added. The mixture is stirred for 0.5 hour at 5° C and then allowed to warm to room temperature and stirred for about 16 hours. The precipitated material is collected, washed with water and crystallized from glyme/water (3:1) yielding 8.1 g of the title compound, melting point 192°-194° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=O)[CH:4]=O.[CH2:9]([NH:16][CH2:17][CH2:18][NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH3-]C#N.[Na+].[OH-].[Na+]>CN(C=O)C>[CH2:9]([N:16]1[CH2:17][CH2:18][NH:19][CH:3]([C:2]([F:8])([F:7])[F:1])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC(=O)C(F)(F)F
Reactant: NCCNCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A solution of 3,3,3-trifluoro-2-oxopropanal (0.31 g, 2.3 mmol; Intermediate 43) in DMF (10 mL) was cooled to 0° C. and a solution of N-benzylethane-1,2-diamine (0.37 g, 2.72 mmol) in DMF (10 mL) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was redissolved in THF (5 mL) and citrate buffer (5.3 mL; 0.4 M), followed by NaBH3CN (0.31 g, 4.9 mmol), were added. The resulting mixture was stirred at room temperature overnight. The mixture was made basic (pH 8) with aqueous NaOH (8 mL; 1 M) and the aqueous layer was extracted twice with DCM (15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by LC-MS prep to give 1-benzyl-3-(trifluoromethyl)piperazine (66 mg, 12%). HPLC 94%, RT=1.25 min (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 2.77 (s, 2H) 3.17-3.31 (m, 1H) 3.32-3.64 (m, 3H) 3.83-4.02 (m, 1H) 4.13-4.31 (m, 2H) 6.68 (s, 1H) 7.30-7.55 (m, 5H). MS (ESI+) m/z 245. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]2[C:12]=1[C:20](=[O:22])[N:24]([CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27])[C:14]2=[O:16])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCC(=O)NC1=O
Reactant: CN(Cc1cccc(C(=O)O)c1C(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CN(Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)C(=O)OC(C)(C)C
Yield: 59.6 %

Procedure:
A stirred mixture of 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid (2.3 g, 7.1 mmol) from above and α-aminoglutarimide hydrochloride (1.3 g, 7.8 mmol) in pyridine (40 mL) was refluxed for 5 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and water (50 mL). The EtOAc solution was separated and washed with water (40 mL), IN citric acid (2×40 mL), water (2×40 mL), and brine (40 mL), and then dried (MgSO4). Solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, CH2Cl2: EtOAc 8:2) to give [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl ester (1.7 g, 60%): mp 138-140° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.91-7.81 (m, 2H), 7.57 (b, 1H), 5.19-5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.85 (s, 2H), 2.97-2.83 (m, 1H), 2.89 (s, 3H), 2.63-2.50 (m, 2H), 2.07-2.03 (m, 1H), 1.44-1.29 (d, 9H); 13CNMR (DMSO-d6) δ 172.70, 169.74, 167.48, 166.87, 154.75, 138.31, 134.99, 132.31, 131.74, 127.42, 121.98, 79.13, 48.86, 47.32, 34.84, 30.90, 27.93, 21.94; Anal. Calcd. for C20H23N3O6: C, 59.84; H, 5.78; N, 10.47. Found: C, 59.51; H, 5.68; N, 10.31.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
To a solution of acid 402a (2.61 g; 8.36 mmol; 1 eq), 1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36 mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64 ml; 33.4 mmol; 4 eq). After stirring overnight most of the DMF was removed under reduced pressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 was obtained in 70% (2.35 g). 1H-NMR (300.07 MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0,1 H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49. found: 403.4.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:19][C:18]1[C:9]([CH2:8][C:7]2[NH:20][S:1][O:2][N:6]=2)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1cc2ccccc2cc1Br)=NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1cc2ccccc2cc1CC1=NOSN1
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Thionyl chloride (2.0M/CH2Cl2 ; 7.4 mL, 0.015 mol) was added dropwise to a stirred suspension of N'-hydroxy-(3-bromo-2-naphthalenyl)ethanimidamide (3.29 g, 0.012 mol), methylene chloride (125 mL) and pyridine (2.4 mL, 0.03 mol) at 5° C. After 20 minutes at -5° C., the reaction solution was added to ice/H2O. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and concentrated in vacuo to a slurry (20 mL). Diethyl ether (20 mL) was added and the title compound (1.40 g, yield 36%) was collected (153°-154° C. decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH:35]2[CH2:39][C:38]3[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:37]=3[O:36]2)[CH2:30][CH2:29]1)=[O:27]>O1CCCC1.CN(C)C=O>[Cl:44][C:41]1[CH:42]=[CH:43][C:37]2[O:36][CH:35]([CH2:34][N:31]3[CH2:30][CH2:29][N:28]([C:26](=[O:27])[CH2:25][O:17][CH:14]4[CH2:15][CH2:16][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=5)[CH2:12][CH2:13]4)[CH2:33][CH2:32]3)[CH2:39][C:38]=2[CH:40]=1
Reactant: O=C(CCl)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-ol (40 mg, 0.13 mmol) in tetrahydrofuran (1 ml) and N,N-dimethylformamide (0.3 ml) was added sodium hydride (26 mg, 1.08 mmol, 8 eq) with stirring for 30 minutes at 0° C. Then 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one (90 mg, 0.27 mmol, 2 eq) in tetrahydrofuran (0.5 ml) was added with stirring for 5 hours at room temperature. The reaction mixture was quenched by water (20 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by Pre-TLC using 50% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (29.8 mg, 38%); (ES, m/z): [M+H]+ 597.35; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=7.2 Hz, 1H), 7.04-7.12 (m, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.71 (m, 2H), 5.01 (broad s, 1H), 4.46 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 3.60-3.73 (m, 3H), 3.40-3.47 (m, 2H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.92-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (m, 1H), 2.62-2.77 (m, 4H), 2.12-2.16 (m, 4H), 1.41-1.52 (m, 3H), 1.22-1.30 (m, 3H).