Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]I.CO.S([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1ccc(F)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
6-Fluoro-3-hydroxypyridine (870 mg) and iodine (9.76 g) were dissolved in a mixed solvent composed of methanol (20 ml) and water (10 ml) to prepare a solution which was then stirred at room temperature for 120 hr. Thereafter, sodium sulfite was added until the solution became transparent. Methanol in the reaction solution was removed under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-fluoro-2-iodo-pyridin-3-ol (350 mg, yield 19%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH:18]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)=[N:10]1)([CH3:20])[CH3:19]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.52 g) was added to a stirred suspension of sodium hydride (60% in oil, 0.096 g) in N,N-dimethylformamide (18 mL) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0° C., treated with 2-iodopropane (0.4 mL) and stirred at room temperature for 16 hours. The mixture was diluted with water (10 mL) and concentrated to low bulk under reduced pressure. The residue was extracted with ethyl acetate, and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound (0.152 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), benzaldehyde (2.05 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.90 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (5.18 g) in a yield of 97.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2].CO.[C:27](=O)([O-])O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([O:21][CH3:27])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To 72 mg of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]-thiepin-2-yl)-propionic acid were added 10 ml of a diazomethaneether solution and 1 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. To this was added acetic acid, and the mixture was made alkaline with a saturated sodium hydrogen carbonate solution and then extracted with benzene. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellow oil, which was chromatographed over 2 g of silica gel and eluted with chloroform, thereby obtaining 44 mg (yield: 57%) of methyl 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate as a yellow oil.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC=O
Reactant: CN(C)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCNCCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A solution of (9Z,12Z)-octadeca-9,12-dienal (1.06 g, 4.0 mmol) and N,N-dimethylpropane-1,3-diamine (408 mg, 4.0 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen for 15 minutes then sodium triacetoxyborohydride (1.7 g, 8.0 mmol). The solution was stirred for 2 hours at room temperature. Upon completion, the solution was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate (2×15 mL) and brine (15 mL). The ethyl acetate layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel (eluted with 100% CH2Cl2 to 1/5/94 NH4OH/MeOH/CH2Cl2) to afford N,N-dimethyl-N′-((9Z,12Z)-octadeca-9,12-dienyl)propane-1,3-diamine as a colorless oil (420 mg, 30%).
Reaction SMILES: [NH:1]([CH:3]=[O:4])[NH2:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][NH:1][CH:3]=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NNC=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=CNNC(=O)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
To hydrazinecarboxaldehyde (1.20 g, 20 mmol) in 100 ml THF, triethylamine (Et3N) (2.63 g, 26 mmol) was added. The mixture was heated at 60° C. to a clear solution and cooled to room temperature. 4-Bromobenzoyl chloride (4.39 g, 20 mmol) was added to the reaction mixture over 20 min. The mixture was refluxed for 1 hr., cooled to room temperature and filtered. The filtrate was concentrated to give a light yellow solid (2-[(4-bromophenyl)carbonyl]-hydrazinecarboxaldehyde).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1([F:42])[CH2:35][CH2:34][CH2:33][N:32]([CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:31]1>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:32]3[CH2:33][CH2:34][CH2:35][C:30]([F:29])([F:42])[CH2:31]3)[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C(O)/C=C/CN1CCCC(F)(F)C1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: Nc1ncnc(Oc2ccc(Oc3ccccc3)cc2)c1-c1cccc(NC(=O)/C=C/CN2CCCC(F)(F)C2)c1
Yield: 48 %

Procedure:
(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(3,3-difluoropiperidin-1-yl)but-2-enoic acid using Method E (48% yield). HPLC: 97%, RT=3.809 min. MS: m/z=558 [M+H]+, RT=1.92 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:26](OC(=N)C(Cl)(Cl)Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.C(S(O)(=O)=O)(F)(F)F.[Cl-].[Na+].O>[CH2:26]([O:25][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate (282 mg, 0.82 mmol) was dissolved in 10 mL DCM and benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol) was added followed by 3 drops of CF3SO3H. The reaction was stirred for 2 h. Reaction was incomplete so added more benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol). After 12 h, diluted with brine and extracted with DCM×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with EtOAc/hexane gradient. Obtained 52 mg (15% yield) of methyl 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate. MS found: (M+H)+=433.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[N+:15]([O-:18])([OH:17])=[O:16]>C(O)C>[N+:15]([O-:18])([OH:17])=[O:16].[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([NH:9][C:2]([NH2:3])=[NH:1])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1cccc(C(F)(F)F)c1

Procedure:
6.3 g (150 mmol) of cyanamide (50% in water) are added to a suspension of 16.1 g (100 mmol) of 3-trifluoromethyl-aniline in 35 ml of ethanol. 7.0 ml of nitric acid (65%, 0.1 mol) are then added to the brown solution and the reaction mixture is heated for 20 h under RF. It is then cooled to 0° and filtered, and the material retained on the filter is washed with ethanol and dried at 60° under HV to give 3-trifluoromethyl-phenylguanidine nitrate; 1H-NMR (dimethyl sulfoxide): 7.6 (7H,m), 9.9 (1H,br,s).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12](Cl)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1Cl)[CH:2]([CH3:4])[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(C)CN1P(Cl)OCC12COP(Cl)OC2
Solvent: C1CCOC1
Product: CC(C)CN1P(c2ccccc2)OCC12COP(c1ccccc1)OC2

Procedure:
Into a solution of 10.0 g (32.7 mmol) of 1-isobutyl-2,8-dichloro-3,7,9-trioxa-1-aza-2,8-diphosphaspiro[4.5]decane, the compound of Example 8, in 60 mL of tetrahydrofuran (THF) is added dropwise 32.7 mL (65.4 mmol) of a 2M solution of phenyl magnesium chloride in THF at ambient temperature. The title compound is isolated in a yield of 11 g as an oil and identified by mass spectrometry: m/z=389.
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34]>O.C(#N)C>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:23][CH2:24]2)=[CH:25][CH:26]=[CH:27][C:28]=1[CH2:29][CH2:30][O:31][CH2:34][CH2:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Triton-B (0.3 molar equivalents of a 40% solution in water) was added to a solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4-yl)methanone (limiting reagent) (step c) and tert-butyl acrylate (5 molar equivalents) in acetonitrile (3.4 volumes). The reaction was stirred at ambient temperature for 1 hr. The solvent was evaporated and the residue was partitioned between water (2 volumes) and 2-MeTHF (2 volumes). The layers were separated and the organics were dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield: 94% of theoretical.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][CH2:22][S:23][CH3:24])[CH:10]([O:14]C1CCCCO1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][CH2:22][S:23][CH3:24])[CH:10]([OH:14])[C:11]([O:13][CH3:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(OC1CCCCO1)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
A solution of Example 11B (0.25g, 0.68 mmol) and trimethylsilyldiazomethane (2.0M in hexanes, 15 mL) in THF at room temperature was stirred for 4 hours, treated with acetic acid (1 mL), and concentrated. The residue was dissolved in methanol, treated with p-toluenesulfonic acid (10 mg), and heated to 55° C. for 16 hours. The mixture was concentrated and purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product. MS (APCI(+)) m/e 294 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:17]=1)C(O)=O)#[N:8]>CN(C=O)C>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[C:16]([O:18][C:19]([F:20])([F:22])[F:21])[CH:17]=1)[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(OC(F)(F)F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.0 M in DCM, 0.636 mL, 1.272 mmol) was added to neat 3-cyano-5-(trifluoromethoxy)benzoic acid (98 mg, 0.424 mmol) and one drop of DMF was added. The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:10]2[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: CCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Yield: 68 %

Procedure:
To a 50 mL three-necked flask containing AlCl3 (7.305 g; 54.79 mmol) under N2, ethyl benzene (IVc) (8.40 mL; 68.48 mmol) was added in one portion at RT. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (10.66 g; 45.65 mmol) was added drop wise keeping temperature below 40° C. Protocol and work-up was then similar with those described above. Title compound was obtained as a white powder (m=9.923 g) in a 68% yield. Melting point: 146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21](OCC)=[O:22])[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1([CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][CH2:32][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:40][CH2:39]3)=[O:22])[N:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: C1CCN(CCCN2CCNCC2)C1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CCCN4CCCC4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (27 mg, 0.07 mmol), 1-[3-(pyrrolidin-1-yl)propyl]piperazine (40 mg, 0.20 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (2 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.Cl.[CH3:60][N:61]([CH3:77])[CH:62]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:62]([N:61]([CH3:60])[CH3:77])[CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-amine trihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[NH:8])=[O:7])[CH3:2].C=O.[CH:23](O)=O.[OH-].[Na+]>O>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[N:8][CH3:23])=[O:7])[CH3:20]
Reactant: CCN(CC)CCS(=N)(=O)c1nsnc1-n1ccnc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCS(=O)(=NC)c1nsnc1-n1ccnc1

Procedure:
A mixture of S-[2-(diethylamino)ethyl]-S-[4-(1H-imidazol-1-yl)-1,2,5-thiadiazol-3-yl]sulfoximine (30 mmol), 17 ml of 37% formaldehyde and 22.6 ml of 98% formic acid is heated at reflux temperature for 48 hr. Water is added to the reaction mixture which is then made slightly basic by addition of 50% sodium hydroxide solution. The mixture is extracted with chloroform and the extract is dried and concentrated to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([O:18]C)[CH:11]=2)=[CH:5][CH:4]=1)=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([OH:18])[CH:11]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1cc(N(c2ccc(C=O)cc2)c2ccc(C=O)cc2)ccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C=O)c(O)c2)cc1
Yield: 87.7 %

Procedure:
A solution of compound 9 (310 mg, 860 μmol) in dichloromethane (5 mL) is added dropwise to a suspension of aluminium chloride (AlCl3, 575 mg, 4.31 mmol, 5 eq.) in dichloromethane (10 mL) at −10° C. The mixture is stirred under reflux for 24 hours. It is then poured into a mixture of water and ice, and it is then vigorously stirred for 10 minutes. It is extracted with dichloromethane. The organic phase is washed with water and with brine, dried and concentrated to give a solid which is triturated in hexane to give 260 mg (754 μmol) of compound 10 in the form of a yellow powder (yield: 87%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH3:22])=[O:20].Cl>C1COCC1>[CH3:22][O:21][C:19]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:20]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 198.7 %

Procedure:
A suspension of L-diphenylalanine (13.87 g, 57.5 mmol) in THF (100 ml), and saturated NaHCO3 (3 mL) stirred at 0° C. was treated with neat methyl chloroformate (11.81 g, 125 mmol) (slow addition), stirred at the same temperature for 10 min and then at room temperature for 14 h, made acidic by addition of 1M HCl and extracted with DCM, dried over MgSO4 filtered and concentrated to give title compound (17.1 g, 99% yield) as white solid. Used without further purification. MS: m/z=322.1 (MNa+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[C:26]([NH:27][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)=[O:13])[CH:28]=[CH:29][CH:30]=1)([O-:23])=[O:22]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 24.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-nitroaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized once from ethanol-ether, then twice from acetonitrile-DMF-water to yield 0.79 g of the title compound, mp >270° C.