Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([F:24])=[C:22](F)[N:21]=[C:20]([F:26])[C:19]=1[F:27]>C(OCC)C>[CH3:17][C:18]1[C:23]([F:24])=[C:22]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:21]=[C:20]([F:26])[C:19]=1[F:27]
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(F)c(F)nc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Butyl lithium (2.7 ml, 6.7 mmol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-trifluoromethyl benzene (1.0 ml, 7.3 mmol) in anhydrous diethyl ether (10 ml) at −20° C. The mixture is stirred for 60 min at −20° C. and for 60 min at 10° C. After cooling to −40° C. 4-methyl-2,3,5,6-tetrafluoropyridine (1.1 g, 6.6 mmol) is added. The resulting mixture is stirred for 120 min at −30° C. and then is allowed to warm to ambient temperature. After 2 days at ambient temperature the mixture is washed twice with saturated aqueous ammonium chloride. The layers are separated and the organic layer is dried with anhydrous magnesium sulfate and filtered. After removal of the solvents in vacuo, the crude product is purified by flash column chromatography (silica gel, pentane/ethyl acetate=9/1 by volume) yielding colorless crystals of 4-methyl-2,3,5-trifluoro-6-(4-trifluoromethylphenyl)pyridine (0.5 g, 1.7 mmol) of mp. 52° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][C:4]#[CH:5].CN(C)CCN(C)C.C([Li])CCC.[CH2:26]1[O:28][CH2:27]1>O1CCCC1.O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][CH2:26][CH2:27][OH:28]
Reactant: C#CCCCOC1CCCCO1
Reactant: C1CO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OCCC#CCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cooled solution (-20° C.) of tetrahydro- 2-(4-pentynyloxy)-2H-pyran (1) (16.8 g. 0.10 mole) and tetramethylethylene diamine (45.2 mL, 0.30 mole, distilled from CaH2 under nitrogen) in anhydrous tetrahydrofuran (100 mL. distilled from sodium/benzophenone under nitrogen) was added via syringe a solution of n-butyllithium (41.0 mL, 0.101 mole, 2.44 N in hexane). The mixture was allowed to warm to 0° C. over 30 minutes and stirred at 0° C. for 1 h followed by the addition, via cannula, of ethylene oxide (8 8 g, 0.20 mole, freshly condensed into an argon filled graduated cylinder). The solution was stirred at 0° C. for 1 h and then stored in a refrigerator (5° C.) for 3 days. The reaction mixture was poured into water (200 mL) and extracted with ether (1×200 mL, 2×50 mL). The organic layers were combined and washed with water (5×50 mL), saturated sodium chloride (50 mL), dried (MgSO4), and concentrated to provide 22.80 g of a crude amber oil which was chromatographed (ethyl acetate/hexane 1:1) to provide 12.09 g (59%) of the title compound: Rf =0.32 (ethyl acetate/hexane:1/1) 1H PMR (CDCl3); δ 4.60 (t, J=3 Hz, 1H), 3.85 (m, 2H), 3.67 (t, J=6 Hz, 2H), 3.50 (m, 2H), 2.71 (bs, 1H), 2.40 (m, 4H), 2.29 (m, 2H), 1.78 (m, 4H), 1.52 (m, 4H); 13C NMR (CDCl3): 98.9, 81.5, 77.1, 65.9, 62.2, 61.3, 30.7, 29.0, 25.5, 23.1, 19.5, 15.7 ppm; IR (CHCl3): 3600, 3460 cm-1 ; Analysis calculated for C13H20O3 : C, 67.89; H, 9.50; Found: C, 67.96; H, 9 79.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=[C:6]([CH3:18])[C:5]=1[C:19]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:29][C:30]1[CH:43]=[CH:42][C:33]2[C@H:34]([CH2:37][C:38]([O:40]C)=[O:39])[CH2:35][O:36][C:32]=2[CH:31]=1>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:7]=[C:6]([CH3:18])[C:5]=1[C:19]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:29][C:30]1[CH:43]=[CH:42][C:33]2[C@H:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:35][O:36][C:32]=2[CH:31]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N6CCOCC6)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (4.1 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(morpholine-4-carbonyl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (55 mg) in ethanol (1.9 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50) to give the title compound. Yield 10 mg, LC (method 20): tR=5.73 min; Mass spectrum (ESI+): m/z=546 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[N:2]1.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: OCc1cc2cn[nH]c2cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1cc2cn[nH]c2cn1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
1H-pyrazolo[3,4-c]pyridine-5-methanol (1.08 g, 7.27 mmol) was dissolved in DCM (120 mL) at rt, and DMSO (30 mL) and NEt3 (3.01 mL, 21.7 mmol) were added. After stirring for 10 min, SO3-pyridine (3.45 g, 13.45 mmol) was added. The mixture stirred at rt for ca. 1.5 hr, and quenched with sat. NH4Cl solution. The reaction mixture was extracted with DCM, washed with water and with brine, and dried with Na2SO4. The crude product was purified by a flash column to afford 1H-pyrazolo[3,4-c]pyridine-5-carboxaldehyde (220 mg, 21%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][CH:10]=2)=[O:6].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][CH:10]=2)=[O:6]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 589 mg) was added to a solution of methyl-4-fluoro-5-benzyloxyindole-2-carboxylate (4 g) in dimethylformamide (100 ml) and the mixture was stirred under an argon atmosphere for 30 minutes. 3,4-dichlorobenzyl chloride (2.22 ml) was added and the mixture stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between diethyl ether (100 ml) and water (100 ml). Organic extracts were washed with water (100 ml), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography; using iso-hexane followed by 5% ethyl acetate/iso-hexane as eluent, to give the product as a yellow crystalline solid (4.61 g) 1H NMR (DMSO-d6) δ 3.80(s, 3H), 5.15(s, 2H), 5.80(s, 2H), 6.85(m, 1H), 7.25-7.52(m, 10H); M/z(+) 458.2 (MH+)
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[NH:5][CH:6]=1)=[O:20]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc(C(=O)c2ccc3ccccc3c2)c[nH]1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A mixture of 7.5 g (0.069 mole) of 2-acetylpyrrole, 17 g (0.089 mole) of 2-naphthalenoyl chloride and 18.3 (0.14 mole) of aluminum chloride in 200 mL of 1,2-dichloroethane was stirred for 4 h and then heated at 65° C. for 1.5 h. After cooling, the reaction mixture was poured into 2N HCl/ice. The organics were separated, washed with water, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from EtOAc to give 9.25 g (51%) of 1-[4-(2-naphthalenoyl)-1H-pyrrol-2-yl]ethanone. mp 172-174° C. CIMS m/z 264 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.4 (Ar, 1H); 8.0-7.9 (Ar, 4H); 7.7-7.55 (Ar, 3H); 7.5 (Ar, 1H); 2.55 (s, 3H).
Reaction SMILES: Br[C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C[C@]12CCC(=O)C(Br)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 75 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 4-bromoandrosta-4,6-diene-3,17-dione (545 mg, 1.5 mmole), dioxane (15 ml) and 30% NH4OH aqueous solution (30 ml) is stirred at 75° C. in a pressure vessel during 8 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example I. There are obtained 126 mg (0.42 mmole, 28% yield) of the title compound as a yellowish solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4.0 g (40 mmol) of hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction system was then allowed to cool to room temperature. To the reaction system was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.0 g (yield: 52%) of 5-(p-hydroxyphenyl)hydantoin.
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH3:14])[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: CNC
Reactant: Brc1ccn2nc(Br)nc2c1
Product: CN(C)c1nc2cc(Br)ccn2n1
Yield: 72.3 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.16 g, 7.8 mmol) in dimethylamine (30% in EtOH, 60 ml, 355 mmol) is heated in 4 portions a ca. 540 mg/15 ml of dimethylamine in a high pressure vessel to 100° C. for 3 hours each. The batches are combined and the solvent evaporated. The light brown crude material (4.77 g) is loaded on silicagel and purified by chromatography on a 70 g silica column using heptane/ethyl acetate 10-40% as eluent affording 7-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.36 g, 72.3%) as a light yellow solid. Mp.: 133-4° C. MS: m/z=243.2 (M+H+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]([C:13]([OH:15])=O)[CH2:11][CH2:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][CH:2]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][N:29]([C:13]([CH:10]4[C:8]5[C:9]6[CH:1]=[CH:2][NH:3][C:4]=6[CH:5]=[CH:6][C:7]=5[CH2:12][CH2:11]4)=[O:15])[CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCc2ccc3[nH]ccc3c21
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(C1CCc2ccc3[nH]ccc3c21)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 38.5 %

Procedure:
A solution of 14a (1.4 g), 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-H-indole (1.6 g), dicyclohexylcarbodiimid (1.9 g), and 4-dimethylaminopyridine (0.1 g) in THF (100 ml) was stirred for 24 hours at room temperature. The mixture was filtered and evaporated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (3:2) giving 1.1 g of the title product as an amorpheous powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)NC(=O)c1cccc(N)c1
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
3-Nitro-N-(2-propylsulfonyl)phenylcarboxamide (0.6 g) was dissolved in 30 ml of ethanol, treated with 300 mg of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 15 minutes. The reaction mixture was filtered through Celite and concentrated to give the title compound (307 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:38][C:39]2[CH:40]=[C:41]([CH:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=2)=[O:11])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(N)c1
Reactant: COc1cc(C(C)(C)C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C)ccc1C(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 17 h
Yield: 34.8 %

Procedure:
To a solution of 4-tert-butyl-2-methoxy-benzoic acid (0.05 g) in DMF (1.5 mL) at room temperature, was added in order, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.046 g), 1-hydroxy-benzotriazole (0.033 g) and 15 min. later, (±)-2-(3-aminophenyl)-1-(tert-butyloxycarbonyl)-pyrrolidine (0.05 g). The reaction mixture was allowed to stir for 17 h and then poured into water. The aqueous mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo to afford an amber oil. Suction silica gel chromatography eluting with ethyl acetate in hexane (from 30% to 100%, in 10% increments) gave desired product as an amber solid (0.03 g).
Reaction SMILES: [N+:1]([C:4]1[C:21]([N+:22]([O-])=O)=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:22][C:21]1[C:4]([NH2:1])=[CH:5][C:6]2[O:10][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:8][C:7]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1N)OC(CC(F)(F)F)(C(F)(F)F)O2

Procedure:
339 g of the product of Example 17a were dissolved in 2000 ml of tetrahydrofuran and treated with 20 g of catalyst (palladium on charcoal, 5% strength by weight). The mixture was hydrogenated with hydrogen for 13 hours at 25 to 30 bar and at room temperature. The batch was then filtered and the solvent was stripped off in vacuo. A solid remained. The yield was 274 g (=96% of theory). 19F-NMR: -61.2 and -86.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH2:25][C:26]1[N:31]=[C:30]([N:32]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])[CH:29]=[CH:28][CH:27]=1>C(#N)C.O>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:25][C:26]2[N:31]=[C:30]([N:32]3[C:33](=[O:42])[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:40]3=[O:41])[CH:29]=[CH:28][CH:27]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][N:12]=[N:13]1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Yield: 85.9 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (21.5 g, 0.106 mol) in acetonitrile (638 mL) was added cesium carbonate (72.4 g, 0.222 mol), potassium iodide (1.76 g, 0.011 mol) and then 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (35.23 g, 0.111 mol), the white slurry was stirred at room temperature for four hours at room temperature. Water (700 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to yield to of 2-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [40.0 g; 86% of theory; HPLC/MS: m/z=440 (M+H); log P(HCOOH)=3.04].
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]3[N:25]=[CH:26][NH:27][C:22]3=[CH:21][CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]3[N:25]=[CH:26][NH:27][C:22]3=[CH:21][CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc4[nH]cnc4n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc3[nH]cnc3n2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A mixture of 217b (40 mg, 0.070 mmol) and lithium hydroxide (26 mg, 0.70 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 217 (15 mg, 40%) as a white solid. MS-ESI: [M+H]+ 537.3. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.91-8.64 (m, 2H), 8.52 (d, J=4.5 Hz, 1H), 8.19-8.06 (m, 1H), 7.89-7.79 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.40 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 5.06-4.96 (m, 1H), 4.5-4.40 (m, 2H), 4.26-4.11 (m, 3H), 3.88-3.85 (m, 1H), 3.62 (s, 3H), 2.62-2.54 (m, 2H), 2.50-2.48 (m, 2H), 1.81-1.79 (m, 2H), 1.71-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([O-:10])=[O:9])=[C:4]([NH:13]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[N+:23]([C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:31])[CH2:29]Br)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:29]([C:28](=[O:31])[C:27]3[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=3[N+:23]([O-:25])=[O:24])[NH:13]2)=[CH:11][CH:12]=1
Reactant: O=C([O-])/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)Cc1c(C(=O)c2ccccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a mixture of polymer-bound trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1, 100 mg, 53 μmol) and 2-nitrophenacyl bromide (39 mg, 0.16 mmol) in acetone (3 ml) was added potassium carbonate (37 mg, 0.27 mmol). The mixture was agitated for 18 h. and filtrated. The residual resin was washed with water (20 ml×3), acetone (20 ml×3), dichloromethane (20 ml×3) and THF (20 ml×2) and dried. The resin was diluted with THF (4 ml) and then DBU was added (40 μl, 0.27 mmol). After agitating for 6 h, the resin was filtered off and washed with THF (20 ml×3), acetone (20 ml×3) and dichloromethane (20 ml×3). To the resin was added 95% trifluoroacetic acid in dichloromethane (5 ml) and the mixture was agitated for 3 h. The mixture was filtered and the residue was washed with dichloromethane (20 ml×5). The filtrate was concentrated and the residue was purified by HPLC (MeOH/AcONH4 aquous solution=60/40-90/10) to give 3.2 mg (17%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: COc1ccc(CCO)cc1
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 40 ml of anhydrous tetrahydrofuran. To this solution was added 0.897 g (5.9 mmol) of 2-(4-Methoxy-phenyl)-ethanol, 5.35 g (equivalent to 16.1 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14]>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:15]([N:12]=[N+:13]=[N-:14])[C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)N=[N+]=[N-]

Procedure:
Following the general procedure of PREPARATION 57 and making non-critical variations but starting with p-nitrobenzaldehyde (10 g) and methyl azidoacetate (30.4 g), the title compound is obtained, NMR 8.34, 8.07, 7.02, and 4.07 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16]C(=O)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: NS(=O)(=O)c1ccccc1
Product: C[C@H](CCCNC(=O)OCc1ccccc1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 81 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[(benzyloxy)carbonyl]amino]-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with benzyl chloroformate. Yield=81%; MS (ESI+), 555 (M+H)+.