Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[S:39]([CH3:38])(=[O:41])=[O:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1)S(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by methanesulfonyl chloride (29 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 137 mg, 76%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47-8.56 (2 H, m), 7.61-7.68 (2 H, m), 7.23-7.35 (2 H, m), 7.03-7.19 (2 H, m), 6.52 (1 H, s), 5.10-5.29 (2 H, m), 4.37 (1 H, d, J=13.39 Hz), 3.90-3.99 (3 H, m), 3.74-3.89 (1 H, m), 3.06-3.19 (1 H, m), 2.93 (3 H, s), 2.68 (3 H, s), 2.58-2.65 (1 H, m), 1.62-1.77 (3 H, m), 1.42-1.59 (1 H, m); m/z (APCI+) for C24H28N5O3FS 486.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:20]([O-:23])(=[O:22])[CH3:21].[NH2:24][N+:25]1[CH:29]=[CH:28][N:27]([NH2:30])[C:26]=1[CH2:31][CH3:32]>C(O)(=O)C.C(O)C>[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[N:30][N+:27]3[CH:28]=[CH:29][NH:25][C:26]=3[CH2:31][CH3:32])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCc1n(N)cc[n+]1N
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)N1CCN(c2ccc(C=N[n+]3cc[nH]c3CC)cc2)CC1
Reaction time: 18 h

Procedure:
1.95 g (7.4 mmol) of p-[4-(ethoxycarbonyl)-1-piperazinyl]benzaldehyde are added to a solution of 0.69 g (3.7 mmol) of 1,3-diamino-2-ethyl-imidazolium acetate in 10 ml of glacial acetic acid, the mixture is left to stand at room temperature for 18 hours, then diluted with 30 ml of ethanol and the product is crystallized out by the addition of ether. There is obtained 1,3-bis[[[p-(4-(ethoxycarbonyl)-1-piperazinyl]benzylidene]amino]-2-ethyl-imidazolium acetate diacetate of melting point 187°-188°.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH2:20]([NH:22][C:23](=S)[NH:24][NH2:25])[CH3:21]>>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:23]([NH:22][CH2:20][CH3:21])=[N:24][N:25]=3)[N:14]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCNC(=S)NN
Reactant: CCC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Product: CCNc1nnc2ccc(-c3cccc(N(C)C(=O)CC)c3)nn12
Yield: 20.4 %

Procedure:
A solution of 5.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 4.3 g 4-ethyl-3-thiosemicarbazide was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 1.2 g of yellow crystals, mp 198°-199° C.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O>CN(C=O)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH2:28])=[O:30])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Temperature: 50 °C
Yield: 48.1 %

Procedure:
To 100 mg (0.33 mmol) of the product of Example 27 step 1 in 15 mL of DMF was added 57 mg (0.50 mmol) of trimethylsilyl isocyanate the solution was heated to 50° C. for 1.5 hr. At the end of this time it was poured into 100 mL of water. The resulting precipitate was collected by filtration and taken up in hot ethyl acetate. The excess water was removed by decantation and the solution allow to cool. Hexane was introduced to cloudiness and the solution allow to cool further to yield 55 mg (48%) of product as a colorless solid, m.p. 143-144° C. NMR (400 MHz, DMSO) δ 8.42 (s, 1H); 7.34 (m, 10H); 7.10 (t, J=7.7 Hz, 1H); 6.73 (d, J=7.7 Hz, 1H); 5.77 (s, 2H); 4.30 (s, 2H); 3.53 (t, J=6.8 Hz, 2H); 2.72 (t, J=6.8 Hz, 2H). Anal. Calcd. for C21H21N O: C, 83.13; H, 6.98; N, 4.62 Found: C, 75.13; H, 6.41; N, 8.11. (+)FAB m/z 347 (M+H), 369 (M+Na).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCc1cccc(F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of methyl salicylate (1.512 g, 9.93 mmol) in N,N-dimethylformamide (15 ml) were added 3-fluorobenzyl bromide (1.3 ml, 10.6 mmol) and potassium carbonate (1.780 g, 12.88 mmol), and the mixture was stirred at 80° C. for 5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-fluorobenzyloxy)benzoate (1.991 g, 7.65 mmol, yield 77%). This was dissolved in methanol (15 ml), 1N-aqueous sodium hydroxide solution (15 ml) was added at room temperature, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-(3-fluorobenzyloxy)benzoic acid (1.790 g, 7.27 mmol, yield 95%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)CCC.I[C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[C:28](=[O:30])[CH:29]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:24]2[CH:25]=[N:26][NH:27][C:28](=[O:30])[CH:29]=2)=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)n1ncc(I)cc1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(COc2ccc(Cl)cc2)cn[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of tributyl((4-chlorophenoxy)methyl)stannane (29.5 mg, 0.068 mmol), tert-butyl 4-iodo-6-oxopyridazine-1(6H)-carboxylate (20 mg, 0.062 mmol) and bis(triphenylphosphine)palladium(II)chloride (2.18 mg, 3.10 μmol) in toluene (1.0 mL) under nitrogen in a sealed tube was stirred at 110° C. for 2 hours. After removal of the precipitate, the filtrate was concentrated and dissolved in CH2Cl2 (3.0 mL). After addition of TFA (1.0 mL, 12.98 mmol), the solution was stirred at RT for 15 min before being concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) to give 5-((4-chlorophenoxy)methyl)pyridazin-3(2H)-one 8B (5.0 mg, 33% yield). 1H NMR (400 MHz, THF-D8) δ ppm 5.99 (1H, d, J=1.76 Hz), 5.55 (2H, d, J=8.78 Hz), 5.27 (2H, d, J=9.03 Hz), 5.08 (1H, d, J=1.51 Hz), 3.24 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)(=[O:10])=[O:9].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])([CH3:21])[CH3:20].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CO.C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH2:12][NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:24]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1S(=O)(=O)NCCc1ncc[nH]1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(C(=O)Nc2ccccc2S(=O)(=O)NCCc2ncc[nH]2)c1
Yield: 84.2 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 1C using 2.80 g (0.0107 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl] benzene sulfonamide and 4.20 g (0.0213 mol) of meta-t-butylbenzoyl chloride with the exception that, after reducing the reaction solution to dryness under reduced pressure the resultant residue was dissolved in methanol. The resulting solution was heated to reflux for approximately one hour and then reduced to dryness under reduced pressure. The resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with water and then a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then reduced to dryness under reduced pressure. The resultant residue was purified using preparatory high performance liquid chromatography (8000 ml of a gradient of methylene chloride to 10% methanol and 0.5% ammonium hydroxide in methylene chloride). Fractions containing the free base form of the desired titled compound were combined and then reduced to dryness under reduced pressure to provide an oil. This oil was dissolved in methanol and 0.36 g of oxalic acid were added, with stirring. The resulting solution was reduced to dryness under reduced pressure to provide a foam. This foam was crystallized from a 1:10 solution of methanol/ethyl acetate to provide 1.74 g of the desired titled compound (m.p. 191°-193.5° C.).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[CH2:31]([C@@H:27]([CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:11]=2)=[O:22])[C:28]([OH:30])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC[C@H](Cc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@H](Cc2ccccc2)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol), (S)-3-amino-2-benzyl-propionic acid (crude as TFA salt, 0.38 mmol) and sodium methoxide (40 mg, 0.74 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 17 mg. MS: (−) m/z 465.96 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C(NCc1cccc(Br)c1)c1ccccc1
Product: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Yield: 49.9 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 7.4 g (25.4 mmol) of N-(3-bromo benzyl)-benzamide with 5.7 g (38.2 mmol) of 4-formylbenzene-boronic acid, 4 g (50%) of the expected product are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:14]=[CH:13]N=C[CH:10]=2)=[N:5][N:4]=1.Cl.C(Cl)(=O)C1C=CC=[N:19][CH:18]=1>>[CH3:1][NH:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[N:19][CH:18]=[CH:13][CH:14]=2)=[N:5][N:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CNc1nnc(-c2ccncc2)n1C
Agent: Cl
Product: CNc1nnc(-c2cccnc2)n1C

Procedure:
The title compound is prepared according to the procedure for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (example 16a) from nicotinoyl chloride hydrochloride.
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][OH:11])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][O:11]2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 7 (44 g, 0.27 mol), 4-bromobenzaldehyde (49 g, 0.27 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:37]([CH2:36][C:35]3[CH:46]=[C:47]([Cl:49])[CH:48]=[C:33]([Cl:32])[CH:34]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:28])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Reactant: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
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: O=C(c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (48 mg, 0.10 mol) in DMF, were added. N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (28 mg, 0.1 mmol), HATU (48 mg, 0.15 mmol), and DIPEA (0.052 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 h and purified by preparative HPLC (Column YMC S5 ODS C18 20×100 mm; Solvent A=10% MeOH-90% H2O with 0.1% TFA; Solvent B=10% H2O-90% MeOH with 0.1% TFA). The desired fractions were combined, concentrated and lyophilized to give the title compound (40 mg, 51%) as a white solid. 1H NMR (CD3OD) δ 7.71 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.5 Hz), 7.37-7.05 (m, 13H), 6.85 (t, 2H, J=8.8 Hz), 4.70 (br, 1H), 4.64 (br, 1H), 4.54 (s, 2H), 4.50 (s, 2H), 4.46 (br, 1H), 4.42 (br, 1H). MS (ESI): 750.8 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15](=O)[CH2:14][CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(OC(=O)C)(=O)C>[C:1]([O:9][CH2:10][C@H:11]1[S:15][C@H:14]([O:20][C:17](=[O:19])[CH3:18])[CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1SCCS1=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@@H]1CS[C@@H](COC(=O)c2ccccc2)S1
Yield: 9 %

Procedure:
A mixture of 2-benzoyloxymethyl-3-oxo-1,3-dithiolane (example 13) (5.1 g), sodium acetate (65 g) and acetic anhydride (100 ml) was heated at refluxing for 3 hours. Excess reagent was removed under reduced pressure. The residue was dissolved in methylene chloride (200 ml), washed first with saturated aqueous NaCO3 solution (3×100 ml), then with water (100 ml), and finally with brine solution (100 ml), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica gel using hexane:ethyl acetate (9:1) as eluant. The desired product was a byproduct and obtained in 9% yield (535 mg) as a mixture cis- and trans-isomer which was characterized by spectroscopic methods.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])C.O.[NH2:29][NH2:30]>C(O)C>[CH2:20]([N:6]([CH2:5][C:4]([NH:29][NH2:30])=[O:3])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 22 h
Yield: 93.3 %

Procedure:
To a stirred solution of [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.52 g) in ethanol (15 mL) was added hydrazine monohydrate (1.60 g). The mixture was stirred for 5 h at r.t. and for 22 h at 50° C. The mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (2.27 g) as a colorless oil. MS: 388.4 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-bromo-1H-indole-3-carboxylate (1.0 g, 4.0 mmol) in dimethylformamide was added sodium hydride (0.32 g, 8.0 mmol, 60% in oil) under ice bath. The resulting mixture was stirred at room temperature for 0.5 hour. Then (1-bromoethyl)benzene (1.1 g, 6.0 mmol) was added in portion slowly. Then the mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (100 mL), and the product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column Chromatography (silica gel: ethyl acetate:petroleum ether=1:8) to give the pure product methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (1.1 g, 75%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:14]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:11][OH:12])=[CH:4][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCI
Reactant: OCc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.8 %

Procedure:
Sodium hydride (0.17 g, 7.20 mmol) was added to a solution of 1,4-benzene dimethanol (1.00 g, 7.20 mmol) in THF at 0° C. The reaction was stirred for 1 h. 1-iodooctane (1.73 g; 7.20 mmol) was added and the reaction mixture was warmed to rt for 4 h and then heated at 50° C. for 2 days. The reaction was cooled and filtered. Silica gel chromatography eluting with 15% ethyl acetate/hexane gave 0.14 g of product: 1H NMR (500 MHz) δ 7.34-7.40 (m, 4H), 4.68-4.72 (m, 2H, 4.51 (s, 2H), 3.46-3.50 (m, 2H), 1.61-1.68 (m, 2H), 1.24-1.40 (m, 10H), 0.88-0.92 (m, 3H).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
A solution of (2-fluoro-3-methylphenyl)-(4-methoxy-phenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) in pyridine was heated at 100 C for 24-48 hrs. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.IC.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)nc(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(Br)nc1C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-3-hydroxypyridine (8.7 g, 43.1 mmol), iodomethane (4.0 mL, 64.6 mmol) and potassium carbonate (11.9 g, 86.1 mmol) in acetone (250 mL) was heated at reflux temperature for 3 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 7.9 g (85%) of the title compound.