Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:18]=2)=[CH:8][C:7]=1[CH3:26].[Li+].[OH-].Cl>O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:7]([CH3:26])[CH:8]=2)[S:15][CH:16]=1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3Cl)cs2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCc2nc(-c3ccccc3Cl)cs2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The solution of {4-[4-(2-chloro-phenyl)-thiazol-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester from Step C is treated with a solution of 1 M LiOH in H2O (1 mL), and the mixture is stirred for 12 h at rt. The mixture is acidified with 1 M HCl (1.2 mL) and extracted into EtOAc (20 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound F1 as a white solid: MS calcd. for C19H17ClNO4S (M+H+) 390.0. found 390.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24]>O1CCOCC1.[Ag-]=O.[Ag]=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: COc1cc(C#N)ccc1CBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
An efficiently stirred mixture of 5-nitroindole (3.24 g.), bromide (W) (4.57 g.) and silver (I) oxide (4.87 g.) in dry dioxane (90 ml.) was heated at 100° C. for 5 hours. Additional silver oxide (2 g.) was added, and heating continued for 1 hour. The cooled mixture was evaporated, the residue diluted with dichloromethane, filtered, washing the filter cake with dichloromethane until the washings were colorless, and the combined filtrate evaporated. The product was purified by flash chromatography on silica gel, eluting with 3:7 v/v ethyl acetate:hexane, giving a product which was crystallized from a mixture of ethyl acetate and hexane to give 3-(4-cyano-2-methoxybenzyl-5-nitroindole (1.87 g., 30% ) as a yellow powder, m.p. 204°-206° C.; partial NMR (80 MHz, DMSO--d6): 3.92(s,3H, OMe); 4.12(s,2H, ArCH2).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NCc1ccc(N)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of trimethyl acetic acid (9.98 g, 97.7 mmol) in methylene chloride (200 ml) cooled to 0° C. is added 4-aminobenzyl amine (11.1 ml, 97.7 mmol), triethyl amine (34.1 ml, 244 mmol), HOAt (13.3 g, 97.7 mmol), and EDC (18.73 g, 97.7 mmol). The reaction mixture is allowed to slowly warm to 25° C. and stirred at this temperature for 18 hrs. The reaction mixture is diluted with water and the organic layer is extracted, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 40% to 65% ethyl acetate in hexane) to give N-(4-amino-benzyl)-2,2-dimethyl-propionamide (16.8 g), as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39]C2CCCCO2)=[CH:32][CH:31]=1)[C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])=O)(C)(C)C.Cl.[N-:47]=[N+:48]=[N-].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.N1C=CC=CC=1.O>[N:8]([C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1)[C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)[C@H](Cc1ccc(OCCOC2CCCCO2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)[C@H](Cc1ccc(OCCO)cc1)N=[N+]=[N-]
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a stirring solution of the amide 147 (5.5 g, 8.6 mmol) in dioxane (20 mL) at 23° C. was added a solution of 4 M HCl in dioxane (172 mL). The mixture was stirred for 4 h and concentrated in vacuo to afford crude, clear, viscous pale-yellow oil. A slurry of NaN3 (839 mg, 12.9 mmol) in pyridine (13 mL) was then cooled to 0° C. and trifluoromethanesulfonic anhydride (2.17 mL, 12.9 mmol) was added dropwise before allowing the mixture to warm to 23° C. and stir for 3 h. A solution of the amine hydrochloride 148 (4.22 g, 8.6 mmol) in H2O (6 mL) was then added followed by CuSO4.5H2O (321 mg, 1.29 mmol). The combined mixture was allowed to stir at 23° C. overnight. An aqueous saturated solution of NaHCO3 was then added and the organic layer was extracted 3×EtOAc. The combined organic extracts were washed 1×10% CuSO4, 2×1 M HCl, 1×brine, and dried over MgSO4. Solvents were removed in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the azide 149 as a pale yellow, viscous oil (800 mg, 20%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Product: O=C(O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1

Procedure:
This was prepared analogously from 4-fluoro-3-nitrobenzoic acid and 3-bromoaniline.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH3:19])[C:10]=1[C:11]#[N:12])=[O:7])(=O)C.N>CO>[CH2:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[C:10]=1[C:11]#[N:12])[CH3:19]
Reactant: CCNc1cccc(NC(=O)COC(C)=O)c1C#N
Agent: N
Solvent: CO
Product: CCNc1cccc(NC(=O)CO)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of 2-(acetoxyacetylamino)-6-(ethylamino)benzonitrile (4.5 g) in methanol (250 ml) is added dropwise 28% aqueous ammonia (5.5 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (2.6 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([CH:28]([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(#N)C.O>[CH:31]([NH:34][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([CH:28]([F:29])[F:30])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:33])[CH3:32]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: CC#N
Solvent: O
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v), is added 1.2 mL (14.0 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue in ethyl acetate affords 106 mg (15% over two steps) of the product as a pale yellowish solid; LC/MS:488/490 (M+H)+; m.p.: 250-253° C.
Reaction SMILES: N([O-])=O.[Na+].[N:5]1([C:11]([C:13]2[N:18]=[CH:17][C:16](N)=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.NC(N)=O.[I-:24].[Na+]>Cl>[I:24][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:12])=[N:18][CH:17]=1
Reactant: Nc1ccc(C(=O)N2CCCCC2)nc1
Reactant: [I-]
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Product: O=C(c1ccc(I)cn1)N1CCCCC1
Reaction time: 0.17 h
Yield: 23 %

Procedure:
A solution of sodium nitrite (69 g) in concentrated hydrochloric acid (1.5 L) was added to crude 6-(piperidin-1-ylcarbonyl)pyridin-3-amine at 0 C, and the mixture was stirred for 10 minutes. Urea (20 g) was added, and the mixture was stirred for 15 minutes. Sodium iodide (150 g) was added, and the product was separated by filtration and recrystallized from ethanol to give 5-iodo-2-(piperidin-1-ylcarbonyl)pyridine (yield 23% calculated for methyl 5-nitropyridine-2-carboxylate, 71 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([Si:12]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:13][CH:14]1[CH:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[OH:37])([CH3:11])[CH3:10].[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:50][S:51]([O:37][CH:15]1[CH2:16][CH:17]([CH2:18][O:19][Si:20]([C:33]([CH3:34])([CH3:35])[CH3:36])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:14]1[O:13][Si:12]([C:9]([CH3:8])([CH3:10])[CH3:11])([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:53])=[O:52]
Reactant: CC(C)(C)[Si](OCC1CC(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CC(OS(C)(=O)=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59.8 %

Procedure:
Freshly distilled triethylamine (1.28 g, 8.2 mmol) was dissolved in 75 mL of freshly distilled methylene chloride. To this solution was added 2.3 g (3.9 mmol) of 2-O-((1,1-dimethylethyl)diphenylsilyl)-3-(((1,1- dimethylethyl)diphenyl-silyl)oxymethyl)-1,2-cyclobutanediol from Step K and the resultant solution was cooled to -78° C. with stirring, under a nitrogen atmosphere. Methanesulfonyl chloride (0.99 g, 8.2 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 3.5 h, the reaction mixture was diluted with 125 mL of methylene chloride and this solution was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue (2.9 g) was dissolved in 25 mL of 10% acetone in hexane and purified on a 2.5×45 cm silica gel column eluted at 2 psi with 500 mL of 5% acetone in hexane, followed by 250 mL of 10% acetone in hexane, to give 1.57 g (60% yield) of the title compound; MS DCI-NH3M/Z: 690 (M+NH4)+ ; 1H NMR (CDCl3) δ 1.95, m, 1H), 2.20 (m, 1H), 2.77 (m, 1H), 2.90 (s, 3H), 3.39 (d, 2H), 4.39 (m, 1H), 4.88 (m, 1H), 7.30-7.54 (m, 15H), 7.60-7.70 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].ClCCl.[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: CC(C)C(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture (ice bath, 0° C.) of 30 parts of 1-(4-amino-3-nitrophenyl)-2-methyl-1-propanone and 390 parts of dichloromethane were added dropwise 33 parts of acetyl chloride. Upon complete addition, the reaction mixture was stirred for 12 hours at room temperature. The whole was poured into water and after the addition of sodium carbonate, stirring was continued for 15 minutes. The separated organic layer was dried, filtered and evaporated, yielding 36 parts (100%) of N-[4-(2-methyl-1-oxopropyl)-2-nitrophenyl]acetamide (interm. 14).
Reaction SMILES: [O:1]=[C:2]1[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.I[CH:28]([CH3:30])[CH3:29].O>CN(C=O)C>[CH3:29][CH:28]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:2]1=[O:1])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
A mixture of tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1480 mg) and 2-iodopropane (714 mg) in DMF (5 mL) was stirred at 60° C. for 4 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (570 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:51]([C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH2:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)#[N:52]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:62][S:59]([C:56]3[CH:55]=[CH:54][C:53]([C:51]#[N:52])=[CH:58][CH:57]=3)(=[O:60])=[O:61])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
A mixture of [6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 31) (100 mg, 0.21 mmol), 1,3-dicyclohexylcarbodiimide (41.5 mg, 0.23 mmol), 4-cyanobenzene-1-sulfonamide (41.5 mg, 0.23 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) in dichloromethane (4 ml) is stirred for 48 hours. The product is extracted with dichloromethane, washed with 2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][S:7]([N:10]([CH2:12][C:13]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[N:15]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1)[CH3:11])(=[O:9])=[O:8].[OH-].[Na+]>CO>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1)[CH2:6][S:7]([N:10]([CH2:12][C:13]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[N:15]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1)[CH3:11])(=[O:9])=[O:8]
Reactant: COC(=O)c1cc(CN(C)S(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1cc(C(=O)O)n(-c2ncccc2Cl)n1)S(=O)(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.30 g (5.78 mmol) of methyl 3-{[{[3,5-bis(trifluoromethyl)benzyl]sulphonyl}(methyl)amino]methyl}-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate were dissolved in 50 ml of methanol, and aqueous sodium hydroxide solution (0.28 g of sodium hydroxide dissolved in 25 ml of water; 6.94 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The methanol was then removed under reduced pressure and the aqueous residue was extracted three times with methylene chloride. The organic phase was discarded. The aqueous phase was then adjusted to a pH of 3 using 5% strength hydrochloric acid and extracted with dichloromethane (2×100 ml). The combined organic phases were dried over sodium sulphate. (logP: 3.07; MH+: 557; 1H-NMR (400 MHz, DMSO, δ, ppm): 2.78 (s, 3H), 4.40 (s, 2H), 4.78 (s, 2H), 6.97 (s, 1H), 7.62 (dd, 1H), 8.05 (, 1H), 8.09 (s, 2H), 8.15 (d, 1H), 8.51 (d, 1H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]#[N:42])=[CH:35][C:34]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]#[N:42])=[CH:35][C:34]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3ccccc3)c2)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
0.90 ml (0.90 mmol, 3 eqv) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 164.3 mg (0.30 mmol) 3-(3′,3″-Dibenzyl-2-isobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (27) in 7 ml dry CH2Cl2 at 0° C. via syringe. After that, the solution was stirred for 2 h at 0° C. and then for 4 h at rt. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (2+1)) yielded 137.5 mg (0.26 mmol, 86%) 28 as a colorless oil: Rf (Hexanes/EtOAc (2+1)) 0.35; 1H NMR (500 MHz, CDCl3) δ 0.67 (d, 6H, J=6.62 Hz), 1.61 (m, 1H), 2.40 (d, 2H, J=7.09 Hz), 2.58 (t, 2H, J=7.41 Hz), 2.91 (t, 2H, J=7.41 Hz), 3.89 (s, 2H), 3.93 (s, 2H), 5.57 (s, 1H), 6.74 (d, 1H, J=8.04 Hz), 6.90 (m, 2H), 6.99-7.26 (m, 16H); LRMS (EI) m/z 536 (19), 535 (46), 501 (10), 446 (9), 369 (21), 91 (100), 78 (12), 76 (10); HRMS (EI) Calcd. for C39H37NO: 535.287514. Found: 535.287420.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:29])=CC=1>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:12][C:13](=[S:29])[NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: c1nc(Cc2ccc3c(c2)OCO3)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: S=c1[nH]cc(Cc2ccc3c(c2)OCO3)[nH]1
Reaction time: 3 h

Procedure:
A solution of 4-benzo[1,3]dioxol-5-ylmethyl-1H-imidazole (Intermediate D4) (0.24 g, 1.18 mmol) in THF (4 mL) and water (4 mL) was treated with NaHCO3 (1 g, 11.9 mmol) at rt for 10 m. Phenyl chlorothionoformate (0.42 mL, 3.1 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give a white solid (˜36%) 4-benzo[1,3]dioxol-5-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 5)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:24](Br)[CH:25]=[CH:26][CH3:27]>O>[CH2:24]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:25]=[CH:26][CH3:27]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Reactant: CC=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CC=CCON=C(C)c1ccc(NC(=O)NCC(=O)OCC)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-ethoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-crotyloxyiminoethyl)phenyl]-N'-ethoxycarbonylmethylurea.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)#[N:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N#Cc1ccc(O)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Reaction time: 0.33 h
Yield: 60.1 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of p-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred overnight at room temperature in 20 ml of dry pyridine. Any insoluble materials were filtered, washed with pyridine and extracted with a solution of 20 ml of water and 20 ml of t-butanol, followed by stirring for about 20 minutes. The filtrate, washings and extract were combined together, and the solvent was removed under reduced pressure. The residue was recrystallized from water to obtain 3.4 g (yield: 59%) of p-cyanophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 164.5° to 169° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Br[C:41]1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.Cl.CNC>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([N:8]([CH3:41])[CH3:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CNC
Agent: Cl
Product: CN(C)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (18A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and dimethylamine hydrochloride. MS (m/z) 643.09 [M+H]+.