Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:23]([NH:22][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a round bottom flask was added (1R,2R)—N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine (3.23 g, 8.05 mmol), THF (30 mL), isocyanatobenzene (0.958 g, 8.05 mmol) and Et3N (5.61 mL, 40.2 mmol). The reaction was stirred at rt for 2 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 ml). The resulting solution was washed with water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with 5% MeOH/CH2Cl2 with NH3) to give the product, 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol, 42.8% yield), as a white solid. Anal. Calcd. for C25H32N4O m/z 407, found: 408.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.15 (m, 9H), 6.97 (q, J=7.15 Hz, 1H), 4.51-4.27 (m, 1H), 3.58-3.34 (m, 2H), 3.23-3.08 (m, 1H), 2.96-2.80 (m, 1H), 2.66 (br. s., 1H), 2.40 (br. s., 1H), 2.29-2.11 (m, 2H), 2.11-1.92 (m, 2H), 1.77-1.57 (m, 5H), 1.57-1.42 (m, 1H), 1.31 (d, J=3.85 Hz, 1H), 1.30-1.05 (m, 4H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P([O-])([O-])([O-])=O.CCOCC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol)in THF (100 mL) at 0° C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0° C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL),dried (Na2SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[I:17](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[C:1]([NH:4][C:5]1[C:6]([I:17])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)cc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(NC(C)=O)c(I)c1O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Methyl 4-acetylamino-5-bromosalicylate (I-249) (576 mg, 2.0 mmol) was dissolved in a mixed liquid of methylene chloride (20 ml) and methanol (10 ml), then benzyltrimethylammonium dichloroiodate (835 mg, 2.4 mmol) and sodium bicarbonate (1.1 g, 13.0 mmol) were added, followed by stirring at room temperature for 30 hours. The reaction liquid was filtered, the filtrate was concentrated under reduced pressure, then saturated ammonium chloride water was added to the residue, followed by extraction twice with chloroform, then the organic layer was washed with saturated sodium thiosulfate water, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform/methanol (50:1) gave the entitled compound (889 mg, quant.) as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:27][C:28]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: OCc1cccc(F)c1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3-difluorobenzyl alcohol (113 mg; 0.736 mmol), example 80 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[C:5]=12
Reactant: COc1cccc2c1CC(CC=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reaction time: 0.58 h
Yield: 28.8 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-4-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.13 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:4). There was obtained 0.7 g (29%) of (RS)-1-(5-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.FC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1cccc(F)c1
Reactant: NN
Agent: Nc1cccc(F)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(F)c1
Yield: 37 %

Procedure:
This compound was prepared using 94 mg (0.5 mmol) of 2-[(3-fluorophenyl)-hydrazono]malononitrile, which was derived from 3-fluoroaniline (96 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 41 mg (37%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.0 (t, 1H), 7.35-7.62 (m, 3H), 10.80 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C.C(COC)OC.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccccc1-c1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
2-Bromothiophene (7.2 g, 43.9 mmol), 2-methoxyphenylboronic acid (6.7 g, 43.9 mmol), palladium acetate (0.14 g, 0.62 mmol), triphenylphosphine (0.6 mg, 2.3 mmol) and potassium phosphate (9.40 g, 44.3 mmol) were added to a flask. A mixture solution of 10 mL of water and 40 mL of dimethoxyethane was added and reflux was performed for 6 hours. After cooling to room temperature, aqueous ammonium chloride solution (50 mL) and diethyl ether (100 mL) were added. The organic layer was separated. After extracting the residue using diethyl ether, the collected organic layer was dried with magnesium sulfate. After removing volatile materials, followed by purification via silica gel chromatography using hexane, 7.9 g (yield: 95%) of 2-(2′-methoxyphenyl)thiophene was obtained as colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:24]#[N:25])C.[Li+].[OH-].O.Cl>C1COCC1>[C:24]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:26])=[O:3])#[N:25]
Reactant: CCOC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a clear solution of [2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-acetic acid ethyl ester ((D38), 90 mg, 0.25 mmol) in THF (20 mL) was added LiOH (15.3 mg, 0.76 mmol) and water (5 mL). The resulting mixture was stirred at room temperature for 2 hours. Then 1 N HCl was slowly added to pH 2. The mixture was evaporated under vacuum. The residue was purified with reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 48 mg of the title compound in 58% yield. 1H NMR 400 MHz (CD3OD) δ: 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.09 (s, 1H), 7.05 (dd, J=1.9, 8.21 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.63 (dd, J=1.9, 8.6 Hz, 1H), 5.06 (s, 2H), 4.78 (s, 2H); MS (ES) m/z: 326 (M+H)+; HPLC purity: 96.33% (220 nm), 96.44% (254 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][CH:13]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][CH:13]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnc(C)s1
Solvent: CCO
Product: COc1cc(N)ccc1-c1cnc(C)s1
Yield: 91.5 %

Procedure:
A suspension of 5-(2-methoxy-4-nitro-phenyl)-2-methyl-thiazole (330 mg, 1.32 mmol) and anhydrous stannous chloride (1.28 g, 6.6 mmol) in ethanol (21 mL) was stirred at reflux for one hour. The yellow solution was evaporated and the residue dissolved in ethyl acetate. This solution was washed twice with 2N aqueous sodium hydroxide solution, with brine, dried with magnesium sulfate and evaporated to dryness to afford the title compound (266 mg, 91%) as an orange solid. MS ISP (m/e): 221.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.81 (s, 1H), 7.33 (d, 1H), 6.31 (m, 2H), 3.87 (s, 3H), 3.83 (m, 2H), 2.69 (s, 3H). Mp 125-129° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:13]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][OH:15])[O:12][CH:11]([O:25][CH3:26])[CH:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH:10]([OH:27])[CH:11]([O:25][CH3:26])[O:12][C:13]1([CH2:14][O:15][N:29]1[C:33](=[O:34])[C:32]2[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]1=[O:39])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1OC(CO)(COCc2ccccc2)C(OCc2ccccc2)C1O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1OC(COCc2ccccc2)(CON2C(=O)c3ccccc3C2=O)C(OCc2ccccc2)C1O

Procedure:
The O-phthalimido compound is prepared following the reference cited and the procedures illustrated in Example 13 above. The reaction can be adjusted to preferentially react at the primary hydroxyl e.g. the 4′-C-hydroxymethyl group (Bhat, B., et. al., J. Org. Chem. 1996, 61, 8186-8199). Generally, a solution of 21 (1 eq.), N-hydroxyphthalimide (1.1 eq.), and triphenylphosphine (1.1 eq.) in anhydrous tetrahydrofuran is treated with diethyl azodicarboxylate (1.1 eq.). After several hours at room temperature, the mixture is concentrated and subjected to silica gel chromatography to give Compound 22.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].S([O-])([O-])=O.[Na+].[Na+].CC(C)=O>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:20]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1N
Reactant: CCCCc1ccc(C=O)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1ccc(-c2nc3ccccc3[nH]2)cc1
Reaction time: 1 h

Procedure:
Into a four-necked flask of 1 l capacity were charged 40.5 g (0.25 mol) of p-n-butylbenzaldehyde, 27.0 g (0.25 mol) of o-phenylenediamine, 28.6 g (0.23 mol) of sodium sulfite and 350 ml of dimethylformaldehyde, and a reaction was effected for 1 hour while refluxing the reaction solution. Then, 250 ml of water was added to the reaction mass, and the resulting mixture was cooled and filtered. The filter cake was washed with water to obtain the aimed 2-p-n-butylphenylbenzimidazole in an yield of 52.2 g (82.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:33](=[O:35])=[O:34].Cl>C(OCC)(=O)C.O.C1COCC1>[Si:11]([O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:33]([OH:35])=[O:34])([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=O
Reactant: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](OCCc1cccc(C(=O)O)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3.27 g of [2-(3-bromophenyl)ethoxy](tert-butyl)diphenylsilane and 50 mL of THF was slowly added 5.5 mL of butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes at −78° C. In addition, carbon dioxide was blown into the reaction mixture at −78° C., and the temperature thereof was slowly increased to room temperature, followed by stirring for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was neutralized with 9.0 ml of 1.0 M hydrochloric acid. Ethyl acetate was added thereto to separate the organic layer, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:6), thereby obtaining 1.45 g of 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoic acid.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:39].F[P-](F)(F)(F)(F)F.CNC>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:37][N:38]([CH3:39])[C:34]([CH:31]1[CH2:30][CH2:29][N:28]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:33][CH2:32]1)=[O:35]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C(=O)O)CC2)C1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.17 mmol) of 1-({3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)piperidine-4-carboxylic acid together with 80 mg (0.21 mmol) of HATU and 34 mg (0.28 mmol) of 4-dimethylaminopyridine were initially charged in 1.3 ml of DMF, and 6 mg (0.14 mmol) of N-methylmethanamine were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 62 mg (69% of theory)
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([S:17][CH3:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-].O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[I:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=[C:7]2[S:17][CH3:18])=[CH:11][CH:12]=1
Reactant: CSc1nc(CN=[N+]=[N-])cn1-c1ccc(I)cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nc(CN)cn1-c1ccc(I)cc1
Yield: 52.6 %

Procedure:
To a solution of 4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.26 g, 0.70 mmol) in EtOAc (10 mL), Tin(II) chloride dihydrate (0.63 g, 2.8 mmol) was added. The mixture was heated at reflux for 10 min. After being cooled down, 1N NaOH (10 mL) was added. The white precipitate was filtered off through celite. The EtOAc phase was separated, dried over Na2SO4, concentrated in vacuo to give (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine (127 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O1CCCC1>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCOCc1ccccc1
Reaction time: 2 h
Yield: 48 %

Procedure:
While a suspension containing 2.5 g of 60% sodium hydride was in 50 ml of tetrahydrofuran was allowed to stand at room temperature, 5.7 g of 1,4-butanediol was slowly added dropwise thereto. Then, a solution containing 7.5 ml of benzyl bromide in 20 ml of tetrahydrofuran was added dropwise to the reaction mixture at room temperature, followed by stirring at the same temperature for 2 hours. After the addition of a 10% aqueous solution of HCl, the reaction mixture was extracted with diethyl ether. After the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using 150 g of silica gel [with an elution solvent comprising hexane-ethyl acetate (4:1)]. Thus, 5.5 g (48% yield) of the title compound was obtained.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Br[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([S:7][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1nccs1
Reactant: [S-]c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Sc2nccs2)cc1

Procedure:
A solution of sodium thiophenolate (0.61 g, 4.62 mmol) and 2-bromothiazole (0.38 mL, 4.2 mmol) in 20 mL of toluene was treated with 0.19 g (0.21 mmol) of Pd2 dba3 and 0.12 g (0.21 mmol) of Xantphos and heated at reflux for 10 min. The crude solution was concentrated onto 5 g of silica gel and then purified by flash chromatography to give the title compound. MS (M+H)+ 194.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]([Cl:20])([Cl:19])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)O.O>C(Cl)Cl>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([Cl:2])[C:8]([Cl:20])([Cl:19])[Cl:7])[CH:12]=1
Reactant: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(Cl)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.4 g (11.0 mmol) of phosphorous pentachloride in 7.0 mL of CH2Cl2 was added a solution of 2.28 g (9.0 mmol) of the product of Step A in 5.0 mL of CH2Cl2. The reaction mixture became homogenous while it was stiffed at room temperature for 3 h. The reaction mixture was then cooled to 0° C. with an external ice-water bath and ice and water were added. The reaction mixture was allowed to warm to room temperature while stirring for 1 h, and was then extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5-20% EtOAc-hexane. Evaporation of the purified fractions afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:58][CH2:59][C:60]([OH:62])=[O:61]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([S:58][CH2:59][C:60]([OH:62])=[O:61])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)SCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
To a solution of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (for reference procedure see Example 18, WO2010/089107, which is incorporated herein by reference in its entirety) (0.2 g, 0.519 mmol), in dry DMF (6 ml), HATU (0.198 g, 0.521 mmol) and 4-methylmorpholine (0.057 ml, 0.521 mmol) were added and the mixture was stirred at RT until the complete conversion of the carboxylic acid into the activated ester occurred. 2-mercaptoacetic acid (0.030 ml, 0.434 mmol) was then added drop-wise, and the reaction mixture was stirred in the same conditions overnight. DMF was removed under reduced pressure and the crude was partitioned between EtOAc and HCl 1N; the organic layer was dried over Na2SO4, and the resulting crude was purified by trituration with Et2O affording 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoylthio)acetic acid as an off-white solid containing some impurities (0.253 g, yield supposed to be quantitative, MS/ESI+ 459.7 [MH]+). The product was used for the next step without any further purification.