Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH2:10][CH2:11]Br.N1(N[C:20](=[O:28])[CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])CCCCC1.S(=O)(=O)(O)O>O1CCCC1>[CH2:23]([O:22][C:21]([O:25][CH2:26][CH3:27])([CH2:11][CH2:10][C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:9])[CH:20]=[O:28])[CH3:24]
Reactant: Cc1cccc(C)c1CCBr
Reactant: CCOC(OCC)C(=O)NN1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(C=O)(CCc1c(C)cccc1C)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9 g of magnesium turnings are covered with 400 ml of dry tetrahydrofuran and the mixture is warmed to boiling. To that mixture is then added 2-(2',6'-dimethylphenyl)-1-bromoethane at such a rate that a gentle boiling is maintained. When the magnesium turnings have reacted the solution containing the Grignard reagent is cooled to room temperature. The reaction mixture is then added dropwise, over a period of 3 hours, to a cooled (0°-5° C.) solution of diethoxyacetic acid piperidinyl amide (80.8 g) in 200 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is stirred for two hours at about 5° C. The mixture is then poured into a cold 2% sulfuric acid solution (1000 ml). The solution is extracted with toluene and the combined toluene extracts are washed with water and evaporated to dryness to give a residue of about 95 g. The residue is distilled under reduced pressure. The forefraction distilling below 120° C./0.6 mmHg is discarded and the rest, about 66 g, is crude 2-(2',6'-dimethylphenyl)-ethylglyoxal diethyl acetal, which is used without purification in step (b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=O)[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH2:21][N:22]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:24]=3)[C:6]=2[CH:15]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nccn1-2

Procedure:
In the manner given in Example 33, 5-bromo-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 8-bromo-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1.C(=O)(OCC[Si](C)(C)C)N.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1ccccc1COc1cc(COC2CN(C(=O)OCC[Si](C)(C)C)CCC2c2ccc(F)cc2)cc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)CCOC(N)=O
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1ccccc1COc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
From β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate by cleaving the β-trimethylsilylethyl carbamate with tetrabutylammonium fluoride in tetrahydrofuran in analogy to the procedure described in Example 5 there was obtained (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine as a rose coloured oil; MS: 588 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([NH2:13])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]#[N:13]
Reactant: Cc1nc2ccccn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1nc2ccccn2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a mixture of 2-methylimidazo[1,2-a]pyridine-3-carboxamide (3.50 g, 20 mmol) produced above, pyridine (4.85 mL, 60 mmol) and tetrahydrofuran (50 mL) was added dropwise a solution of trifluoroacetic anhydride (4.24 mL, 30 mmol) in tetrahydrofuran (10 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate/diisopropyl ether to give the title compound (2.5 g, 80%) as a pale-brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23](O)=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23]([NH2:28])=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)N2Cc3c(C(=O)O)c(I)nn3CC2CO)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)N2Cc3c(C(N)=O)c(I)nn3CC2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of Intermediate 351F (0.12 g, 0.257 mmol) in dry DMF (3 mL) was added HATU (0.195 g, 0.512 mmol), diisopropylethylamine (224 μL, 1.128 mmol) and ammonium chloride (0.0687 g, 1.128 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated completely to dryness and the crude was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 3-5% methanol in chloroform). Fractions containing the product were combined to afford Intermediate 351G (0.08 g, 67%) as an off-white solid. MS(ES): m/z=467 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 7.69-7.74 (m, 2H), 7.63-7.69 (m, 2H), 7.37-7.48 (m, 1H), 6.93 (br. s., 1H), 5.22 (d, J=18.07 Hz, 1H), 5.13 (t, J=5.27 Hz, 1H), 4.72 (d, J=4.52 Hz, 1H), 4.51 (d, J=18.57 Hz, 1H), 4.31-4.38 (m, 1H), 4.20-4.28 (m, 1H), 3.43 (t, J=6.02 Hz, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:23])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:2][CH2:3][CH3:4].[S:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:23])[CH:7]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O
Reactant: c1ccsc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)c1cccs1
Reaction time: 16 h

Procedure:
A solution of 1.6 g. (5.0 mmol.) of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester and 1.0 ml. of thiophene in 10 ml. of methylene chloride was treated with three drops of boron trifluoride etherate and left to stir at 25° for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride and chromatographed on silica gel with methylene chloride containing increasing amounts of ethyl acetate to give the title compound, m.p. 37°.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([CH2:62][CH3:63])[C:19]2[CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32]CCCCCCCC)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][C:10]([C:41]1[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([O:53]CCCCCCCC)=[CH:49][CH:48]=3)=[CH:43][CH:42]=1)=[CH:11][CH:12]=2)[CH3:6]>C(Cl)Cl>[CH2:62]([C:7]1([CH2:5][CH3:6])[C:8]2[CH:9]=[C:10]([C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=4)=[CH:45][CH:46]=3)[CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][C:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=2)[CH3:63]
Reactant: CCCCCCCCOc1ccc(-c2ccc(-c3ccc4c(c3)C(CC)(CC)c3cc(-c5ccc(-c6ccc(OCCCCCCCC)cc6)cc5)ccc3-4)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(CC)c2cc(-c3ccc(-c4ccc(O)cc4)cc3)ccc2-c2ccc(-c3ccc(-c4ccc(O)cc4)cc3)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
Boron tribromide (99.9%, 1.05 cm3, 0.0111 mol) in DCM (10 ml) was added dropwise to a cooled (0° C.) stirred solution of 9,9-diethyl-2,7-bis(4-octyloxybiphenyl-4′-yl)fluorene (2.90 g, 0.0037 mol) in DCM (100 cm3). The reaction mixture was stirred at room temperature overnight, then poured onto an ice/water mixture (50 g) and stirred (30 minutes). The crude product was purified by column chromatography on silica gel with a mixture of ethyl acetate and hexane (30:70) as the eluent and recrystallisation from ethanol to yield a white powder (0.83 g, 40%, m.pt. >300° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:27][CH2:26][N:25]([C:35](=[O:37])[CH3:36])[CH2:24][CH2:23]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc(-c3cnc4cc(C5CCNCC5)ccn34)ccn2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-phenyl-pyridin-4-yl)-7-piperidin-4-yl-imidazo[1,2-a]pyridine (Ex. 1.198) (1.0 eq, 0.20 mmol, 80 mg) in CH2Cl2 (2 ml) is added triethylamine (3 eq, 0.61 mmol, 0.09 ml) and acetyl chloride (1.5 eq, 0.31 mmol, 0.02 ml) and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is poured into NaHCO3 (50 ml) and the organic phase is extracted with CH2Cl2. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 1-{4-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-piperidin-1-yl}-ethanone as a white solid; [M+H]+=397
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH3:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O.C(Cl)Cl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 3-neck, 2 L rbf, NaOH (135 g, 3.37 mol) was added slowly to water (1 L). After the addition was complete, the solution was cooled to room temperature and DCM (2 L) added, followed by triethylene glycol monoethyl ether (500 g, 2.81 mol). p-Toluenesulfonyl chloride (535 g, 2.81 mol) was added portion-wise over a period of 10 minutes, and the mixture refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (2 L), mixed well and separated. The organic phase was washed with water (2×2 L), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting clear, colourless oil was stirred at room temperature with a 10% aqueous NaOH solution (1 L) to hydrolyze unreacted p-toluenesulfonyl chloride. After 18 hours, the material was poured into water (1 L), extracted with chloroform (500 mL) and separated. The organic portion was washed with water (2 L), 10% HCl (2 L) and water (2 L). The material was dried over anhydrous MgSO4, filtered and solvent removed by rotavap to afford (103) as a clear, colourless oil (595 g, 64%).
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19]>C(OC(=O)C)(=O)C.I>[CH3:21][CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:3]=2[O:19][C:18]1=[O:20]
Reactant: COc1c(Oc2ccccc2C)cccc1C(C)C(=O)O
Agent: I
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2C
Yield: 54.4 %

Procedure:
A solution of 2-[2-methoxy-3-(o-tolyloxy)phenyl]-propionic acid (2.9 g) in acetic anhydride (10 ml), hydroiodic acid (55-58%, 20 ml) and acetic anhydride (20 ml) were treated in a similar manner to that of Example 10-(7) to give 3-methyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (1.4 g). mp 45°-46° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:23])=[C:14]([C:20](O)=[O:21])[N:15]=[C:16]2[Cl:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[C@@H:28]([NH:29][C:20]([C:14]1[N:15]=[C:16]([Cl:19])[C:17]2[C:12]([C:13]=1[OH:23])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)=[O:21])[CH3:30]
Reactant: O=C(O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O

Procedure:
7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with L-Alanine methyl ester hydrochloride, 0.150 g, analogously to Example A-1 a). 0.264 G of white solid were obtained: MS-(+)-ion, M+1=415. amu.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(O)=O.[Cl:23][C:24]1[N:25]=[C:26]([S:46]([NH:49][CH3:50])(=[O:48])=[O:47])[N:27]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:28]=1[CH2:29][O:30][Si](C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:23][C:24]1[N:25]=[C:26]([S:46]([NH:49][CH3:50])(=[O:48])=[O:47])[N:27]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:43])[CH3:44])[C:28]=1[CH2:29][OH:30]
Reactant: CNS(=O)(=O)c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNS(=O)(=O)c1nc(Cl)c(CO)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1M solution of TBAF (1.2 mL, 1.2 mmol) was neutralized with a drop of HOAc and added to a solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-N-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide in THF (3 mL). The reaction mixture was stirred for 2 h at RT. Sat'd NaHCO3 was added and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4), filtered, and evaporated to give 4-chloro-5-(hydroxymethyl)-N-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide as a light yellow oil that was used without purification and assumed to be quantitative.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:24][OH:25])[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:35][S:36]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH3:14])[C@@H:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@@H:18]1[CH2:24][O:25][S:36]([CH3:35])(=[O:38])=[O:37])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CC[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.82 g (3.7 mmol) [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol (step G) in 50 mL methylene chloride cooled to −5° C. in an ice/salt bath was added 1.0 mL (3.5 equiv.) methane-sulfonyl chloride; 2.1 mL (4 equiv.) TEA and 44mg (0.1 equiv.) DMAP. The reaction mixture was stirred at −5° C. for 30 min then quenched at that temperature by the addition of 20 mL sat. aq. NaHCO3. The mixture was warmed to RT. The organic layer was separated and the aqueous layer extracted with additional 50 mL methylene chloride. The combined organic layer was washed with 20 mL 2N aq. HCl, 30 mL sat. aq. NaHCO3, brine, dried over MgSO4 drying agent, filtered and the solvent evaporated under vacuum to give the title compound as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([OH:17])=[O:16]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(F)cc2)n1
Yield: 94.1 %

Procedure:
2-(4-Fluoro-phenylamino)-thiazole-4-carboxylic acid (224 mg) was prepared according to General Procedure B using (4-fluoro-phenyl)-thiourea (170 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]2[S:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH:41]=[C:40]([CH2:42][NH:43][CH3:44])[C:39]([CH3:45])=[N:38]1.C(N(CC)CC)C.CCCP(=O)=O.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:36][N:37]1[CH:41]=[C:40]([CH2:42][N:43]([CH3:44])[C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([SH:16])=[N:10][CH:11]=2)=[O:15])[C:39]([CH3:45])=[N:38]1
Reactant: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Reactant: CNCc1cn(C)nc1C
Agent: CCCP(=O)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6) (3.24 g, 6.74 mmol), 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (0.95 g, 6.80 mmol), triethylamine (5.70 mL, 40.9 mmol) and propylphosphonic anhydride (T-3-P)(50% in ethyl acetate, 4.85 mL, 8.15 mmol) in dichloromethane (50 mL) was stirred overnight at room temperature. To the reaction 6N HCl (10 mL) was carefully added and was stirred at room temperature for 40 minutes. The solution was basified with saturated sodium bicarbonate and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-20% MeOH in dichloromethane) to afford N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluorophenyl)-2-mercapto-N-methyl-1H-imidazole-5-carboxamide
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)([CH3:14])[CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])=[CH:4][N:3]=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[CH2:9][C:10]([Cl:11])([Cl:12])[Cl:13])=[CH:4][N:3]=1
Reactant: CC(Cl)(CC(Cl)(Cl)Cl)c1ccc(Cl)nc1
Solvent: Clc1ccccc1
Product: C=C(CC(Cl)(Cl)Cl)c1ccc(Cl)nc1

Procedure:
A solution of 40 g (0.013 mole) of 2-chloro-5-(1,3,3,3-tetrachloro-1-methylpropyl)pyridine and 7.8 g (0.026 mole) of SbCl5 in 300 ml of chlorobenzene was heated to 138° C. for one hour. The darkened solution was cooled and carefully quenched with water. The heterogeneous mixture was filtered, the organic layer separated, dried (MgSO4) and concentrated in vacuo. The product was crystallized from 350 ml of pentane at -50° C. The yield was 19.5 g (55%), m.p. 54°-55° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)(=O)C.C(OCC)C>O>[C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of glutathione (1 g, 3.25 mmole) in 10 ml of water was added over 1 hr to a mixture of acetic anhydride (10 ml) and acetic acid (10 ml) at room temperature. After the addition was complete, the reaction mixture was chilled on ice. Additional acetic anhydride (5 ml) was added and the reaction mix was stirred while it gradually warmed to room temperature overnight. The reaction mixture was treated with 300 ml of ethyl ether and cooled overnight to obtain crystallized product. A white solid was obtained by filtering the reaction mix, and washing with more ether. More crystallized product was generated in the filtrate. The filtration and washing were repeated a second time and the white solids were combined and air-dried (585 mg, yield 51.5%).
Reaction SMILES: C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([NH:27][CH2:28][C:29]([OH:31])=O)=[O:26])([O-:21])=[O:20].Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[N+:19]([C:22]1[CH:23]=[C:24]([C:25]([NH:27][CH2:28][C:29]([NH:42][CH2:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:43])=[O:31])=[O:26])[CH:32]=[CH:33][CH:34]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)CNC(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CNC(=O)c1cccc([N+](=O)[O-])c1
Yield: 97 %

Procedure:
N,N'-Disuccinimidyl carbonate (14 g, 5.5 mmol) was added to 3-nitrobenzoyl glycine (10 g, 4.5 mmol) of Example BB in dry dimethylformamide (30 mL) followed by N,N-dimethylaminopyridine (200 mg). After a period of 1 hour beta-alanine ethyl ester hydrochloride (7 g, 4.6 mmol) in 20% aqueous potassium carbonate (50 mL) was added in one portion. After complete reaction the product was collected by filtration (14 g, 97% yield). 1H-NMR (d6 -DMSO) δ, 1.18 (t, 3H, J=7.2 Hz), 2.46 (t, 2H, J=7.0), 3.34 (q, 2H, J1 =6.7 Hz, J2 =12.6 Hz), 3.87 (d, 2H, J=5.9 Hz), 4.05 (q, 2H, J1 =7.4 Hz, J2 =14.2 Hz), 7.8 (t, 1H, J=8.0 Hz), 8.1 (t, 1H, J=5.6 Hz), 8.35 (m, 2H), 8.71 (s, 1H), 9.22 (bs, 1H).