Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[K+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-fluoro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-fluoro-1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].[OH-].[Na+].Cl>O1CCCC1.O.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][O:23][C:29](=[O:31])[CH3:30])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1nc(Cl)c(COC(C)=O)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1

Procedure:
A solution of 0.10 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole, 5 mg of N,N-dimethylaminopyridine, 0.10 mL of acetic anhydride, and 0.14 mL of triethylamine in 8 mL of tetrahydrofuran was stirred for 4.5 hours at 25°. The reaction mixture was poured into water, and dilute aqueous sodium hydroxide was added until the pH of the solution remained in the range of pH 8-9. The solution was then acidified to pH 3.5 using 10% aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography on silica gel (elution: 0.5% i-propanol/chloroform) furnished 0.065 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxymethylimidazole, m.p. 172°-173°; NMR (200 MHz, DMSO-d6): δ 8.17 (s, 1H); 7.93 (t, 2H); 7.61 (t, 1 H); 7.43 (A2M2, 4H); 5.32 (s, 2H); 4.99 (s, 2H); 2.60 (t, 2H); 1.76 (s, 3H); 1.53 (quint., 2H); 1.28 (sext., 2H); 0.82 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].ClC1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:33][CH2:34][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:36][CH2:37]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Agent: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5ccccc5Cl)c4)cc23)CC1
Yield: 29 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 2-chlorobenzenesulfonyl chloride (74 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 17.3 mg the title compound (29%).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH:18][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[S:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cc(C(F)(F)F)ccc3F)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A mixture of 0.5 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.33 g of 4-methoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted lo with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol yielded 0.26 g of N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methoxy-benzenesulfonamide as colorless crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (370 mg, 0.827 mmol) (obtained as described in Reference Example 53(7)) in methylene chloride (19 ml) were added methanesulfonyl chloride (192 μl, 2.48 mmol) and triethylamine (348 μl, 2.48 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (422 mg, yield 97%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=S)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Pb+2]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:9]=[C:10]=[N:12][C:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=S)NC(C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Pb+2]
Solvent: Cc1ccccc1C
Product: CCCCCCCCN=C=NC(C)(C)c1ccccc1
Yield: 80 %

Procedure:
A mixture of 14.2 grams of N-n-octyl-N'-(2-phenyl-2-propyl)-thiourea, 20 grams of basic lead carbonate and 100 ml of dry xylene was heated under reflux for 3 hours. The reaction liquid was then separated by filtration followed by concentration of the mother liquor, whereupon N-n-octyl-N'-(2-phenyl-2-propyl)carbodiimide of high purity was obtained. When this was distilled further, 10.1 grams of the intended product of b.p. 121°-3° C./0.15 mmHg was obtained as a pure product.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=2)[C:6]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:7]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Product: CS(=O)(=O)n1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21
Yield: 70.3 %

Procedure:
2-(5-Trifluoromethyl-1H-indazol-3-yl)-isoindole-1,3-dione (350 mg, 1.06 mmol), TEA (0.3 mL, 2.12 mmol) in DCM (5 mL) was treated with MsCl (182 mg, 1.59 mmol) at 0° C. for 2 hours. The solvent was removed and the residue was purified by silica gel column chromatography using hexanes:ethyl acetate 1:1 to give the title compound as white solid (305 mg, 69%).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[N:48]=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)[O:36][N:35]=1.CO>C(COC)OC.O>[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39][O:40][C:41]2[C:42]([CH2:43][C:16]#[N:17])=[CH:45][CH:46]=[CH:47][N:48]=2)[O:36][N:35]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mixture of potassium t-butoxide (0.40 g) and dimethoxyethane (10 mL) was added a solution (10 mL) of toluenesulfonylmethylisocyanide (0.37 g) in dimethoxyethane at −78° C. Further, a solution (10 mL) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde (0.70 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.45 g, 63%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[Cr](O)(O)(=O)=O>CC(C)=O.CC(O)C.O>[CH2:1]([CH:8]1[CH2:9][CH2:10][CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC(Cc2ccccc2)CCC1
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCC(Cc2ccccc2)CCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
1.3 g of 5-benzyl-1-cyclooctanol prepared in the aforementioned Reference Example 1 was dissolved in 40 ml of acetone. To the solution was added 2.5 ml Jones reagent which was prepared in the ratio of 11.5 ml of sulfuric acid, 13 g of chromic acid and 20 ml of water. The reaction solution was stirred at room temperature for twenty minutes. To the reaction solution was added 2 ml of 2-propanol, followed by filtration through Celite. The residue was washed with dichloromethane and the washing liquid was combined with the filtrate. The filtrate was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated. The crude product was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:15) was collected, to afford 1.23 g of the titled compound as colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([NH:7][C:8]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:11])[CH2:9][NH:21][C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(NCC(C)(NC(=O)OC(C)(C)C)c2cc(F)cc(F)c2)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To tert-butyl[1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate (28.9 g, 101 mmol) were added methyl 1-aminocyclopentanecarboxylate (43.4 g, 303 mmol) followed by titanium(IV) isopropoxide (44.5 mL, 152 mmol) and the reaction mixture was stirred at ambient temperature for 90 min, diluted with MeOH (130 mL), and cooled in an ice-water bath. To this stirred mixture were added AcOH (29 mL, 507 mmol) followed by NaCNBH3 (7.64 g, 122 mmol), portionwise, over 5 min. Stirring was continued for 5 min, then the ice-water bath was removed, and stirring was continued for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 L) and extracted with EtOAc (3×1.5 L). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 50:50, to give a mixture of the title compound and the corresponding isopropyl ester. MS: m/z=413 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CC(C)=O>[F:30][C:29]([F:32])([F:31])[CH2:28][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCC(F)(F)F)c1
Temperature: 50 °C
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl 3-hydroxyphenylcarbamate (2 g, 9.56 mmol) in acetone (38 mL) were added potassium carbonate (6.61 g, 47.8 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.07 mL, 14.34 mmol). The reaction mixture was heated at 50° C. overnight, cooled and filtered. The filtrate was concentrated, and the residue was dissolved in CH2Cl2, washed with brine, dried over anhydrous sodium sulfate and concentrated to yield the title compound (2.7 g, 97% yield). MS (ES): m/z=314.25 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:14]([F:28])[CH:13]=2)=[N:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:6][N:7]=1>CO>[NH2:1][C:2]1[C:3]([C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:14]([F:28])[CH:13]=2)=[N:4][C:5]([CH2:8][C@H:9]([OH:11])[CH3:10])=[CH:6][N:7]=1
Reactant: CC(O)Cc1cnc(N)c(-c2ccc(C(=O)NCc3ccccc3)c(F)c2)n1
Solvent: CO
Product: C[C@@H](O)Cc1cnc(N)c(-c2ccc(C(=O)NCc3ccccc3)c(F)c2)n1

Procedure:
The racemic (+/−)-4-(3-amino-6-(2-hydroxypropyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide was resolved by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), methanol+0.1% DEA=40%, 5 mL/min). The polar enantiomer, (R)-4-(3-amino-6-(2-hydroxypropyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide, was obtained at Rt=1.39 min. LCMS (m/z): 381.2 (MH+), 0.67 min. The less polar enantiomer, (S)-4-(3-amino-6-(2-hydroxypropyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide was obtained at Rt=1.97 min. LCMS (m/z): 381.2 (MH+), 0.67 min. The stereochemistry was assigned arbitrarily.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:29])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of (5Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl)hept-5-enoic acid (2 g from Example 53) was dissolved in 20 ml N,N-dimethylformamide in 50 mL round-bottom flask, followed by addition of potassium carbonate (2.2 g, 16.2 mmol) and iodomethane (1.1 g, 8.1 mmol). The reaction mixture was heated to 40° C. and stirred for 2 hours. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was subsequently diluted and extracted with 20 ml ethyl acetate and 20 ml water. The mixture was phase separated and the organic layer was dried over anhydrous MgSO4, the solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the title compound was 1.6 g (73.5% in 2 steps)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].C>C(C(C)=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Reaction time: 8 h

Procedure:
A mixture of m-nitrophenol (28 g, 0.2 mole), 2-chloroethanol (53.6 ml, 0.8 mole), and potassium carbonate (110.4 g, 0.8 mole) in 300 ml methyl ethyl ketone was kept at reflux temperature with stirring overnight. The solid was filtered and dissolved in water. The filtrate was concentrated and some wolid was crystallized from 2-propanol/isopropyl ether. This light-brown solid was collected and weighed 22.78 g (62%). The mother liquor was concentrated and redissolved in toluene/ethyl acetate and extracted with the above aqueous solution. The aqueous layer was further extracted with fresh toluene/ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated to give a second crop of 6.46 g (17.6%). The second crop was dissolved in methanol, stirred with charcoal, filtered, evaporated, and crystallized from 2-propanol/isopropyl ether to give a pure sample. The sample was dried under vacuum at room temperature overnight, mp 85°-86° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CC(O)=O.O>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1CN(Cc1cccc(CCOC2CCCCO2)c1)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1CN(Cc1cccc(CCO)c1)C(=O)OC(C)(C)C

Procedure:
(2-Methoxy-benzyl)-{3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzyl}-carbamic acid tert-butyl ester (51 g) was dissolved in a mixture of THF (250 mL), AcOH (225 mL) and water (150 mL) and the resulting mixture refluxed for a total of 10 hours. The majority of the tetrahydrofuran and acetic acid was evaporated and the pH of was adjusted to 8 using saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3×250 mL) and the combined organics were washed with water (250 mL), brine (250 mL), dried over sodium sulfate, filtered and evaporated. The crude material was purified in two portions by column chromatography eluting with dichloromethane:ethyl acetate (95:5 to 80:20 gradient) to give a yellow oil (total of 17.2 g).
Reaction SMILES: [Cl-].[NH+]1C=CC=CC=1.C[O:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl>[C:13]1([NH:12][C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[OH:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1Nc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: Oc1ccccc1Nc1ccccc1
Temperature: 200 °C

Procedure:
A 1 L three neck flask was charged with pyridinium chloride (52.2 g, 452 mmol) and 2-methoxy-N-phenylaniline (9 g, 45.2 mmol). The reaction mixture was heated to 200° C. for 4 hours. The reaction mixture was poured into 5% HCl (200 mL) and extracted with EtOAc (3×300 mL). The organic portion was combined and purified by column chromatography (100% DCM) to yield the desired product. (6.5 g, 77%)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:51]([O:53]C(C)(C)C)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:51]([OH:53])=[O:52])[CH2:43][C:44]3[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Tyr-OtBu (47 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.81-13.15 (br.s, 1 H), 8.95 (s, 1 H), 8.69-9.58 (br.s, 1 H), 8.03 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 1 H), 7.12 (d, 2 H), 7.00 (m, 5 H), 6.88 (m, 4 H), 6.64 (d, 2 H), 4.36 (m, 1 H), 4.05 (s, 2 H), 4.02 (s, 2 H), 2.94 (d, 1 H), 2.91 (s, 3 H), 2.72 (d, 1 H), 2.44 (t, 2 H), 2.39 (s, 3 H), 2.06 (m, 2 H), 1.69 (m, 2 H); MS (APCI+) m/z 723 (M+H)+.