Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:27])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: COc1ccccc1CSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CSc1nc2ccccc2n1CC(=O)O
Yield: 97.4 %

Procedure:
A solution of tert-butyl[2-(2-methoxy-benzylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor C-01b, 20 mg, 0.05 mmol) is stirred in TFA/dichloromethane (1:1, 4.0 ml) at rt overnight. The volatiles are removed in vacuo and the residue is dried under high vacuum, yielding the title compound (16.0 mg) in 94% as a white solid: tR=5.27 min (LC-1), MS (pos.): m/z 329.22 [M+H]+, MS (neg.): m/z 327.20 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 3.82 (s, 3H, OCH3), 4.51 (s, 2H, SCH2), 4.92 (s, 2H, CH2CO2), 6.89 (t, 1Harom), 7.04 (d, 1Harom), 7.18 (m, 2Harom), 7.30 (t, 1Harom), 7.40 (d, 1Harom), 7.50 (m, 1Harom), 7.61 (m, 1Harom).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>C(O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: CN(C)CCN
Solvent: CCO
Product: CN(C)CCNC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A mixture of 28 mg (0.1 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester from example A-1 c), 116 μl (1 mmol) of N,N-dimethyl-ethane-1,2-diamine and 0.5 ml of absolute ethanol was stirred at ambient temperature for 18 h. Then the solvent was evaporated in vacuo, the residue suspended in 5 ml of water, and mixture was extracted with 2×35 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 29 mg of the title compound were obtained; MS-(+)-ion: M+1=294.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[O:9][N:8]=1.O.[OH-].[Li+].Cl>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[O:9][N:8]=1
Reactant: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (511 mg, 1.79 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added lithium hydroxide, hydrate (74.9 mg, 1.79 mmol). The reaction mixture was stirred for 1 hr. A 1N aqueous solution of hydrochloric acid (1.8 mL) was added, and the solvent were removed under reduced pressure to afford 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid+1LiCl (531 mg, 1.767 mmol, 99% yield) as a white solid. The compound had an HPLC ret. time=0.725 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.8. 1H NMR (400 MHz, CD3OD) δ ppm 7.59 (dd, J=7.03, 5.02 Hz, 1H), 7.82 (d, J=7.78 Hz, 1H), 8.01 (td, J=7.78, 1.76 Hz, 1H), and 8.73 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:15]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:14]=[CH2:13]
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN1CCCC1c1ccc(Br)cc1
Yield: 62.4 %

Procedure:
2-(4-Bromo-phenyl)-pyrrolidine (640 mg, 2.83 mmol) and allyl bromide (343 mg, 2.83 mmol) is mixed in THF (15 mL) and K2CO3 (390 mg, 2.83 mmol) is then added. The mixture is heated at reflux for 2 h before THF is removed under reduced pressure and the residue is partitioned between EtOAc and H2O. The EtOAc layer is dried and concentrated and the residue is then subjected to chromatography to provide the desired product (470 mg, 62.4%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1cccc(OC)c1C=O
Reactant: Cn1c(CN)cc2ccccc21
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2n1C

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-indol-2-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.78 min.; [M+H]+: 379.31 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20]S(C)(=O)=O)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][C:27]3[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=3[F:25])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1

Procedure:
A mixture of 4-(3-methanesulfonyloxymethyl-[1,2,4]triazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1, 0.222 g, 0.641 mmol), 2-Fluoro-4-methanesulfonyl-phenol (0.122 g, 0.641 mmol) and CsCO3 (0.250 g, 0.769 mmol) in acetonitrile (10 mL) was heated under reflux for 4 hours. After cooling, the solution was filtered through a pad of celite and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel with Hexanes and EtOAc to afford the desired product. 1H NMR (CDCl3): δ 8.15 (1H, s), 7.62 (2H, m), 7.37 (1H, m), 5.25 (2H, s), 4.25 (3H, m), 3.05 (3H, s), 2.85 (2H, m), 2.18 (2H, m), 1.97 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH2:12])[CH2:7][CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:23])[NH2:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1

Procedure:
A solution of trans-4-carbamoyl-cyclohexanecarboxylic acid methyl ester (2.00 g, 10.8 mmol) and Lawesson's reagent (2.2 g, 5.4 mmol) in tetrahydrofuran (55 ml) was heated at reflux for 3.5 h. The heating bath was removed and the solvent was evaporated. The residue was purified by flash-chromatography with n-heptane/ethyl acetate as eluent to give a pink solid, which was triturated in toluene (10 ml). The precipitate was collected by filtration and dried in vacuo to give the title compound (1.04 g, 48%) as off-white solid. MS m/e: 202 ([M+H]+)
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6]Cl)[CH2:2]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:16]=[C:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O.CN(C)C=O>[C:17]([C:18]1([C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:1][CH2:2]1)(=[O:16])[CH3:23]
Reactant: ClCCOCCCl
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(C)=O)CCOCC1
Temperature: 80 °C
Yield: 51 %

Procedure:
In a flask made of glass having an inner volume of 1000 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 143 g (1.0 mol) of 2,2′-dichloroethyl ether, 276 g (2.0 mol) of anhydrous potassium carbonate, 10 g (0.06 mol) of potassium iodide and 600 ml of N,N-dimethylformamide, and the temperature of the mixture was raised to up to 80° C. with stirring. Then, 139 g (1.2 mol) of methyl 3-oxobutanoate was gently added dropwise to the mixture, and the mixture was reacted at the same temperature for 8 hours. After completion of the reaction, 1000 ml of water was added to the reaction mixture, and the resulting mixture was extracted three times with 600 ml of ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure (125 to 127° C., 1.3 kPa) to give 95 g (Isolation yield: 50%) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 98% (areal percentage by gas chromatography) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[I:11]Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[NH2:10])[CH2:5][NH2:6]
Reactant: ClI
Reactant: NCc1ccc(N)c(Cl)c1
Solvent: CO
Product: NCc1cc(Cl)c(N)c(I)c1
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To 3-Chloro-4-aminobenzylamine (200 mg, 1.28 mmol) in methanol (5 mL) was added Iodine monochloride (230 mg, 1.42 mmol). The mixture was stirred for 1 hour, then purified by HPLC to give 3-chloro-4-amino-5-iodobenzylamine (150 mg, 42%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:22])[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:9](=O)[CH3:10].[NH2:23][C:24](=[CH:26][C:27](=[O:29])[CH3:28])[CH3:25]>CO>[C:27]([C:26]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]([C:7](=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:9]([CH3:10])[NH:23][C:24]=1[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)C=C(C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCBr
Solvent: CO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCBr)C1c1cccc([N+](=O)[O-])c1

Procedure:
42 g (0.11 mol) 1-bromo-7-(3-nitrophenyl-methylene)-6,8-nonanedione and 22 g (0.22 mmol) 2-amino-2-penten-4-one are boiled under reflux in 270 ml methanol for 20 h. The mixture is concentrated and the residue is chromatographed over silica gel with toluene/acetone=95/5. The title compound is obtained as a yellow oil. Yield: 22 g (44%).
Reaction SMILES: [C:1]([C:4]1([CH2:13][OH:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CCOCC>[S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)([O:14][CH2:13][C:4]1([C:1]([CH3:3])=[CH2:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)C1(CO)Cc2ccccc2C1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)C1(COS(=O)(=O)c2ccc(C)cc2)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
To a mixture of 3.20 g (0.017 mole) of 2-isopropenyl-2-indanemethanol and 3.16 g (0.04 mole) of pyridine, with ice-cooling, was added 3.90 g (0.02 mole) of tosylchloride. The mixture was stirred for 24 hours, with ice-cooling, to complete the reaction. The reaction mixture was poured into ice water, mixed with 50 ml of ether. And then the ether layer was separated, the aqueous layer was extracted twice with 25 ml of ether. The ether layers were combined, washed with 2% aqueous hydrochloric acid solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 5.80 g of 2-iso-propenyl-2-indanylmethyl tosylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1.Cl>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:12]2[C:13]([O:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[O:10][CH3:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(OC)cc(OC)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(OC)c(C2=CCN(C)CC2)c(OC)c1
Temperature: 87.5 °C
Reaction time: 3.5 h

Procedure:
1-methyl-4-piperidone (340 g, 3.0 mol) was added slowly, to a solution of 1,3,5-trimethoxybenzene (500 g, 2.97 mol) in glacial acetic acid (600 mL), maintaining the temperature of the reaction mixture below 40° C. Conc. HCl (450 mL) was added over 20 min. The temperature was raised to 85-90° C. and the reaction mixture was stirred for 3.5 h. It was allowed to cool to 40° C., poured over crushed ice (4 kg) and stirred for 20 min. The precipitate of unreacted 1,3,5-trimethoxybenzene was filtered off. The filtrate was basified, below 10° C., to pH 11-12 using a 50% aqueous NaOH solution. The off white solid obtained was filtered, washed with water and dried to obtain the compound, 1-methyl-4-(2,4,6-trimethoxy-phenyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]1
Reactant: CCCC1CCC(CC(O)c2c(C)cc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (6) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with a saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 2.01 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-propylcyclohexyl)ethene (Compound 1-1-3-17) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([OH:8])=O.[NH2:9][CH2:10][C@H:11]1[C@H:19]2[N:14]([C:15]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C:25]4=[O:30])=[CH:20][C:16]=3[O:17][CH2:18]2)[C:13](=[O:31])[O:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([NH:9][CH2:10][C@H:11]1[C@H:19]2[N:14]([C:15]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C:25]4=[O:30])=[CH:20][C:16]=3[O:17][CH2:18]2)[C:13](=[O:31])[O:12]1)=[O:8]
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C(O)CSCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(CSCCCl)NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 61.3 %

Procedure:
Using compound 2-((2-chloroethyl)thio) acetic acid (58 mg, 0.377 mmol), compound (3S,3aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (the product of step (e) in Example 1) (80 mg, 0.251 mmol), TEA (76.2 mg, 0.753 mmol), and HATU (171 mg, 0.452 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid 70 mg, yield 61.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:13][C:12](=O)[CH2:11][C@H:10]1[C:15](OCC1C=CC=CC=1)=O)=[O:8])=[O:4].Cl.Cl.Cl.[F:31][C:32]1([F:83])[C:44]2[CH:43]=[C:42]([C:45]3[CH:46]=[CH:47][C:48]4[N:52]=[C:51]([C@@H:53]5[CH2:57][CH2:56][CH2:55][N:54]5[C:58](=[O:71])[C@@H:59]([NH:66][C:67](=[O:70])[O:68][CH3:69])[CH:60]5[CH2:65][CH2:64][O:63][CH2:62][CH2:61]5)[NH:50][C:49]=4[CH:72]=3)[CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([C:73]1[NH:77]C([C@@H]3CCCN3)=[N:75][CH:74]=1)=[CH:36][CH:37]=2>>[CH3:69][O:68][C:67](=[O:70])[NH:66][C@@H:59]([CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1)[C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:50][C:49]2[CH:72]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]4[C:38]5[C:33](=[CH:34][C:35]([C:73]6[NH:77][C:15]([C@@H:10]7[CH2:11][CH2:12][CH2:13][N:9]7[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:25]([CH3:26])[CH3:27])=[N:75][CH:74]=6)=[CH:36][CH:37]=5)[C:32]([F:83])([F:31])[C:44]=4[CH:43]=3)[CH:46]=[CH:47][C:48]=2[N:52]=1)=[O:71]
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that methyl (S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride. MS (ESI) m/z 879.88 [M+H]+. (122 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[O:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=[N:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:27]([C:26]2[O:22][N:23]=[CH:24][CH:25]=2)=[O:28])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccno1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)c2ccno2)nn1
Yield: 77 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using isoxazole-5-carbonyl chloride instead of methoxyacetyl chloride, to the title compound (290 mg, 77%) which was obtained as a white solid. MS: m/e=378.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:14]([O-])(O)=O.[Na+].IC>CN(C=O)C.[Na+].[Cl-]>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(=O)c1ccc(C(=O)OC)cc1
Yield: 77.4 %

Procedure:
4-propionylbenzoic acid (890 mg, 5 mmol), NaHCO3 (1.26 g, 15 mmol), and iodomethane (935 μL, 15 mmol) in DMF (10 mL) were stirred at RT overnight. The mixture was diluted with saturated aqueous NaCl (50 mL) and extracted with ether (3×50 mL). The organic phase was washed with water (50 mL), dried, and evaporated. Flash chromatography (90 g silica, 2/1 petroleum ether—EtOAc) gave white solids of 4-Propionyl-benzoic acid methyl ester (744 mg, 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([NH2:13])[CH3:12].C(N(CC)C(C)C)(C)C>>[CH2:11]([NH:13][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1)[CH3:12]
Reactant: CCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Yield: 67.2 %

Procedure:
2,4,6-Trichloro-s-triazine (1, 1 g, 5.4 mmol), and ethylamine hydrochloride (0.44 g, 5.4 mmol) were combined in a round bottom flask and cooled to −5° C. using an ice-salt bath. To the cooled, stirred solution was added N,N-diisopropylethylamine (1.88 mL, 10.8 mmol). The resultant yellow colored solution was stirred at −5° C. for 1 h, the solvents removed under reduced pressure, and the resultant residue was dissolved in 1:1 v/v of ethyl acetate and water. The organic layer was separated, washed with saturated solution of NaHCO3, and dried over Na2SO4. The organic solvent was removed under reduced pressure to yield an orange colored solid. The solid was triturated with hexane to yield the product 2 as a yellow-orange powder (0.7 g) with a yield of 68%.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.[CH2:25]([N:27]([CH2:38][CH3:39])[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]O)[CH3:26].C(OC([N:47]1[CH:51]=[C:50]([I:52])[N:49]=[CH:48]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([N:27]([CH2:38][CH3:39])[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:49]1[C:50]([I:52])=[CH:51][N:47]=[CH:48]1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccccc1CO
Reactant: CC(C)(C)OC(=O)n1cnc(I)c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccccc1Cn1cncc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with dichloromethane (200 mL) and trifluoromethanesulfonic anhydride (19.34 g, 67.20 mmol) and cooled to −78° C. A solution of diisopropylethylamine (9.57 g, 73.30 mmol) and N,N-diethyl-2-hydroxymethyl-benzamide (12.92 g, 61.09 mmol) in dichloromethane (40 mL) is added over 10 min. After 30 min, a solution of 4-iodo-imidazole-1-carboxylic acid tert-butyl ester (12.83 g, 42.76 mmol) in dichloromethane (40 mL) is added. The mixture is allowed to gradually warm overnight and after 18 h, saturated aqueous sodium bicarbonate (100 mL) is added and the mixture is stirred vigorously for 30 min. The aqueous layer is extracted with dichloromethane. The combined organic phase is dried over MgSO4, filtered through a cotton plug and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1) to afford N,N-diethyl-2-(5-iodo-imidazol-1-ylmethyl)-benzamide; MS (ESI) m/z 384.1 (M+H).
Reaction SMILES: C(N(CC)CC)C.ClC([O:11][CH2:12][CH3:13])=O.[OH:14][CH:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]2[CH2:33][CH2:34][CH2:35][C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)CO>>[OH:11][CH2:12][CH2:13][O:42][C:41]([C:39]1[S:40][C:36]([CH2:35][CH2:34][CH2:33][C@H:28]2[CH2:29][CH2:30][C:31](=[O:32])[N:27]2[C:24]2[CH:23]=[CH:22][C:21]([CH:15]([OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=2)=[CH:37][CH:38]=1)=[O:43]
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Reactant: CCOC(=O)Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OCCO)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Triethylamine (17.5 μL, 0.13 mmol) and ethyl chloroformate (6 μL, 0.063 mmol) were added sequentially to a solution 5-(3-{(S)-1-[4-(1-hydroxyhexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid (derived from the faster eluting [HPLC] ester diastereomer, see U.S. Ser. No. 10/599,046 or U.S. Provisional Patent Application No. 60/777,506, filed on Feb. 28, 2006, incorporated by reference herein, 18 mg, 0.042 mmol) in CH2Cl2 (0.6 mL) at 0° C. The mixture was allowed to warm to room temperature. After 30 min at room temperature, ethylene glycol (25 μL, 0.45 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under a stream of nitrogen. The residue was diluted with EtOAc (20 mL) and washed with H2O (2×5 mL) and brine (5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 8.5 mg (43%) of the title compound (1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:19][CH:16]([CH3:18])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)O
Product: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A14(c) from 5-ethanesulfonyl-2-fluoro-benzoic acid (Example A17(b)) and isopropanol. MS (m/e): 271.1 ([M−H]−, 100%)