Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1)=[O:5])=[N-]>ClCCl.C1(C)C=CC=CC=1>[O:5]=[C:4]1[O:6][CH2:7][C@H:8]2[C@@H:3]1[C@@H:9]2[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc([C@@H]2[C@H]3COC(=O)[C@H]32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of (2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)prop-2-enyl diazoacetate (0.7 g, 2.0 mmol) in dichloromethane (20 mL) was added dropwise over 18 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.041 g, 0.01 mmol) in 80 mL of toluene. After the addition was complete, the reaction mixture was heated for another 2 h at reflux and stirred at room temperature for 36 hours. Then the reaction mixture was cooled, filtered and concentrated. The crude oil was purified by silica gel column chromatography (gradient 0-1.5% MeOH-DCM) to provide the title compound and its enantiomer as a racemic mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][OH:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][O:40][S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)(=[O:11])=[O:12])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](COS(=O)(=O)c4cccc([N+](=O)[O-])c4)OC3=O)cc2F)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Nitrobenzenesulfonyl chloride (1.70 g, 7.67 mmol) was added to an ice cooled solution of (R)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-hydroxymethyl-2-oxo-3-oxazolidinyl]-pheny]azetidine (Example 81, Step 5, 2.79 g, 6.97 mmol) and triethylamine (1.41 g, 14.0 mmol) in methylene chloride (40 mL). After 16 hr, water (50 mL) and methylene chloride (100 mL) were added. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 25-100% ethyl acetate-hexane to give the title compound as a sticky foam. FAB-HRMS: theory 586.1290 (M+1); meas 586.1295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:16]=2[O:17][CH2:18][CH2:19][OH:20])[C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:35])=[CH:32][CH:31]=1>>[OH:20][CH2:19][CH2:18][O:17][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][C:10]([C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=2)=[O:12])=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1
Reactant: COc1ccc(C(=O)OCCCCCCN)cc1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Product: COc1ccc(C(=O)OCCCCCCNC(=O)c2cc(-c3cccc(Cl)c3)c(OCCO)c(-c3cccc(Cl)c3)c2)cc1

Procedure:
The product was prepared as a colorless, viscous oil (0.675 g, 71%) from 3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid (0.605 g, 1.5 mmol) and 4-methoxybenzoic acid, 6-aminohexyl ester (0.565 g, 2.25 mmol) using a procedure similar to step 3 of example 164; 1H NMR (400 MHz, DMSO-d6) 1.33-1.46 (m, 4H), 1.50-1.58 (m. 2H),1.65-1.73 (m, 2H), 3.10-3.15 (m, 2H), 3.22-3.30 (m, 4H), 3.80 (s, 3H), 4.21 (t, J=6.6 Hz, 2H), 4.44 (t, J=6.6 Hz, 1H), 6.99-7.03 (m, 2H), 7.45-7.52 (m, 4H), 7.57-7.61 (m, 2H), 7.69 (s, 2H), 7.85-7.91 (m, 4H), 8.56 (t, J=5.5 Hz, 1H); IR (film) 3350, 2940, 1710, 1640, 1605, 1540, 1510, 1275 cm−1; mass spectrum[(+)ESI], m/z 636 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3](O)=O.[CH2:32]([NH2:34])[CH3:33].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[CH2:32]([N:34]([CH2:3][C:2]([CH3:1])=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:35](=[O:37])[CH3:36])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCN
Product: CCN(CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O)C(C)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid; ethylamine (70% aqueous ethylamine solution); and acetic anhydride.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1CC1CC1.CON(C)[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20].[CH2:35]1[CH2:39][O:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:39][O:38][C:6]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=2[C:19]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]2)=[O:20])[CH2:36][CH2:37]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Br)c1CC1CC1
Agent: II
Agent: [Mg]
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2OCC2CC2)C1
Yield: 70 %

Procedure:
A 50 mL three-necked flask was charged with magnesium turning (240 mg, 10 mmol) and a small crystal of iodine. The flash was evacuated and refilled with N2. A portion of a solution of 1-bromo-2-cyclopropylmethyl-3-fluoro-benzene (2.1 g, 8.57 mmol) in dry THF (10 mL) was added dropwise to trigger the reaction. When the color of iodine had disappeared, the residual solution was added dropwise slowly. The mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used for the next step. To another 100-mL three-necked flask was added (R)-tert-butyl 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (1.55 g, 5.7 mmol) and THF (15 mL). The flask was evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent prepared above (10 mL) was added slowly. The reaction mixture was stirred at −20 to −10° C. for 2.5 h. The mixture was quenched with sat'd aq NH4Cl (20 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (1.5 g, 70%). 1H NMR (400 MHz, CDCl3): 0.27 (m, 2H), 0.57 (m, 2H) 1.20 (m, 1H), 1.43 (s, 9H), 1.60-1.51 (m, 4H), 1.73 (m, 1H), 2.02 (m, 1H), 2.79 (m, 1H), 3.47 (m, 1H), 3.98 (m, 3H), 4.20 (m, 1H), 7.04 (m, 1H), 7.20 (m, 2H). MS (E/Z): 378 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([CH3:9])=[CH:7][S:6][C:5]=1[C:10]1([C:15]2[N:16]([CH3:21])[C:17](=[S:20])[NH:18][N:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][S:20][C:17]1[N:16]([CH3:21])[C:15]([C:10]2([C:5]3[S:6][CH:7]=[C:8]([CH3:9])[C:4]=3[Cl:3])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:19][N:18]=1
Reactant: Cc1csc(C2(c3n[nH]c(=S)n3C)CCCC2)c1Cl
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1csc(C2(c3nnc(SCc4ccccc4Cl)n3C)CCCC2)c1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (55%, 24 mg) was added to a THF (10 ml) solution of 5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (154 mg) at 0° C. and the whole was stirred for 5 minutes. Then, 2-chlorobenzyl bromide (0.07 ml) was added thereto, followed by stirring at 0° C. for 3 hours. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with brine, dried over anhydrous sodium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=1:1) to obtain 200 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole (pale yellow foam). It was converted into an ethyl acetate (5 ml) solution and 4M hydrogen chloride-ethyl acetate (0.23 ml) was added, followed by removal of the solvent by evaporation under reduced pressure. The resulting solid washed with ether to obtain 185 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole hydrochloride (colorless solid).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:11])[CH:8]([OH:10])[CH3:9].[C:12]([O:16][O:17][C:18]([CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:18]([O:17][O:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:19])[CH2:20][CH2:21][C:22]([O:11][CH2:7][CH:8]([OH:10])[CH3:9])=[O:23]
Reactant: CC(O)CO
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)COC(=O)CCC(=O)OOC(C)(C)C
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
A 250 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 50 mL of methylene chloride, 4.2 g (0.052 mole) of pyridine and 19.0 g (0.25 mole) of 1,2-propanediol. The resulting vigorously stirred solution was cooled to 10° C. and to it was slowly added a solution of 11.5 g (0.050 mole) of 94% 3-(t-butylperoxycarbonyl)propionyl chloride in 10 mL of methylene chloride over a period of 20 minutes. The reaction mass was warmed to 20° C. and stirred at 20° C. for 210 minutes. The reaction mixture was washed at 10°-15° C. with 50 mL of aqueous 5% HCl solution and then twice with 100 mL portions of 5% aqueous NaHCO3 solution. The methylene chloride solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 12.4 g (100% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band, a strong and broad carbonyl band at ca. 1720-1780 cm-1 and a strong --OO-- band at ca. 850 cm-1. The product has a peroxyester Act[O] content of 6.29%. Based on a theoretical Act[O] of 6.45% for the desired title product, the assay was 97.5% and the corrected yield was 97.5%.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccncc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccncc3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(bromomethyl)pyridine to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 347.1 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[NH:7]1[CH2:15][CH2:14][CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8]1.[CH2:16]=O.[Cl-].[Na+]>C(Cl)Cl.O1CCOCC1>[C:11]([CH:10]1[CH2:14][CH2:15][N:7]([CH2:16][C:3](=[CH2:4])[C:1]#[N:2])[CH2:8][CH2:9]1)([OH:13])=[O:12]
Reactant: O=C(O)C1CCNCC1
Reactant: C=O
Reactant: N#CCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(C#N)CN1CCC(C(=O)O)CC1
Temperature: 35 °C

Procedure:
Cyanoacetic acid (12.8 g. 0.15 mole) was dissolved in 25 ml. of dioxane. Next, isonipecotic acid (19.4 g., 0.15 mole) was added. Then, 37% aqueous formaldehyde (25 g., 0.3 mole) was dripped in and the temperature maintained at a maximum of 35° C. After mixing overnight sodium chloride was added to saturation and methylene chloride used to extract the mixture. The organic phase was washed with water, dried over anhydrous sodium sulfate and after filtration, concentrated. Most of the product appeared in the aqueous phase. This was extracted twice with 500 ml. of methylene chloride in a continuous extractor. The residue obtained after solvent removal weighed 14.2 g., m.p. 109°-111° C. of analytical purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]=[O:9].[C:14]([Mg]Br)#[CH:15]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]([OH:9])[C:14]#[CH:15]
Reactant: O=CCc1sc2ccccc2c1Cl
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)Cc1sc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A solution of 2-(3-chlorobenzo[b]thiophen-2-yl)acetaldehyde (1.100 g, 5.60 mmol) in 10 mL THF was added dropwise (cannula) to an ice-cold solution of the ethynylmagnesium bromide (25 mL, 12.5 mmol, 0.5 M/THF). The reaction was stirred for 1 h at 0° C. and for 1 h at room temperature and then was quenched by addition of 100 mL saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (3×) and the combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (475 mg, 65%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](C(N)=O)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:27])[N:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:51]>CCOC(C)=O.O>[NH2:51][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:27])[N:3]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)picolinamide (111 mg, 0.25 mmol) in EtOAc (2 mL), CH3CN (2 mL) and H2O (1 mL) was added PhI(OAc)2 (97 mg, 0.3 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 12 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light beige solid (85 mg, 81.7%).
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O:13][CH2:14][CH3:15])=O.Cl.[NH:17]([CH:19](O)C)[NH2:18]>O1CCCC1>[N:18]1([CH2:15][CH2:14][OH:13])[C:2]2[C:10]3[CH:9]=[CH:8][S:7][C:6]=3[CH2:5][CH2:4][C:3]=2[CH:19]=[N:17]1
Reactant: CCOC=O
Reactant: CC(O)NN
Reactant: O=C1CCCc2sccc21
Agent: Cl
Solvent: C1CCOC1
Product: OCCn1ncc2c1-c1ccsc1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a tetrahydrofuran (20 ml) solution containing 2.95 g of potassium tert-butoxy was added dropwise a tetrahydrofuran (10 ml) solution containing 2.00 g of 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene and 3.89 g of ethyl formate under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After addition of 26 ml of 1 N hydrochloric acid to the reaction solution, 3.16 g of hydrazinoethanol was added under ice-cooling, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride, and the organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the resulting filtrate was concentrated under a reduced pressure to give 1.56 g of 2-(4,5-dihydro-1H-thieno[2,3-g]indazol-1-yl)ethanol as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:4]2[CH:5]=[C:6]([Cl:32])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.52 g, 0.8 mmol), 4-methoxycarbonylphenylboronic acid (0.174 g, 0.966 mmol), sodium carbonate (0.256 g, 2.41 mmol) in THF (20 mL) and water (6 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.046 g, 0.04 mmol) and raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.49 g (96%) of the titled product. MS (m/z): 633 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:47]3[CH2:46][CH2:45][C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([O:37][CH3:36])[CH:39]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: COc1cccc(C2(C(N)=O)CCNCC2)c1
Agent: Cl
Product: COc1cccc(C2(C(N)=O)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)c1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.75 g, 1.4 mmol) and 4-(3-methoxy-phenyl)-piperidine-4-carboxylic acid amide hydrochloride (0.5 g, 1.85 mmol) to give the title compound: Rf =0.43 (silica gel, 10%methanol/chloroform).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:27]([C:39]2[CH:44]=[CH:43][C:42]3[O:45][CH2:46][O:47][C:41]=3[CH:40]=2)[C:28](N2[C@@H](C(C)C)COC2=O)=[O:29])[N:23]=[C:22]1[CH2:48][CH2:49][CH2:50][CH3:51])=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:27]([C:39]2[CH:44]=[CH:43][C:42]3[O:45][CH2:46][O:47][C:41]=3[CH:40]=2)[C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[N:23]=[C:22]1[CH2:48][CH2:49][CH2:50][CH3:51])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCCc1nc(CC(C(=O)N2C(=O)OC[C@@H]2C(C)C)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1nc(CC(C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
To a solution of benzyl alcohol (1.29 g) in tetrahydrofuran (60 ml) was added dropwise n-butyl lithium (6.6 ml, 1.6M n-hexane solution) at 2-8° C. and the mixture was stirred for 20 minutes. A solution of (4S)-3-[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-one (4.86 g) was added dropwise to the mixture and the resulting solution was stirred at 2° C. for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and then the solution was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude product. The crude product was purified by a silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to give benzyl 3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (2R:2S=1:4) (3.67 g) as a slightly yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([F:34])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1Cl.[OH2:35]>CC(C)CO.C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:34])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1[O:35][CH2:13][CH:14]([CH3:19])[CH3:15]
Reactant: O
Reactant: COC(=O)c1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(C)CO
Solvent: C1CCOC1
Product: CC(C)COc1ncc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (700 μL; 1 M; 0.70 mmol) was added to a solution of methyl 4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-fluorobenzoate, obtained in step 1 (73.63 mg; 0.20 mmol) in 2-methyl-1-propanol (3 mL) and THF (2 mL). The resulting mixture was stirred at RT for 1 h. Water (500 uL) was added and the mixture was stirred at RT for 3 h, saponification was complete. The reaction mixture was then diluted with EtOAc and washed with HCl 1N, NaCl sat. solution and dried over magnesium sulfate. After evaporation of the solvents, the crude was purified by HPLC prep to afford the title compound as a slightly yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.94 (d, J=2.2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 8.01 (dd, J=8.1, 1.5 Hz, 1H), 7.94 (dd, J=11.1, 1.5 Hz, 1H), 4.27 (d, J=6.5 Hz, 2H), 2.16-2.07 (m, 1H), 1.01 (d, J=6.6 Hz, 6H). LC/MS (Method B): 390.3 (M−H)−, 392.2 (M+H)+. HPLC (Method A) Rt 5.49 min (Purity: 98.6%).