Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]C)=O)[C:6]([N+:13]([O-:15])=[O:14])=[N:5]1.[CH3:16][NH2:17]>CO>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([NH:17][CH3:16])=[O:11])[C:6]([N+:13]([O-:15])=[O:14])=[N:5]1
Reactant: CN
Reactant: COC(=O)c1cn(CCO)nc1[N+](=O)[O-]
Solvent: CO
Product: CNC(=O)c1cn(CCO)nc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
Four gm. of methyl 1-(2-hydroxyethyl)-3-nitro-4-pyrazolecarboxylate was dissolved in a cold mixture of 25 ml. of absolute methanol and 25 ml. of condensed monomethylamine. The solution was allowed to stand in a stoppered container for 48 hours at room temperature. Evaporation of the volatile liquids under vacuum yielded a solid, which after decolorization and recrystallization from methanolisopropanol was proved to be 2.3 gm. of 1-(2-hydroxyethyl)-N-methyl-3-nitro-4-pyrazolecarboxamide, m.p. 138°-140° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[C@H:9]([CH3:12])[C@@H:8]([C:13]([OH:15])=[O:14])[CH2:7]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:12][C@H:9]1[C:10](=[O:11])[NH:6][CH2:7][C@@H:8]1[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(CN2C[C@H](C(=O)O)[C@@H](C)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a crude product of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (8.11 g) were added anisole (3.76 ml) and trifluoroacetic acid (40 ml), and the mixture was stirred at 80° C. for 5 hours. This reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the mixture was stirred. The insoluble substance was collected by filtration, and dried under reduced pressure to give a crude product of the titled compound (2.23 g). To the resulting solid was added ethanol (8 ml), and the mixture was heated at reflux to dissolve, and then the solution was stirred at room temperature. A solid precipitated from the mixed solution was collected by filtration, washed with a small amount of cooled ethanol, and dried under reduced pressure to give the titled compound (1.36 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC([O-])=[O:27].[K+]>CC(O)=O.O>[F:22][C:21]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([OH:27])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 3 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (100 mg, 0.28 mmol) and KOAc (55 mg, 0.56 mmol) in AcOH/H2O (1:1, 2 mL) was heated at 150° C. After 3 h, the solvent was evaporated and the mixture diluted with water (2 mL), extracted with (3×2 mL) EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.86-1.93 (m, 2H), 2.10-2.14 (m, 2H), 3.33-3.39 (m, 2H), 3.54-3.60 (m, 2H), 4.88-4.90 (m, 1H), 6.77 (d, 1H), 7.10 (t, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](Cl)=[O:7])[CH3:2].[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>N1C=CC=CC=1>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:6](=[O:7])[CH:5]=[CH:4][O:3][CH2:1][CH3:2]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccccc1Br
Reaction time: 1 h

Procedure:
10 g (74.31 mmol) of 3-ethoxy-acryloyl-chloride are added dropwise at 0° C. to a solution of 11.6 g (67.43 mmol) of 2-bromo-aniline in 60 ml of pyridine and stirred for one hour at this temperature. The mixture is allowed to come up to ambient temperature and stirred for two hours. Then the reaction mixture is extracted with water and ethyl acetate. The organic phase is extracted with water and 1 N hydrochloric acid, combined with activated charcoal and dried over sodium sulphate. The solvent is distilled off and the residue is recrystallised from isopropanol/water 2:1.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].Cl.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][C:32]([N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:31][CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(N2CCN(C)CC2)cc1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2cc(N3CCN(C)CC3)ccc2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.18 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(4-methylpiperazin-1-yl)benzamide (0.152 g) and glacial acetic acid (0.011 ml) in ethanol (30 ml). The mixture was heated to 90° C. and stirred for 16 hours. To the mixture was added 1N HCl (1 ml) and heated to 90° C. for 2 hours. The reaction mixture was made basic with sodium bicarbonate and evaporated, dissolved in ethyl acetate and washed with water. The organic phase was dried (magnesium sulphate) and evaporated to give the title compound (0.098 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 2.13 (s, 3H), 2.31 (s, 3H), 2.56 (m, 4H), 2.86 (m, 1H), 3.44 (m, 4H), 7.05 (d, 1H), 7.27 (m, 1H), 7.51 (d, 1H), 7.80 (d, 1H), 7.89 (m, 1H), 7.99 (d, 1H), 8.16 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH3:10].[Cl:11][CH2:12][CH2:13][CH:14]=[O:15].[Cl-].[NH4+]>CCCCCC>[Cl:11][CH2:12][CH2:13][CH:14]([OH:15])[C:6]#[C:7][CH2:8][CH2:9][CH3:10]
Reactant: O=CCCCl
Reactant: C#CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCC#CC(O)CCCl

Procedure:
To 68 ml. of 1.6M butyllithium in hexane at -50° C. is added dropwise, with stirring, 7.4 g. of 1-pentyne. The resulting white sludge is diluted with 20 ml. of hexane, brought to 10° C. and treated with 11 g. of freshly prepared β-chloropropionaldehyde (Org. Syn., Coll. Vol. I, p. 166) at such a rate that the temperature is maintained at 10°-15° C. The solution is allowed to stir at ambient temperature for 18 hours then treated with saturated ammonium chloride solution. The organic phase is separated, washed with dilute hydrochloric solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives 5.1 g. of product b.p. 65°-66° C. at 0.3 nm.; λmax. 2.95 (--OH) and 4.55 μ (--C≡C--); vapor phase chromatography shows one peak.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[OH-].[Na+]>C1COCC1.CO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]([C:9]2[CH:8]=[N:7][C:6]([S:5][CH2:4][C:3]([OH:22])=[O:2])=[N:11][CH:10]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: COC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 86.7 %

Procedure:
To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid methyl ester (95.5 mg, 0.3 mmol) in THF (2 mL) and methanol (0.25 mL) was added 1 N NaOH (0.3 mL). After 20 min an additional 0.2 mL of 1 N NaOH was added, and after 40 min an additional 0.1 mL 1 N NaOH was added. After 45 min total reaction time the solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed once with water. The aqueous layers were combined and acidified to pH 1 with 3% HCl resulting in the formation of a solid precipitate. The solids were collected by filtration, washed and dried to afford 79.9 mg (88% yield) of the titled acid as a pale beige solid. API-MS m/z 308 (MH+), 306 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:30][C:31](=[O:40])[NH:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35]([OH:37])=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:47]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[OH-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:30][C:31](=[O:40])[NH:32][C:33]([CH3:38])([CH3:39])[CH2:34][C:35]([NH2:47])=[O:37])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)NC(=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(CC(N)=O)NC(=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a solution of 3-(3-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-3-methylbutanoic acid (17.4 mg, 0.03 mmol) in DMF (1 mL) was added HOBt (20 mg, 0.148 mmol) and EDCI (29 mg, 0.151 mmol). The resulting mixture was stirred at room temperature over night, followed by addition of NH4OH (1 mL). After 5 min, the reaction mixture was concentrated and the residue was purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give 3-(3-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-3-methylbutanamide as a white foam (15.5 mg, 88% yield). LCMS: RT=1.99 min [M+H] 585.3 (LCMS Method 2); NMR: 400 MHz 1H (CDCl3) 8.30 ppm, 1H, d, J=2.0 Hz; 7.75 ppm, 1H, dd, J=8.7, 2.4 Hz; 7.44 ppm, 1H, br. s; 7.16 ppm, 5H, m; 6.99 ppm, 1H, s; 6.92 ppm, 1H, d, J=8.8 Hz; 6.67 ppm, 1H, br. s; 6.57 ppm, 2H, d, J=7.1 Hz; 5.97 ppm, 1H, t, J=53 Hz; 4.10 ppm, 1H, d, J=12.9 Hz; 3.63 ppm, 1H, d, J=13.1 Hz; 2.97 ppm, 1H, d, d=13.1 Hz; 2.44 ppm, 1H, d, J=13.1 Hz; 1.47 ppm, 3H, s; 1.36 ppm, 3H, s.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]([S:28]([CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])(=[O:30])=[O:29])[CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CCC(C2C3C(=CC=C(F)C=3)NC=2)CC1)=O)(C)(C)C>>[C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:28]([CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])(=[O:29])=[O:30])[CH:18]=[C:17]2[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)#[N:27]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Agent: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCNCC2)c2cc(C#N)ccc21

Procedure:
Proceeding as described in Example 19, Step 3, but substituting 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine with 1-benzyloxycarbonyl-4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (prepared as described in Example 14, Step 2, by substituting 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine for N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine] gave 4-[5-cyano-1-(2-trimethylsilyl-ethanesulfonyl)indol-3-yl]piperidine.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][C:10]([C:13]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:14]=1[O:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21])([CH3:12])[CH3:11].Cl[CH2:31][C:32]([O-:34])=[O:33].[Na+]>CS(C)=O>[CH3:12][C:10]([C:13]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:14]=1[O:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[O:21][CH2:31][C:32]([OH:34])=[O:33])([CH3:9])[CH3:11]
Reactant: O=C([O-])CCl
Reactant: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2OCC(=O)O)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To 103 mg of 60% sodium hydride, prewashed with hexane, in 10 ml of dimethyl sulfoxide was added 500 mg of the title product of Example 100. The mixture was stirred at 40° C. until gas evolution ceased, and then 290 mg of sodium chloroacetate was added, the resulting mixture stirred at room temperature overnight and then at 80° for 1 hour. After cooling, the mixture was partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer further extracted with ether, the combined organic extracts washed with several portions of water and then brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 30% ethyl acetate-2% acetic acid-68% hexane gave the title compound (155 mg) as a pure white crystalline solid, DSC 96.5° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:14])[CH:8]=[C:9]([CH:13]=1)C(O)=O)[CH2:2][CH2:3][CH3:4]>N1C2C(=CC=CC=2)C=CC=1.[Cu-]=O>[CH2:1]([C:5]1[NH:6][C:7](=[O:14])[CH:8]=[CH:9][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: O=[Cu-]
Solvent: c1ccc2ncccc2c1
Product: CCCCc1cccc(=O)[nH]1

Procedure:
4.9 g (25 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid are refluxed for 1.5 h with 1.79 g (12.5 mmol) of copper(I) oxide in 50 ml of quinoline (237° C). After filtering off, the volatile constituents are removed by distillation in vacuo (110° C. at 17 mbar, then 67° C. at 9 mbar). The residue is chromatographed twice on silica gel using dichloromethane/methanol (40:1) → (20:1) and the product is stirred in petroleum ether.
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:36][O:35][C:28]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1ccc(C(O)Cn2ccnc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(OC)cc2OC)cc1
Reaction time: 1.5 h
Yield: 40.9 %

Procedure:
10.9 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 766 mg of methyl 4-mercaptobenzoate and 754 mg of 1-[2-hydroxy-2-(2,4-dimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 1.5 hours. The resulting solution was treated and purified according to the same procedure as described in Example 13, to give 495 mg of the title compound as a colorless oily substance.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:52])[CH3:51]>CN(C=O)C.C(Cl)(Cl)Cl>[C:50]([N:53]1[CH2:58][CH2:57][N:56]([C:29]([C:28]2[C:24]([CH3:23])=[N:25][O:26][C:27]=2[CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])=[O:31])[CH2:55][CH2:54]1)(=[O:52])[CH3:51]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(C(=O)c2c(C)noc2CC(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1,5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 1-acetylpiperazine (0.13 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C19H21N3O4: 355.1532, found 355.1538.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH:14]([N:17]1[C:22](=[O:23])[CH2:21][O:20][CH:19]([C:24]([O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH:30]3[CH3:36])=[O:25])[CH2:18]1)([CH3:16])[CH3:15]>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[OH:25][C:24]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][CH2:31][CH:30]2[CH3:36])([CH:19]1[O:20][CH2:21][C:22](=[O:23])[N:17]([CH:14]([CH3:15])[CH3:16])[CH2:18]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1CCc2ccc(OC(=O)C3CN(C(C)C)C(=O)CO3)cc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCc2ccc(OC(O)(c3ccccc3)C3CN(C(C)C)C(=O)CO3)cc21
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2.7 g. of phenylmagnesium bromide in 30 ml. of tetrahydrofuran was added dropwise to a mixture of 3.17 g, of 4-isopropyl-2-(3-methyl-1-oxo-5-indanyloxymethyl)-5-oxomorpholine and 200 ml. of tetrahydrofuran with stirring at room temperature and the mixture was further stirred for 30 minutes. Then, adding a small amount of water to the reaction mixture, tetrahydrofuran was distilled off from the reaction mixture under reduced pressure. To the residue formed were added 100 ml. of ethyl acetate and 100 ml. of water to dissolve the residue therein and the ethyl acetate layer formed was recovered and washed twice each with 50 ml. of water and then with 50 ml. of saturated sodium chloride aqueous solution. Then, ethyl acetate was distilled off and the residue formed was adsobed on a silica gel column prepared from 150 ml of silica gel. in chloroform. The residue adsorbed was then eluted with ethyl acetate and after removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 300 ml. of the ethyl acetate eluate thereafter was collected and dried to provide 3.25 g. (yield 82.3%) of oily 2-(1-hydroxy-3-methyl-1-phenyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[O:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: c1c[nH]cn1
Product: CCOC(=O)c1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (600 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (115.5 mg) together with a by-product having lower polarity. The by-product was not investigated further.
Reaction SMILES: [OH-].[Na+].C(O)C.C[O:7][C:8](=[O:29])[C:9]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>O>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:18]=[C:9]([C:8]([OH:29])=[O:7])[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cc(-c2cccs2)c(C(=O)OC)cc1-c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2cccs2)c(C(=O)O)cc1-c1cccs1
Temperature: 78 °C
Yield: 84.5 %

Procedure:
Sodium hydroxide (4.80 g, 120.0 mmol) is dissolved in water (30 cm3), then ethanol (250 cm3) and 2,5-dithien-2-ylterephthalic acid dimethyl ester (5.30 g, 14.8 mmol) are added. This mixture is heated at 78° C. overnight. The solvent is evaporated under reduced pressure to about half of original volume then water is added. The resultant mixture is neutralized with concentrated hydrochloric acid. The precipitate is collected by filtration and washed with water and ethanol, then dried in vacuo, to yield the product as an off-white solid (4.13 g, 84%). 1H NMR (300 MHz, DMSO-d6): δ(ppm) 13.46 (s, 2H, COOH), 7.72 (s, 2H, Ar—H), 7.70 (dd, J=5.1 and 1.1 Hz, 2H, Ar—H), 7.28 (dd, J=3.6 and 1.1 Hz, 2H, Ar—H), 7.17 (m, 2H, Ar—H); 13C NMR (75 MHz, DMSO-d6): δ(ppm) 168.7 (C═O), 139.7 (q), 134.5 (q), 131.4 (q), 130.2 (CH), 127.9 (CH), 127.5 (CH), 127.1 (CH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:45])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25](COCC[Si](C)(C)C)[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:46])[C:12]([CH3:48])([CH3:47])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:45])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:46])[C:12]([CH3:48])([CH3:47])[CH2:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide from Step B (38 mg, 0.057 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) and the resulting mixture was stirred at ambient temperature for 1 h then concentrated to dryness in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was adjusted to pH 10 by addition of 1 N aqueous NaOH and ethylenediamine (5.7 mg, 0.095 mmol). After 30 min, the mixture was partitioned between H2O (30 mL) and EtOAc (40 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH-100:0 to 95:5, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2388; calculated m/z=545.2359 for C31H31F2N4O3.