Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:45])=[O:46])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
A solution of triphenylphosphine (194 mg, 0.74 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (132 mg, 0.74 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (200 mg, 0.57 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (143 mg, 1.43 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford pure 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide (178 mg, 72%) as a light yellow foam: mp 61-64° C. (foam to gel); EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0790.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([N:6]([CH3:13])[C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[Br:16]Br.II.O>C(O)(=O)C>[Br:16][CH2:11][C:9](=[O:10])[CH2:8][C:7]([N:6]([CH3:13])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)CC(=O)N(C)c1ccc(Cl)cc1
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CN(C(=O)CC(=O)CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
A 500 ml reaction flask fitted with a condenser, drying tube, magnetic stirrer, thermometer and dropping funnel was charged with 38.9 g (0.172 mole) of 4'-chloro-N-methylacetoacetanilide and 350 ml of glacial acetic acid. The dropping funnel contained 27.5 g (0.172 mole) of bromine and a crystal of iodine dissolved in 85 ml of acetic acid. The bromination solution was added dropwise over 45 minutes to the stirred reaction solution while maintaining a pot temperature of about 25°. The solution was allowed to stir at ambient temperature for 48 hours. The acetic acid solution was poured into 800 ml of cold water. The aqueous mixture was twice extracted with 400 ml of ether. The combined ether extracts were washed with water and dried over sodium sulfate. The solvent was removed on the rotary evaporator to give a residual liquid (40.4 g, 77%) which was used in subsequent reactions without further purification. N.M.R. (CDCl3) ∂3.2 (NCH3), 3.7 (O=C CH 2 C=O), 4.0 (O=CCH2Br), 5.0 (CH, enol), 7.2-7.4 (aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[NH:12][C:13](=[O:15])[NH2:14])[CH:5]([OH:8])[CH2:6]Br.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[NH:12][C:13](=[O:15])[NH:14][C:4]([CH3:9])([CH3:5])[CH3:3])[CH:5]([OH:8])[CH2:6][NH:21][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: NC(=O)Nc1c(Cl)cc(C(O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NCC(O)c1cc(Cl)c(NC(=O)NC(C)(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
A mixture of 0.86 g. of 3,5-dichloro-4-carbamoylamino-αbromomethylbenzyl alcohol and 10 ml. of tert-butylamine was heated to 90°-100° C. for 2 days in a sealed tube. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and after adding to the residue formed 50 ml. of ethyl acetate, 50 ml. of water, and an excessive amount of sodium carbonate followed by stirring for 30 minutes, sodium chloride was added to the mixture until the mixture was saturated. Then, the mixture was separated into an ethyl acetate layer and an aqueous layer. The ethyl acetate layer formed was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Then, after filtering, the solvent was distilled off from the filtrate under reduced pressure. By recrystallizing the residue from ethyl acetate, 0.24 g. of 3,5-dichloro-4-tert-butylcarbamoylamino-α-(tert-butylaminomethyl)benzyl alcohol having a melting point of 167°-169° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.O.[OH-].[Li+].O>O1CCOCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:25][CH:26]=1)([OH:32])=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(C(=O)O)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a solution of 390 mg (0.84 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-ethoxycarbonylphenyl)-1-piperazinecarboxamide obtained in Example 89 in 10 ml of 1,4-dioxane were added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate and 1 ml of water, followed by stirring at room temperature for 4.5 hours. To the resulting mixture was further added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate, followed by overnight stirring at room temperature. After the solvent was evaporated, water was added to the residue, and the resulting mixture was adjusted to pH 4 with 4 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].C[O-].[Na+].CO.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 4.5 h

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.40 g), methyl 3-mercaptopropionate (1.42 ml) and 28% sodium methylate methanolic solution (1.25 ml) in methanol (10 ml) was refluxed for 4.5 hours in an oil bath under heating. To the reaction mixture was added methyl 3-mercaptopropionate (0.53 ml, 0.32 ml) respectively after 2 hours and 3.5 hours of heating. Further, 28% sodium methylate-methanol solution (0.63 ml) was added after 2.5 hours. After 4.5 hours, the reaction mixture was cooled, neutralized with 1N hydrochloric acid (9.6 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=1:3) for purification. The objective fractions were concentrated. Then, the collected precipitate was washed with isopropyl ether to afford (2R, 3R)-2-(2,4-difluorophenyl )-3-mercapto-1-(1-H-1,2,4-triazol-1-yl)-2-butanol (0.22 g) as colorless needles.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Mg]Br)[CH2:36][CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:31])[CH2:35][CH2:36][CH3:37])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC[Mg]Br
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 64A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)-octanamide (prepared as described in Preparation 63A) and propylmagnesium bromide, the title compound was obtained as a foam-like substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(C1C=CC(C(N)=S)=CC=1)(C)C.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([O:33][CH:34]1[CH:39]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])=[CH:42][CH:41]=2)[CH2:38][CH2:37][NH:36][CH2:35]1)[C:12]1[C:20]2[N:19]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[N:17](COCC[Si](C)(C)C)[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([O:8][C:9]([CH:11]([O:33][CH:34]1[CH:39]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])=[CH:44][CH:45]=2)[CH2:38][CH2:37][NH:36][CH2:35]1)[C:12]1[C:20]2[N:19]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2c(C(OC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)C(=O)OCc3ccccc3)cccc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc2c(C(OC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)C(=O)OCc3ccccc3)cccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The mixture of 1.03 g of methyl 4-(1-benzyloxycarbony-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidin-3-yloxymethyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole-2-carboxylate, 10 ml of methanol and 10 ml of 2M HCl is stirred at 50° C. over 2 hours. The reaction mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (70 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (2:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:31][NH:32][CH3:33]>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:32]([CH3:33])[CH3:31])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CNC
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N(C)C)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (example 147c) and dimethylamine hydrochloride as starting materials and isolated (23 mg, 51%); MS (ESI, m/z): 442.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:19][C:18](=[O:20])[C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 35 °C
Reaction time: 18 h

Procedure:
A solution of 1.15 g (9.19 mmol) 1H-pyrrole-2-carboxylic acid methyl ester and 2.70 g (10.1 mmol) 2-bromo-(1-(4-trifluoromethyl-phenyl)-ethanone in 20 ml acetonitrile is treated with 3.30 g (10.1 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 18 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester as yellow oil; HPLC/MS 2.52 (A), [M+H] 312.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>C(Cl)(Cl)Cl.CN(C)C=O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH2:7][C:8]([Cl:20])=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Biphenylacetic acid (6.0 g (0.028 mol)) manufactured by Sigma-Aldrich Co. LLC was dissolved in dehydrated chloroform (60 ml). To this, oxalyl chloride (3.7 g (0.029 mol)) and N,N-dimethylformamide (0.04 ml (0.51 mmol)) were added. The mixture was stirred at room temperature for 72 hours. Chloroform, excessive oxalyl chloride and N,N-dimethylformamide were distillated away under reduced pressure to obtain biphenylacetyl chloride (6.5 g (0.028 mol)).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)s1
Agent: NCCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Cl)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080 g, 0.304 mmol) and 5-(4-chorophenyl)thiophene-2-carbaldehyde (0.068 g, 0.304 mmol) in acetic acid 5 mL is added β-alanine (2.7 mg, 0.030 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.110 g, 0.235 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.66 (dd, J=8.7, 1.5 Hz, 2H), 7.50 (dm, J=12.6 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.18 (m, 5H), 6.69 (s, 1H), 5.65 (dd, J=12.0, 4.5 Hz, 1H), 3.68 (dd, J=13.8, 12.0 Hz, 1H), 3.51 (dd, J=14.4, 4.5 Hz, 1H). MS (ES+, m/z): 469.5 (M++1, 30.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1.[C:40]1([C:46]2([C:52]([OH:54])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(OCC)(=O)C.ClCCl>CO.ClCCl>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:22][CH2:23][N:49]3[CH2:48][CH2:47][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:52]([OH:54])=[O:53])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccccc1)N1CC[C@@](CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC[C@](CCN2CCC(C(=O)O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate, dichloromethane, 2% methanol/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane, and then 8% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, methanol/dichloromethane 1/9).
Reaction SMILES: [CH2:1]([S:8]([C:11]1[C:25]([OH:26])=[C:24]([C:27]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])[CH:23]=[C:22]([OH:36])[C:12]=1[C:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH2:1]([S:8]([C:11]1[C:25](=[O:26])[C:24]([C:27]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:23][C:22](=[O:36])[C:12]=1[C:13]([O:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:14])(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCCCC1)c1cc(O)c(C(=O)OC2CCCCC2)c(S(=O)(=O)Cc2ccccc2)c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C1C=C(C(=O)OC2CCCCC2)C(=O)C(S(=O)(=O)Cc2ccccc2)=C1C(=O)OC1CCCCC1
Reaction time: 2 h
Yield: 60 %

Procedure:
One part of dicyclohexyl 2-benzylsulfonyl-3,6-dihydroxyterephthalate, 2 parts of electrolytic manganese dioxide and 3 parts of toluene were agitated at 35°-45° C. for 8 hours and then at its boiling point for additional 2 hours. The reaction mixture was hotfiltered and the volume of the resultant filtrate was concentrated to about 1/3. After adding ligroin to the concentrate, the resultant mixture was allowed to cool to obtain light-yellowish crystals with a yield of 60%. Upon recrystallization, they showed a melting point of 160°-162° C. Detailed analysis data of this compound, such as its elementary analysis data, are as described before.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23]N[CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH:28]1CCNCC1>>[OH:27][CH:28]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24][CH2:23]1
Reactant: OC1CCNCC1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCC(O)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 4-hydroxypiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.39 (2H, brm), 1.83 (2H, brm), 3.15 (1H, d, J=5.22 Hz), 3.71 (1H, m), 4.19 (2H, m), 4.74 (1H, d, J=4.40 Hz), 7.16 (1H, tt, J=7.40, 1.10 Hz), 7.21 (1H, d, J=9.34 Hz), 7.42 (2H, m), 7.78 (1H, d, J=9.34 Hz), 8.21 (2H, ddd, J=7.69, 1.92, 1.10 Hz), 8.52 (1H, s). m/z 362.4 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:11])=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][N:2]=1
Reactant: Nc1cncc2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cncc2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Isoquinolin-4-amine (296 mg, 2.05 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.20 mL, 2.46 mmol) and phenyl chloroformate (0.27 mL, 2.15 mmol), respectively and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl isoquinolin-4-ylcarbamate (318 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1.[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:16])([CH2:11][C@H:12]([OH:13])[C:23]([F:25])([F:24])[F:22])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CC=O)c1nc(Br)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL round-bottomed flask was added (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.9 g, 15.39 mmol) and THF (130 mL). The mixture was cooled to −78° C. and (trifluoromethyl)trimethylsilane (Apollo Scientific Ltd.; 24.46 mL, 154 mmol) was added. After stirring for 10 min, tetrabutylammonium fluoride (Aldrich; 27.7 mL, 27.7 mmol, 1.0 M in THF) was added over 10 min. The solution was stirred at −78° C. for 2 h. To the solution was added 1 N HCl (10 mL) and the solution was allowed to warm to rt. The solution was carefully diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (100 mL) and brine (50 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 60% EtOAc/hexane, 120 g Silicycle HP) afforded: