Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:12])([O-:11])[CH3:10].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:9]([O:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:8]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.2 %

Procedure:
A typical procedure is given for the reaction of Entry 1 in Table 1. A 4 mL vial was charged with bromobenzene (63 mg, 0.40, mmol), Pd(dba)2 (11.5 mg, 0.02 mmol), Ph5FcP(t-BU)2 (14.2 mg, 0.02 mmol) and sodium t-butoxide (47 mg, 0.48 mmol). Anhydrous toluene (2 mL) was added, and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The reaction mixture was stirred at room temperature for 23 h. The reaction solution was then adsorbed onto silica gel, and the product was isolated by eluting with ethyl acetate/hexanes (0 to 10% gradient) to give 58 mg (97%) of t-butoxybenzene.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:19]([NH2:21])=[O:20])[C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:18]=1.[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C([BH3-])#N.[Na+]>[Cl-].[Zn+2].[Cl-].CO.CN(C=O)C>[NH2:21][C:19]([C:4]1[C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:32]4[CH2:33][CH2:34][CH:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:31]4)=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:18]=[CH:2][CH:3]=1)=[O:20]
Reactant: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C=O)cc3)nc12
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(-c3nc4c(C(N)=O)cccc4[nH]3)cc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
A solution of EXAMPLE 7B (300 mg, 1.13 mmol) and 3-(tert-butoxycarbonylamino)pyrrolidine (631 mg, 3.39 mmol) in 1:1 methanol/N,N′-dimethylformamide (20 mL) was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (213 mg, 3.39 mmol) and zinc chloride (154 mg, 1.13 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was concentrated and the residue purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) to provide the title compound (415 mg, 84%). MS (DCI/NH3) m/z 436 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.Cl.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc2cc(F)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-fluoro-2-naphthyl)carbamic acid ethyl ester (548 mg, 2.35 mmol), N-chlorosuccinimide (313 mg, 2.35 mmol) and 1 M HCl in acetic acid (2.35 mL, 2.35 mmol) in acetic acid (20 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature, water (10 mL) is added. The resulting precipitate is removed by filtration to give N-(1-chloro-6-fluoro-2-naphthyl)carbamic acid ethyl ester as a yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][C@@H:15]([CH2:29][OH:30])[CH2:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:30][CH2:29][C@@H:15]1[CH2:16][C@H:17]2[C@@H:27]([CH2:26][C:25]3[C:28]4[C:22](=[CH:21][CH:20]=[CH:19][C:18]2=4)[NH:23][CH:24]=3)[N:13]([CH3:12])[CH2:14]1)(=[O:9])=[O:8]
Reactant: CN1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
5.0 g of p-toluenesulfonyl chloride was added in small portions to a mixture of 5.0 g of 6-methylergolin-8β-ylmethanol and 50 ml of pyridine while stirring, and the resulting mixture was stirred for 3 hours. After completion of the reaction, 4 ml of water was added to the mixture which was then stirred for 30 minutes. The mixture was diluted with ice-water, rendered alkaline with potassium carbonate and allowed to stand. The precipitated crystals were separated by filtration, washed with water and dried to obtain 6.9 g of the titled compound as colorless crystals. The crystals thus obtained were recrystallized from dichloromethane-isopropyl acetate to obtain colorless leaflets having a melting point of 195°-199° C. (with decomposition).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH:18](O)([CH3:20])[CH3:19]>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH:18]([CH3:20])[CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)O
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C(=O)O)c1ccccc1
Yield: 60 %

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.07 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL), and the solution was treated with isopropyl alcohol (0.075 mol, 5.76 mL), refluxed for 2 hours and worked up as before to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.CC1(C)CC(=O)CC(=O)C1.[F:26][C:27]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=1[NH:29][C:9]([C:6]1[C:5]2[C:12](=[O:14])[CH2:13][C:2]([CH3:1])([CH3:15])[CH2:3][C:4]=2[O:8][CH:7]=1)=[O:11]
Reactant: CC1(C)CC(=O)c2c(C(=O)O)coc2C1
Reactant: COc1ccc(N)c(F)c1
Agent: CC1(C)CC(=O)CC(=O)C1
Product: COc1ccc(NC(=O)c2coc3c2C(=O)CC(C)(C)C3)c(F)c1

Procedure:
Starting with (6,6-dimethyl-4-oxo4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid), prepared from dimedone by Procedure A, and 2-fluoro-4-methoxyaniline, General Procedure B provided the title compound as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([N:14]=[C:24]=[O:26])=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)c1ccc(N=C=O)cc1
Temperature: 75 °C

Procedure:
To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10 grams, 47.84 mmol) and triethylamine (9.68 grams, 95.67 mmol) in toluene (150 mL) under nitrogen atmosphere at 0° C. is added triphosgene (5.195 grams, 17.50 mmol) in one lot. Later the reaction mixture is heated to 75° C. over a period of one hour and maintained at this temperature for 20 hours. The reaction mixture is cooled to room temperature. The solids are filtered off, and the toluene is distilled under vacuum to give crude 11, which can be purified by a suitable method.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:17]2[CH:16]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[BH4-].[Na+].C(O)(C(F)(F)F)=O.C(Cl)Cl>O.CC(C)=O>[OH:3][CH:4]1[C:17]2[CH:16]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C(O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: O=C(O)CCCCOc1ccc2c(c1)C(O)c1ccccc1O2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Aqueous NaOH (9 mL, 1 N, 9 mmol) was added dropwise to adjust a solution of 5-(9-oxoxanthen-2-oxy)valeric acid (2.5 g, 8.0 mmol), prepared as described above, in water (60 mL) to a pH of 8. Sodium borohydride (2.5 g, 66 mmol) was added in small portions over 15 min. The mixture was stirred at 50° C. for 3 hours (TLC showed no starting ketone), and then acetone (60 mL) was added carefully to decompose excess sodium borohydride. The mixture was partially concentrated (to ~70 mL) in vacuo at 25° C., and the remaining aqueous solution added dropwise to a well-stirred mixture of ice-water (40 mL) and glacial acetic acid (30 mL). The immediate precipitate was collected, washed with water (3×20 mL) and anhydrous ether (2×20 ml) and dried in vacuo over P2O5 to give a white powder. Yield: 2.4 g(97%). There was a very small amount of by-product (Rf =0.02) in TLC; the main product Rf =0.51; [EtoAc-MeOH(2:1) major spot which became yellow after spraying with TFA-CH2Cl2 (1:19) at 25° C.], 0.02 minor impurity. NMR data in accordance with structure. ##STR11##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(C)=O.C1COCC1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[Br:1])=[CH:16][CH:15]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Br)c(CBr)c1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c(CNCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-3-bromomethylanisole (35 g, 125 mmol) in anhydrous DMSO (50 mL) and dry THF (50 mL) was added 4-trifluoromethylbenzylamine (30 g, 171 mmol) followed by triethylamine (18 mL, 129 mmol). After stirring for 18 h at RT the reaction was concentrated, diluted with aqueous 1 N NaOH (250 mL) and extracted with Et2O (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The residue which remained was purified by flash chromatography on silica gel (10 to 20% EtOAc/CHCl3) to give the title compound (34.17 g, 73%): TLC (20% EtOAc/CHCl3) Rf 0.63; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 6.96 (d, J=3.1 Hz, 1H), 6.70 (dd, 1H), 3.86 (s, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 1.75 (br s, 1H).
Reaction SMILES: [CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].C(O)(C)C>CN(C)C=O>[CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH:17]=[CH2:37])[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=Cc3ccccc3O)[C@H]2SC1
Yield: 78.4 %

Procedure:
To a cooled solution of benzhydryl 7-salicylideneamino-3-chloromethyl-3-cephem-4-carboxylate (4 g) in dimethylformamide (10 ml) were added triphenylphosphine (2.2 g) and sodium iodide with stirring. After stirring for 2 hours at ambient temperature, the reaction mixture was poured into isopropyl alcohol (250 ml), and the precipitated solids (6.7 g) were collected by filtration. To a stirred solution of the above solids in methylene chloride (10 ml) and water (5 ml) was added 36% formaldehyde solution (17.4 ml). Then the reaction mixture was adjusted to pH 9.0 with a saturated aqueous sodium bicarbonate. After stirring for an hour at ambient temperature, the separated organic layer was washed with water and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated under reduced pressure to give benzhydryl 7-salicylideneamino-3-vinyl-3-cephem-4-carboxylate (3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13]Cl)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[CH2:15]([N:11]1[CH2:12][CH2:13][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:25])[C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]1=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCCl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a solution of (R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.0 g, 5.40 mmol) in DMF (30 mL) was added NaH (1.0 g, 27.0 mmol, 60% in oil mineral) at 0° C. under N2. The mixture was stirred at rt for 2 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to afford (R)-tert-butyl 4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (1.13 g, 63% yield) as a white solid. LC-MS m/z 277.1 [M−56+H]+. 1H NMR (CDCl3 400 MHz): δ 7.38-7.29 (m, 3H), 7.29-7.22 (m, 2H), 5.02-4.86 (m, 1H), 4.49-4.39 (m, 1H), 4.31-4.06 (m, 2H), 3.41-3.18 (m, 3H), 2.42-2.31 (m, 1H), 1.46 (s, 9H), 1.12 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[C:22]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N+:27]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>O.[Pt]=O>[NH2:27][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([S:23](=[O:26])(=[O:25])[NH2:24])[C:14]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)[C:18]([OH:20])=[O:19]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid (10 g) in water (250 ml) was adjusted to pH 11 by addition of 1N sodium hydroxide. The resulting solution was hydrogenated at room termperature and at 1.1 atmospheres hydrogen pressure after addition of a platinum oxide catalyst (0.4 g). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid was precipitated by adjusting the filtrate to pH 2.5 by addition of 4N hydrochloric acid. After recrystallization from aqueous ethanol and drying, the compound was obtained with a melting point of 264°-265°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 5.8 g) in THF (200 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 50 mL) was added dropwise at −40° C., and the reaction solution was stirred at −40° C. for seven hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was heated to room temperature. Thereafter, the organic layer was separated, and the resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 3.8 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)#[N:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=1)=[O:25])#[N:2]
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of N-[2-(2-cyanophenylthio)phenyl]-4-hydroxybenzamide and 0.49 g of methyl bromoacetate followed by addition of 0.6 g of potassium carbonate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with water and crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 1.2 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=1)#[N:2].[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:30][CH2:29][C@@H:28]([NH:27][C:16]([C:14]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=1)=[O:17])[CH3:31]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccccc3CO)c2)c(C#N)c1
Reactant: C[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3ccccc3CO)c2)c(C#N)c1
Temperature: 25 °C

Procedure:
A reaction vial was charged with 2-Cyano-2″-hydroxymethyl-4-methyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (50.00 mg, 0.1456 mmol), (2S)-2-aminopropan-1-ol (13.12 mg, 0.1747 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (110.7 mg, 0.2912 mmol), N,N-diisopropylethylamine (0.06341 mL, 0.3640 mmol) and N,N-dimethylformamide (5.0 mL, 64 mmol) and the reaction stirred at room temperature over night. The reaction mixture was then purified by prep HPLC to get the compound as white solid.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][N:12]3[CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[Pt](=O)=O.CO>[ClH:1].[C:3]1([C:9]2[N:10]=[C:11]3[CH2:16][CH:15]([NH2:17])[CH2:14][CH2:13][N:12]3[CH:18]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC1CCn2cc(-c3ccccc3)nc2C1

Procedure:
Concentrated hydrochloric acid (0.11 ml) and platinum(IV) dioxide (83 mg) were added to a methanol (183 ml) solution of 2-phenylimidazo[1,2-a]pyridin-7-amine hydrochloride (900 mg), and the obtained mixture was then stirred in a hydrogen atmosphere for 4 hours. Thereafter, platinum(IV) dioxide (83 mg) was added to the reaction solution, and the obtained mixture was further stirred in a hydrogen atmosphere for 14 hours 30 minutes. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol (15 ml). The filtrate was concentrated under reduced pressure, and diethyl ether (3.6 ml) was then added to the obtained residue to solidify it, so as to obtain the title compound (733 mg) in the form of a gray solid.
Reaction SMILES: [C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]1=[O:30])(=[O:3])[CH3:2].[CH2:31](I)[CH:32]([CH3:34])[CH3:33]>>[C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]1=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1NC(=O)N2C
Reactant: CC(C)CI
Product: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1N(CC(C)C)C(=O)N2C

Procedure:
In the same manner as described in Example 36-(1), 3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione and isobutyl iodide are treated to give 3'-acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:69][C:70]3[S:71][CH:72]=[CH:73][N:74]=3)=[O:25])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
DIPEA (0.5 mL, 3.0 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (503 mg, 1.0 mmol), HATU (495 mg, 1.3 mmol) and 2-amino-1,3 thiazole (300 mg, 3.0 mmol) in DMF (6 mL). The resulting mixture was stirred at RT for 16 hours, water (90 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (585 mg).