Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown sticky solid (90%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])O[C:11]1=O>O1CCOCC1>[CH:1]1([N:7]([CH3:8])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC1CCCCC1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: C1COCCO1
Product: CNc1ccccc1C(=O)N(C)C1CCCCC1
Temperature: 100 °C
Yield: 203 %

Procedure:
A mixture of N-cyclohexyl-N-methylamine (0.17 g, 0.62 mmol) and 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.25, 0.56 mmol) in dioxane (7.5 ml) was heated at 100° C. overnight. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (hexanes ethyl acetate, 1:1) to yield the title compound (0.28 g, 97%) as an orange solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].CN(C)[CH:24]=[O:25]>ClCCl>[CH2:6]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]=1[CH:24]=[O:25])[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCC1=CCCc2cc(OC)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC1=C(C=O)CCc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (16.6 mL) was added dropwise with stirring to dimethylformamide (70 mL) at -5° C. After the addition was completed, the mixture was stirred at 0° C. for 15 minutes, then a solution of 1-butyl-3,4-dihydro-6-methoxy-naphthalene (34.9 g) in dimethylformamide (30 mL) was added slowly over 15 minutes while the reaction temperature was maintained at 0° C. The cooling bath was then withdrawn and after the mixture had stirred at room temperature for 1.5 hours, a few chips of ice were added, followed, after 5 minutes, by 10N sodium hydroxide (200 mL). The reaction was heated to 110° C. which caused the vigorous evolution of dimethylamine from the mixture and after 10 minutes the reaction was cooled, diluted with water (750 mL) and extracted with dichloromethane (1×500 mL; 2×300 mL). The organic layers were washed in turn with water (2×200 mL), then were combined, dried (MgSO4 ) and evaporated to furnish an amber oil which was passed through a short column of silica gel (200 g) in dichloromethane. The fractions containing the product were evaporated to yield 39.4 g of crude 1-butyl-3,4-dihydro-6-methoxy-2-naphthalene-carboxaldehyde as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[Br:11]P(Br)Br.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(Br)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.2 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanol (1 g, 5 mmol) in tetrahydrofuran (80 mL) was added dropwise tribromophosphine (669 mg, 2.5 mmol) at 0° C. The solution was stirred at room temperature for 2 hours, and then water was added to quench the reaction at 0° C. The mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and concentrated to give a residue. And the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:50) to give 1-bromo-4-(1-bromoethyl)benzene as an oil (780 mg, 59%). 1H NMR (300 MHz, CD3OD): δ 7.46 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 5.25 (q, J=6.9 Hz, 1H), 1.98 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI−): m/z=483.1 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:21][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C(F)(F)F)cc4)c3c2)c(F)c1

Procedure:
The title compound, light yellow solid (18 mg, 12%), MS (ISP) m/z=442.2 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:15]([F:18])([F:17])[F:16])[OH:12]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cccc2c1CCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1CCC2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59522.8 %

Procedure:
To an ice-cold suspension of 4-methoxy-indan-1-one (200 mg, 1.23 mmol) and trimethyl(trifluoromethyl)silane (218 mg, 1.48 mmol) in THF (4 mL) was added 1M-TBAF (615 mL, 0.615 mmol) at 0° C. The mixture was stirred overnight at room temperature, and then diluted with EtOAc. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated tinder reduced pressure. The crude residue was purified by column chromatography to give 4-methoxy-1-trifluoromethyl-indan-1-ol (170 g, 60%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27].[H-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:26]([C:19]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=3[O:17][CH3:16])(=[O:28])=[O:27])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2nc(-c3ccc(C(C)C)cc3)cs2)c1

Procedure:
N-[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-2,5-dimethoxy-benzenesulfonamide was prepared (62 mg) following general procedure C (method 1) using 4-(4-isopropyl-phenyl)-thiazol-2-yl amine (50 mg, 0.23 mmol), 2,5-dimethoxybenzenesulfonyl chloride (59 mg, 0.25 mmol), NaH (14 mg, 60%, 0.34 mmol) and THF (1 mL). LCMS m/z: 419 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 1.27 (d, 6H); 2.95 (m, 1H), 3.75 (s, 3H), 3.81 (3, 3H), 6.52 (s, 1H), 6.9 (d, 1H), 7.0 (dd, 1H), 7.31 (m, 2H), 7.44 (m, 2H), 7.6 (d, 1H), 10.2 (brs, 1H).
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: OCC[C@H](O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-1-phenyl-1,3-propanediol (8.0 g, 52.6 mmol) in dichloromethane (80 ml) were added at 0° C. acetic anhydride (5.5 ml) and pyridine (4.7 ml). The mixture was stirred for 6 hours at the same temperature range and for 1.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 4.8 g of (S)-3-hydroxy-3-phenylpropyl acetate. Physico-chemical properties and spectral data of these products are shown in [Table 7].
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)(=O)C.[Pt]=O>[CH2:1]([O:3][P:4]([CH2:9][C@@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOP(=O)(C[C@@H]1CCN[C@@H](C(N)=O)C1)OCC
Reaction time: 6 h

Procedure:
A mixture of 1.19 g of 4-(diethylphosphonomethyl)-2-pyridinecarboxamide and 0.75 g of platinum oxide in 30 ml of acetic acid is hydrogenated at 3 atmospheric pressure for 6 hours at room temperature. The reaction mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in methylene chloride and washed with a small volume of saturated sodium bicarbonate solution. After drying over magnesium sulfate, a methylene chloride solution of a 2:1 mixture of cis and trans 4-(diethylphosphonomethyl)-2-piperidinecarboxamide is obtained. After 3 days at room temperature this mixture isomerizes to the more stable cis isomer. Removal of the solvent in vacuo affords cis-4-(diethylphosphonomethyl)-2-piperidinecarboxamide as an oil, which is converted to the hydrochloride salt, melting at 155°-158°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:36]2[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=2[Cl:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(Cl)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
Triphenylphosphine (786 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (603 mg), 2-chloro-5-methylphenol (428 mg) and diethyl azodicarboxylate (522 mg) in tetrahydrofuran (10 mL) at room temperature. After stirring at room temperature for 18 hr, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6, v/v) to give the titled compound (489 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.84 (m, 4H), 2.28 (s, 3H), 3.44 (m, 2H), 3.65 (ddd, J=4.0, 8.0, 12.7 Hz, 2H), 4.49 (m, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), and 7.19 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH:31]=O)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH2:31][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:18])[CH3:19])=[O:8])[CH3:2]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.28 g, 0.528 mmol) and morpholine (0.07 g, 0.79 mmol) in dichloroethane (3 mL), acetic acid (0.19 g, 3.16 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 38.70%).
Reaction SMILES: C(=O)([O-])O.[Na+].O1CCCC1.[NH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14].[CH3:20][C@@H:21]([C@@H:28]1[C@@:32]2([CH3:50])[CH2:33][CH2:34][CH:35]3[C@@:40]4([CH3:49])[CH2:41][CH2:42][CH:43]([O:45][C:46](Cl)=[O:47])[CH2:44][C:39]4=[CH:38][CH2:37][CH:36]3[CH:31]2[CH2:30][CH2:29]1)[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>O>[CH3:27][CH:25]([CH2:24][CH2:23][CH2:22][C@H:21]([C@@H:28]1[C@:32]2([CH3:50])[C@H:31]([C@H:36]3[C@H:35]([CH2:34][CH2:33]2)[C@:40]2([CH3:49])[C:39]([CH2:44][C@@H:43]([O:45][C:46]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[O:47])[CH2:42][CH2:41]2)=[CH:38][CH2:37]3)[CH2:30][CH2:29]1)[CH3:20])[CH3:26]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCC(=O)NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80.8 %

Procedure:
Sodium hydrogencarbonate (0.168 g) and tetrahydrofuran (20 ml) were added to a suspension of glycylglycine (0.15 g) in water (20 ml). After tetrahydrofuran (20 ml) and cholesteryl chloroformate (0.898 g) were added to the resulting transparent solution at 0° C., the mixture was stirred for an hour. The reaction mixture was concentrated under reduced pressure and, methanl (10 ml) and chloroform (10 ml) were added to the residue. By filtration, the transparent solution was obtained. The solvent was distilled off to give crude crystals (0.98 g). The crude crystals were then purified by silica gel chromatography to give N-(cholest-5-ene-3β-oxycarbonyl)glycylglycine (0.5 g) as white powders.
Reaction SMILES: [C:1]1([C:101]2[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:100])[C:20](=[O:99])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:37]2[CH:42]=[CH:41][C:40]([N:43]([C:45](=[O:98])[CH2:46][CH2:47][N:48]([C:50](=[O:97])[CH2:51][O:52][C@@H:53]3[C:61]4([CH2:66][CH2:65][N:64]([CH2:67][CH2:68][C@:69]5([C:90]6[CH:95]=[CH:94][C:93]([F:96])=[CH:92][CH:91]=6)[O:73][CH2:72][N:71]([C:74](=[O:89])[C:75]6[CH:80]=[C:79]([C:81]([F:84])([F:83])[F:82])[CH:78]=[C:77]([C:85]([F:88])([F:87])[F:86])[CH:76]=6)[CH2:70]5)[CH2:63][CH2:62]4)[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)[CH3:49])[CH3:44])=[CH:39][CH:38]=2)C(=O)OCC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:9]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[C:1]1([C:101]2[CH:102]=[CH:103][CH:104]=[CH:105][CH:106]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([C:20](=[O:99])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:37]2[CH:38]=[CH:39][C:40]([N:43]([C:45](=[O:98])[CH2:46][CH2:47][N:48]([C:50](=[O:97])[CH2:51][O:52][C@@H:53]3[C:61]4([CH2:66][CH2:65][N:64]([CH2:67][CH2:68][C@:69]5([C:90]6[CH:95]=[CH:94][C:93]([F:96])=[CH:92][CH:91]=6)[O:73][CH2:72][N:71]([C:74](=[O:89])[C:75]6[CH:80]=[C:79]([C:81]([F:82])([F:83])[F:84])[CH:78]=[C:77]([C:85]([F:87])([F:88])[F:86])[CH:76]=6)[CH2:70]5)[CH2:63][CH2:62]4)[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)[CH3:49])[CH3:44])=[CH:41][CH:42]=2)[CH3:100])[CH2:13][CH2:12]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
The compound (180 mg, 0.12 mmol) obtained in Example 97f was dissolved in a mixed solvent of ethanol (3 mL) and ethyl acetate (3 mL), 10% palladium-carbon (36 mg, 20% by weight) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 30:1, v/v) to give the title compound (141 mg; yield, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\C4CC4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)C1=C(/C=C\C2CC2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (318 mg) of Example 57 was dissolved in dimethylformamide (4.4 ml), to which a solution of 1-acetoxyethyl bromide (120 mg) in dimethylformamide (2 ml) was added dropwise under ice cooling. The resulting mixture was stirred for one and a half hours. The reaction mixture was diluted with ethyl acetate and the resulting precipitate was filtered off. After the filtrate was washed with water and then saturated saline, anhydrous magnesium sulfate was added to dry the solution. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel, whereby the title compound (18 mg) was obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(O)=O>ClCCCl>[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Temperature: 12 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Sodium triacetoxyborohydride (382 g, 1.8 mol) was added in one portion to a mixture of 1,4-dioxaspiro[4.5]decan-8-one (200.0 g, 1.28 mol), morpholine (111.4 g, 1.28 mol) and glacial AcOH (73.2 mL, 1.28 mol) in 1,2-dichloroethane (4 L). A slightly exothermic reaction occurred accompanied by increase in temperature by 12° C. Then the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10% aqueous NaOH (1.8 L) over a period of 20 min. The organic layer was separated, washed with brine (1 L), dried over MgSO4 and concentrated to afford 1 (237.66 g) as white solid. The aqueous layer was extracted with AcOEt (4×300 mL). Combined extracts were washed with brine (1 L), dried over MgSO4 and concentrated to furnish additional portion of 1 (44 g) as an off-white solid. Total yield of 1 (281.66 g, 97%). 1H NMR data identical with the data obtained earlier.
Reaction SMILES: [NH:1]1[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]1=[O:8].CC1(C2C=CC=CC=2)NC(=O)N([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:23]3[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][O:26][C:22]=3[C:21]=2[CH2:35][CH2:36][CH3:37])C1=O>>[CH2:35]([C:21]1[C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]=2[CH:33]=[CH:34][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][N:1]1[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]1=[O:8])[CH2:36][CH3:37]
Reactant: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(-c3ccccc3)noc12
Reactant: O=C1CCC(=O)NC1
Product: CCCc1c(OCCCN2CC(=O)CCC2=O)ccc2c(-c3ccccc3)noc12

Procedure:
1-(3-{[7-Propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione was prepared as for Example 10 from piperidin-2,5-dione and the bromide from Example 27. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=O.S(Cl)(Cl)=O.[CH2:31](O)[CH3:32]>>[CH2:31]([O:25][C:23]([C:6]1[CH2:5][C:4]2[C:9](=[C:10]([F:19])[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=1)=[O:24])[CH3:32]
Reactant: CCO
Reactant: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)CC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1=CN(CCF)c2c(cc(F)c(N3CCN(C)CC3)c2F)C1
Yield: 81 %

Procedure:
To a stirred suspension of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Fleroxacin; Belgian Patent No. 887,574) (35 g, 0.095 mol) in anhydrous ethanol (2.0 L) was added dropwise thionyl chloride (184 mL, 2.52 mol) over a 2-hour period. The solution was then heated at reflux and monitored by thin layer chromatography, until all starting material had been consumed (at this point a clear solution was obtained). The mixture was evaporated to dryness (36.3 g) and recrystallized from ethanol to give a white crystalline solid (30.4 g, 81% yield).