Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[Na].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH:7]=[O:8].C(OCC)(=O)C.O>CN(C)C=O>[C:9]1([CH:4]2[S:1][CH:7]([OH:8])[CH2:6][CH2:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: S
Reactant: O=CCCC(Cl)c1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: OC1CCC(c2ccccc2)S1
Yield: 61.5 %

Procedure:
32 mg of anhydrous sodium hydrogen sulfide was added to a solution of 61 mg of 4-chloro-4-phenylbutanal in 1 mL of N,N-dimethylformamide at a temperature of 0° C. to 10° ° C. and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 60/40), so as to obtain 37 mg of 5-phenylthiolan-2-ol in the form of a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH2:6]C)[CH:4]=[CH2:5].[O:10]=[O+][O-]>CO>[CH3:9][O:8][C:3]([O:2][CH3:1])([CH2:4][CH3:5])[CH:6]=[O:10]
Reactant: C=CC(CC)(OC)OC
Reactant: O=[O+][O-]
Solvent: CO
Product: CCC(C=O)(OC)OC
Yield: 85.4 %

Procedure:
1 liter of a solution of 195 g (1.5 moles) of ethylacrolein dimethylacetal in methanol is reacted with ozone at -25° C. to -30° C. analogously to the procedure indicated in Example 1, and is then hydrogenated. The absorption of H2 is 29.55 standard liters (87.8% of theory). After working up, which is carried out analogously to the instructions in Example 2 by removing the catalyst, treating the reaction solution with an acid ion exchanger, distilling off the solvent and rectifying the reaction product, 169 g of ethylglyoxal dimethylacetal boiling at 52° C./15 are obtained, corresponding to a yield of 85.4% of theory.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28]O)[N:27]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:27]=1
Reactant: Cc1nc(CO)c(C(F)(F)F)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.281 g, 1.0 mmol) and (2-methyl-5-(trifluoromethyl)oxazol-4-yl)methanol (0.18 g, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added tributylphosphine (0.30 g, 1.5 mmol) at 0° C., followed by additional of N,N,N′/N′-tetramethylazodicarboxamide (0.26 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and stirred at ambient temperature for 16 h. The reaction mixture was quenched with aqueous ammonium chloride (25%, 50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 1′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.30 g, 68%) as a colorless solid: mp 136-137° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 7.32 (ddd, J=7.7, 1.2, 1.2 Hz, 1H), 7.19 (dd, J=7.6, 1.0 Hz, 1H), 7.07-7.03 (m, 2H), 6.70 (s, 1H), 6.29 (s, 1H), 5.93 (dd, J=5.0, 0.7 Hz, 2H), 4.98 (q, J=16.4 Hz, 2H), 4.75 (dd, J=20.8, 9.4 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 163.6, 155.1, 148.2, 141.9, 141.5, 137.6 (d, 3JCF=2.1 Hz), 133.5 (q, 2JCF=42.7 Hz), 131.6, 128.7, 123.5, 123.0, 119.8, 119.2 (q, 1JCF=266.9 Hz), 109.0, 103.0, 101.3, 93.1, 79.3, 57.2, 34.9, 13.4; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]>C(#N)C.P([O-])([O-])([O-])=O>[O:27]=[C:11]1[CH2:12][CH2:13][CH2:14][C@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:28])=[O:2]
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Reaction time: 24 h
Yield: 79.3 %

Procedure:
Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-butoxy}-acetic acid methyl ester (10 mg, 0.026 mmol) in acetonitrile (0.2 mL) and pH 7.2 phosphate buffer (3.0 mL). After 24 h, acetonitrile (5 mL) was added and the reaction mixture was concentrated to dryness in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →3% MeOH(CH2Cl2, gradient) afforded 7.7 mg (80%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[O:9][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(Br)cc2Cl)cc1C(F)(F)F
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of 4-bromo-2,6-dichlorophenol (2.4 g), 5-fluoro-2-nitro-trifluoromethylbenzene (2.0 g), potassium carbonate (2.7 g) in dimethylformamide (30 mL) was heated at reflux for 2 hours. The reaction was cooled to room temperature and concentrated. The residue was partioned between ethyl acetate and hydrochloric acid (2 N), the organic phase concentrated and the residue purified on column (silica gel, ethyl acetate/petrolium ether, 5:95), to give 2.7 g of 3,5-dichloro-4-(4-nitro-3-trifluoromethylphenoxy)bromo-benzene.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH:2]=C.CC([OH:33])C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[O:33]=[CH:2][CH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2
Reactant: CC(C)O
Reactant: C=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reaction time: 14 h

Procedure:
A mixture of N-((S)-6-allyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.50 g), 2-propanol (50 ml) and water (50 ml) was admixed with sodium periodate (0.60 g) and osmium tetroxide (1.3 mg). After stirring vigorously for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a suspension of methanesulfonamide (4.75 g, 50 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (1.98 g, 49.5 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3.66 g, 10 mmol) and 1,1′-carbonyldiimidazole (3.24 g, 20 mmol) in N,N-dimethylformamide (7 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (0.99 g, 22%) as a white solid: LC/MS m/e calcd for C23H29N3O4S (M+H)+: 444.57, observed: 444.1.
Reaction SMILES: Br.[C:2]1([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16]C(=O)OCC3C=CC=CC=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.ClCCl>[C:2]1([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(-c2ccccc2)nc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: NCCc1ccc(-c2ccccc2)nc1
Reaction time: 2 h

Procedure:
9 ml of 33% hydrobromic acid in acetic acid are added dropwise to a solution, cooled to approximately 0° C., of 1.8 g (5.42 mmol) of phenylmethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate, prepared in stage 1.1., in 50 ml of dichloromethane. Stirring is continued at ambient temperature for 2 hours. The mixture is concentrated under reduced pressure and the residue is taken up in dichloromethane and a saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is separated and is extracted twice with ethyl acetate. The combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulphate, and the filtrate is concentrated under reduced pressure.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:31])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([CH3:28])([C:24](=[O:27])[NH:25][CH3:26])[CH3:23])[CH:16]=1)[C:11]([CH3:30])([CH3:29])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:31][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([CH3:28])([C:24](=[O:27])[NH:25][CH3:26])[CH3:23])[CH:16]=1)[C:11]([CH3:30])([CH3:29])[CH2:10]2
Reactant: CNC(=O)C(C)(C)Nc1cccc(C2Nc3c(cc(Cl)cc3C(=O)OC)CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3c(cc(Cl)cc3C(=O)O)CC2(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
A mixture of 6-chloro-3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (75 mg, 0.17 mmol), lithium hydroxide hydrate (71 mg, 1.7 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (24 mg, 33%) as a white solid: LC/MS m/e calcd for C23H28ClN3O3 (M+H)+: 430.95, observed: 430.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:26]1[C:36]2[C:35](=[C:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]3)[C:34]3[CH:48]=[CH:49][CH:50]=[CH:51][C:33]=3[CH2:32][S:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[CH:26]1[C:36]2[C:35](=[C:37]3[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:41][CH2:42]3)[C:34]3[CH:48]=[CH:49][CH:50]=[CH:51][C:33]=3[CH2:32][S:31][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)CCCCc1cccnc1
Reactant: NCCCCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(CCCCc1cccnc1)NCCCCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1

Procedure:
Batch size: 1.6 g (9.0 mmol) 5-(3-pyridyl)-pentanic acid, 1.6 g (9.9 mmol) CDI and 3.0 g (8.2 mmol) 4-[4-(6,11-dihydro-dibenzo-[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), benzyl bromide (4.29 ml), potassium carbonate (6.24 g) and acetone (50 ml) was stirred at room temperature for 16 hours. After the reaction mixture was evaporated under reduced pressure to remove the solvent, water (200 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-benzyloxybenzoic acid (5.10 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH2:32][CH3:33])[NH:26][C:27]=1[C:28]([OH:30])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH2:32][CH3:33])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CCCc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 64.4 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-propyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.062 g, 0.20 mmol), 4-chloro-2-propyl-1H-imidazole-5-carboxylic acid (0.038 g, 0.20 mmol), HATU (0.091 g, 0.24 mmol), DIPEA (0.042 mL, 0.24 mmol) and DMF (2 mL). Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.062 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1H), 8.12 (br. s., 1H), 7.81-7.84 (m, 1H), 7.45-7.52 (m, 3H), 7.37 (t, 1H), 4.53 (d, 2H), 2.55 (t, 2H), 1.64 (sex, 2H), 0.87 (t, 3H). ES-LCMS: m/z 481.0, 483.0 (M+1).
Reaction SMILES: COC1C=CC([N:9]2[CH2:13][C@H:12]([CH2:14][CH2:15][CH3:16])[N:11]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)=[O:19])[C:10]2=[O:31])=CC=1.[N+]([O-])([O-])=O.[Ce].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[O:31]=[C:10]1[NH:9][CH2:13][C@H:12]([CH2:14][CH2:15][CH3:16])[N:11]1[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1)=[O:19]
Reactant: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: O
Product: CCC[C@H]1CNC(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A suspension of 2-[(5S)-3-(4-methoxyphenyl)-2-oxo-5-propylimidazolidin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (137 mg) in acetonitrile (3 mL) was cooled in ice, and a solution of ammonium cerium nitrate (340 mg) in water (3 mL) was added dropwise thereto. After stirring the mixture at room temperature for 2 hr, an additional solution of ammonium cerium nitrate (100 mg) in water (0.5 mL) was added thereto, and the mixture was stirred at room temperature for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added thereto, the resulting mixture was extracted with ethyl acetate, and then the organic layer was washed with brine, followed by drying over anhydrous magnesium sulfate. After the dissicant was filterred off, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=98:2-80:20) to afford the title compound (76 mg). (ESI pos.) m/z: 331 ([M+H]+)
Reaction SMILES: CN([P:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)C.[ClH:19]>>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([P:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[Cl:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(P(c2ccc(C)cc2)N(C)C)cc1
Reactant: Cl
Product: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][CH2:18][NH2:21])[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NCCN)ncc1[N+](=O)[O-]

Procedure:
To 2-chloro-4-methyl-5-nitro-pyridine (250 mg, 1.45 mmol) was added potassium carbonate (320 mg, 2.32 mmol) followed by ethylenediamine (4.2 g, 70 mmol). The mixture turned hot and was filtered after cooling through kieselguhr. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, gradient of 1 to 10% methanol containing 7N ammonia in DCM) to yield 205 mg (1.04 mmol, 72%) MS(ESI) m/z=197.1 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC
Agent: Cl
Product: COc1ccc(C(CN)CP(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 4.6 g of ethyl 3-amino-2-(4-methoxyphenyl)propyl(diethoxymethyl)phosphinate in 30 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 hour. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-methoxyphenyl)propylphosphonous acid (1/2M H2O), m.p. 260°-265° C., 31P=+24.5 ppm (D2O).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2>C(O)(=O)C>[Br:1][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([F:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1c2ccc(F)cc2CC1Br
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Bromine (1.98 mL) was added to a solution of 5-fluoroindanone (5.53 g) in acetic acid (100 mL), and the reaction solution was stirred at 60° C. for 10 minutes. After allowing the reaction solution to be cooled to room temperature, the solvent was evaporated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 8.43 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]=[C:22]=[O:23])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]1[O:10][C:22](=[O:23])[N:21]([C:19]2[CH:18]=[CH:17][C:16]3[O:11][CH2:12][CH2:13][O:14][C:15]=3[CH:20]=2)[CH2:2]1)[CH3:9]
Reactant: CCOC(=O)C[C@@H](O)CCl
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Solvent: c1ccccc1
Product: CCOC(=O)C[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Yield: 90 %

Procedure:
A solution of ethyl (R)-4-chloro-3-hydroxybutyrate (5.0 g, 30 mmol) and 2,3-dihydro-1,4-benzodioxin-6-yl isocyanate (5.3 g, 30 mmol) in benzene (150 ml) was stirred at 80° C. for 48 h. The reaction mixture was concentrated in vacuo, taken up in EA and washed twice with brine. The org. layer was dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hept/EA 9:1 to 1:1) to give the desired carbamate (8.3 g, 81% yield) as a yellow oil. This intermediate was dissolved in DMF (40 ml) and treated with K2CO3 (3.3 g, 24 mmol). The heterogeneous mixture was stirred at rt for 20 h, water was added and the mixture extracted with EA. The org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (Hept/EA 2:1, 1:1) to give the desired oxazolidinone (0.96 g, 13% yield) as an orange solid.