Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([OH:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.CO.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([OH:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 84 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.5 g), methanol (17.5 ml), conc.hydrochloric acid (0.88 g) and tetrahydrofuran (5.0 ml) was stirred for 1.5 hours at room temperature. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate so that the pH was adjusted to pH 5.0. The resulting mixture was evaporated and to the residue was added ethyl acetate. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and evaporated and then the residue was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water, dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.00 g). mp. 152° to 157° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[N:36]=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=[CH:33]4)=[CH:26][CH:25]=2)=[C:20]([CH:44]([CH3:46])[CH3:45])[O:19][N:18]=1)C(=O)C(F)(F)F.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][CH2:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[N:36]=[C:35]([C:40]([OH:42])=[O:41])[CH:34]=[CH:33]4)=[CH:26][CH:25]=2)=[C:20]([CH:44]([CH3:46])[CH3:45])[O:19][N:18]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CN(C(=O)C(F)(F)F)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(CNc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
To a solution of methyl 6-[4-({[3-{[(2,6-dichlorophenyl)(trifluoroacetyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (10 mg, 0.015 mmol) in 1:1 tetrahydrofuran:methanol (0.75 mL) was added 1 N sodium hydroxide (0.37 mL, 0.37 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was concentrated and the residue was taken up with ethyl acetate. Then 1 N hydrochloric acid (0.37 mL, 0.37 mmol) was added followed by water. The layers were separated and the aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (8 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 8.46 (d, J=9 Hz, 1H), 8.31-8.24 (m, 2H), 8.11-8.07 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=9 Hz, 2H), 6.84-6.80 (m, 1H), 4.96 (s, 2H), 4.60 (s, 2H), 3.24 (septet, J=7 Hz, 1H), 1.36 (d, J=7 Hz, 6H). HRMS (ESI) C30H25Cl2N3O4 calculated: 562.1300 (M+H)+, found: 562.1292 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:20])[OH:19]>CN(C)C=O>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:20])[OH:19]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OB(O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OB(O)CCCCn1cnc2c(Cl)ncnc21
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Sodium hydride (0.22 g, 7.2 mmol) was added to a solution of 6-chloropurine (0.93 g, 6.0 mmol) in dimethylformamide (20 mL) and stirred for 10 minutes. 4-Bromobutyl boronic acid (1.1 g, 6.0 mmol) in dimethylformamide (5 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. After the removal of the dimethylformamide under high vacuum, the residue was purified by column chromatography (chloroform/methanol discontinuous gradient 95:5, 9:1) to yield 0.78 g of pure product. Yield 51%; mp 135°-138° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.22-1.35 (m, B CH2 CH2), 1.78-1.91 (m, B CH2 CH2 CH2), 4.26-4.32 (t, CH2 CH2 N), 7.40-7.42 (s, (HO)2 B), 8.68-8.70 (s, H C8 purine), 8.80-8.81 (s, H C2 purine). Elemental Analysis. (C9H12BO2N4Cl); Calcd. C, 42.47%; H, 4.75%; N, 22.02%; Found C, 42.48%; H, 4.80%; N, 22.06%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC([O-])(C)C.[K+].C1COCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2nnc3ccccc32)cc1F
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of benzotriazole (1.2 g, 10.1 mmol) in DMF (40 mL) at r.t. was added a solution of 1M t-BuOK in THF (11 mL, 11 mmol). After stirring for 30 min., 3,4-difluorobenzyl bromide (2.4 g, 11.6 mmol) was added. The mixture was further stirred for 1 h, diluted with H2O, extracted with EtOAc. The EtOAc extract was washed H2O (3×), dried (MgSO4) and concentrated. The residue was chromatographed over silica gel and eluted with hexanes:EtOAc (3:1), then (2:1) to afford 1.6 g (65%) of title compound as a white solid.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[CH:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH:17]1C=CC=CC=1>CS(O)(=O)=O>[CH2:7]([CH:17]=[N+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O-:6])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)NO
Reactant: c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CS(=O)(=O)O
Product: COc1ccc(CC=[N+]([O-])C(C)(C)C)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of t-butylhydroxylamine (1.0 g, 11 mmole) and p-anisaldehyde (1.5 g, 11 mmole) in 20 mL of benzene was refluxed through a Dean-Stark trap for 18 hours. One drop of methanesulfonic acid was then added and refluxing was continued for an additional two hours. The reaction mixture was then washed with saturated aqueous sodium bicarbonate and the benzene removed under reduced pressure. The residue was recrystallized from petroleum ether. Based on the method of preparation, there was obtained 0.8 g (3.9 mmole) or a 35% yield of the α-anisyl-N-t-butylnitrone having a melting point of 90°-1° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:15]([O:17]C)=[O:16].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1nc2ccc(C(F)(F)F)cn2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 10-C (0.978 g, 3.79 mmol) in MeOH (6 mL) and H2O (3 mL) was added sodium hydroxide (0.227 g, 5.68 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2N HCl to pH 4-5 and concentrated in vacuo. The resulting residue was taken up in EtOAc, and the organic layer was washed with H2O and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to give compound 10-D as a light yellow solid (0.866 g, 94%), which was used in the next reaction; MS m/z (M+H+) 245.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>O1CCCC1.O>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Yield: 96.7 %

Procedure:
To a solution of 2-amino-1,3-benzothiazol-6-ol (9.03 g, 54.3 mmol) and triethylamine (8.27 mL, 59.7 mmol) in tetrahydrofuran (100 mL) was added with stirring under ice-cooling a solution of cyclopropanecarbonyl chloride (5.19 mL, 57.0 mmol) in tetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with hexane-ethyl acetate to give the title compound (12.3 g, 97%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[CH:15]=[CH:14][NH:13][C:11]=3[N:12]=2)[CH:2]=1.[H-].[Na+].[H][H].[CH2:22](I)[CH3:23]>C(NC(C)C)(C)C.CN(C)C=O>[CH2:22]([N:13]1[C:11]2[N:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=[CH:9][C:10]=2[C:16](=[O:17])[CH:15]=[CH:14]1)[CH3:23]
Reactant: CCI
Reactant: [H][H]
Reactant: O=c1cc[nH]c2nc(-c3cccnc3)ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(=O)c2cnc(-c3cccnc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
C-2. 8-Ethyl-2-(3-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one--A mixture containing 8.7 g of 2-(3-pyridinyl)-pyrido[2,3-d]pyrimidin-5(8H)-one, 1.9 g of 50% sodium hydride in mineral oil and 250 ml of dimethylformamide was stirred at room temperature until evolution of hydrogen ceased. To the mixture was added an additional 50 ml of dimethylformamide and gentle heating was continued on a steam bath for 30 minutes. The mixture was cooled to room temperature and to it was added one drop of diisopropyl amine with stirring followed by an additional 100 mg of sodium hydride. Gentle heating with stirring was continued for another 30 minutes followed by cooling to room temperature. To the mixture was added with stirring at room temperature 6.1 g of ethyl iodide slowly in a fine stream and resulting reaction mixture was stirred at room temperature for three hours and then heated gently with stirring on a steam bath for four hours. The reaction mixture was then distilled in vacuo to remove the solvent and any other volatile materials and the residue was taken up and shaken well with a mixture of chloroform and water. The layers were separated and the chloroform layer was dried over anhydrous sodium sulfate, treated with decolorizing charcoal and filtered, and the filtrate was distilled in vacuo to remove the chloroform. The residue was dissolved in 150 ml of boiling acetonitrile: the resulting hot solution was treated with decolorizing charcoal and filtered; and, the filtrate was concentrated to a volume of 100 ml and cooled to complete precipitation of the product. The product was collected, washed successively with a small quantity of acetonitrile and n-hexane, and dried in vacuo at 65° C. to yield 6.5 g of 8-ethyl-2-(3-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 195°-196° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCCc1ccccc1
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 60.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-2-thienyl)methanol (0.0688 g, 0.225 mmol) and (3-bromopropyl)benzene (0.070 mL, 0.460 mmol) in 1MeOH/1CHCl3 (4.0 mL) were reacted to give the desired product (0.0685 g, 62.3%). ELMS m/z 424(M+) Rt (1.97 min).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]([CH2:31][CH:32]2[CH2:34][CH2:33]2)([OH:30])[CH2:26][C:27]([CH3:29])=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([N:22]2[CH2:23][CH2:24][C:25]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:26][C:27]([CH3:29])=[CH2:28])[O:30][C:2]2=[O:4])[CH3:21])=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC1(CC2CC2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (653 mg) was added to a solution of 1-[(S)-1-(4-bromophenyl)ethylamino]-3-(cyclopropylmethyl)-5-methylhex-5-en-3-ol (800 mg) and triethylamine (667 mg) in CH2Cl2 (15 mL) at 0° C. The mixture was stirred at room temperature overnight and the reaction was then quenched with water. The resulting mixture was extracted with CH2Cl2 and the combined organic layer was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to afford the title compound. Yield 670 mg (78% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=O)=[C:8]([CH3:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:22].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:35][C:34]3[CH:33]=[CH:32][C:20]([C:21](=[O:22])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)=[CH:19][C:18]=3[N:17]=2)=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: COC(=O)CNc1cc(C)c(C=O)c(C)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cc(C)c(-c2nc3cc(C(=O)Nc4ccc(C)c(C)c4)ccc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-formyl-3,5-dimethylphenylamino)-acetic acid methyl ester (800 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (694 mg) in DMSO (15 mL) was added Yb(OTf)3 (390 mg) and Cu(OTf)2 (228 mg). The solution was stirred at room temperature for 18 h then the reaction mixture was partioned between water and EtOAc The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (amino-column) using hexanes/ethyl acetate (1:4) to give {4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenylamino}-acetic acid methyl ester as a light yellow solid. MS (ESI)m/z 457 (M+H); 1H NMR (MeOD, 400 MHz) δ 8.21 (s, 1H), 7.85 (dd, 1H), 7.67 (s, 1H), 7.47 (d, 1H), 7.42 (dd, 1H), 7.12 (d, 1H), 6.42 (s, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O[Li].O>C(O)C.O>[CH2:7]([O:6][P:4]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)Cc1cccc(P(=O)(OCC)OCC)c1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCOP(=O)(OCC)c1cccc(CC(=O)O)c1
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-(3-(diethoxyphosphoryl)phenyl)acetate, 35i-c, (26 g, 86.7 mmol) and LiOH.H2O (5.5 g, 130 mmol) in ethanol (40 mL) and H2O (40 mL) was stirred overnight. The resulting mixture was concentrated and washed by ethyl acetate. The aqueous layers were adjusted to about pH 1-2 with HCl. The mixture was extracted by ethyl acetate. The combined organic layers were washed by brine, dried over Na2SO4 and concentrated to afford the title compound, 35i-d, as brown oil (19 g, 81%). 1H NMR (300 MHz, CDCl3) δ1.15-1.25 (m, 6H), 3.68 (s, 2H), 3.95-4.06 (m, 4H), 7.43-7.64 (m, 4H), 12.32 (s, 1H). LC-MS (M+H)+ 273.
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH3:27]S(C)=O>>[CH3:25][C:15]([N:26]=[C:12]([O:13][CH3:27])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccccc1C(=O)C=O
Reactant: CS(C)=O
Reactant: COc1ccc(CC(C)(C)N)cc1
Solvent: O
Product: COC(=NC(C)(C)Cc1ccc(OC)cc1)C(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
434 mg of 2-methoxyphenylglyoxal hydrate are dissolved in 0.5 ml of dimethylsulfoxide, and a solution of 427 mg of α,α-dimethyl-4-methoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 20° C. for one hour, whereby a solution of α-(α,α-dimethyl-4-methoxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([N:16]1[CH2:23][S:22][CH2:21][C@@H:17]1[C:18]([OH:20])=[O:19])(=[O:15])[CH3:14].[CH:24]1[CH:25]=[CH:26][C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.CN1CC[O:38][CH2:37]C1.CN([CH:44]=[O:45])C>>[C:13]([N:16]1[CH2:23][S:22][CH2:21][C@@H:17]1[C:18]([OH:20])=[O:19])(=[O:15])[CH3:14].[CH3:37][O:38][C:44](=[O:45])[C@:28]([CH3:27])([CH2:29][C:24]1[CH:21]=[CH:17][C:18]([OH:20])=[CH:26][CH:25]=1)[NH2:30]
Reactant: CN1CCOCC1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Agent: CC(=O)N1CSC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
EDC.HCl (760 mg, 3.96 mmol) was added to a solution of N-acetyl-D-thioproline (630 mg, 3.6 mmol), Intermediate 5 (880 mg, 3.6 mmol), HOBT (535 mg, 3.96 mmol) and NMM (834 μl, 7.6 mmol) in DMF (20 ml). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue dissolved in ethyl acetate (150 ml) and water (50 ml). The organic phase was washed with 10% citric acid (50 ml), saturated aqueous NaHCO3 (50 ml) and water (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO2, methanol/DCM, 7:93) to give the title compound as a colourless gum (680 mg, 52%); δH (DMSO-d6, 400K) 7.40 (1H, br s, CONH), 6.93 (2H, d, J 8.6 Hz, ArH), 6.68 (2H, d, J 8.3 Hz, ArH), 4.84 (1H, dd, J 3.8, 7.4 Hz, CHαthiopro), 4.78 (1H, d, J 9.2 Hz, NCHAHBS), 4.40 (1H, d, J 9.2 Hz, NCHAHBS), 3.63 (3H, S, CO2CH3), 3.30 (1H, dd, J 7.4, 11.5 Hz, CHCHAHBS), 3.16 (1H, dd, J 3.8, 11.5 Hz, CHCHAHBS), 3.13 (1H, d, J 13.7 Hz, CHAHBAr), 3.03 (1H, d, J 13.7 Hz, CHAHBAr), 2.02 (3H, s, CH3CO) and 1.38 (3H, s, CCH3); m/z (ES, 15V) 367 (M+ +1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C([O-])(O)=O.[Na+].[C:24](Cl)([Cl:26])=[O:25]>CCOCC.O.C1C=CC=CC=1>[CH3:14][N:13]([C:12]1[CH:15]=[CH:16][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:17])([F:18])[F:1])=[CH:10][CH:11]=1)[C:24]([Cl:26])=[O:25]
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CN(C(=O)Cl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 99.5 %

Procedure:
To a cold (10°) stirred mixture of 137 g (0.50 mole) 4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl aniline in 500 ml Et2O and 168 g (2.0 mole) NaHCO3 in 500 ml H2O add dropwise 500 g (0.6 mole) 12% phosgene in benzene over 1 hour. Add 500 ml Et2O, separate the organic phase, dry, concentrate and wash the residue with hexane to give 167 g white solid; m.p. 152°-154°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1.[Na]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:19][CH2:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccs1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Na]
Solvent: CCO
Product: O=C(NCCc1cccs1)C1CCN(Cc2ccccc2)CC1

Procedure:
22.15 g of ethyl 1-benzyl-4-piperidinecarboxylate and 1 equivalent of the product obtained in Step B are added to a solution of 4.12 g of sodium in 103 ml of anhydrous ethanol. After 12 hours reaction at reflux, the reaction mixture is evaporated. The residue is taken up in dichloromethane and washed with water, and then the organic phase is dried, filtered and evaporated, enabling an oil to be obtained which crystallises in diisopropyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:44])[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:41]3[CH2:42][CH2:43][CH:38]([N:37]([CH3:44])[CH3:36])[CH2:39][CH2:40]3)=[O:31])[CH:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)C)CC1
Product: Cl

Procedure:
[2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-dimethylaminopiperidine (Aldrich) in an analogous manner as described in example 25. HR-MS (ES, m/z): observed 621.2755 calculated for C35H42Cl2N4O2 [(M+H)+] 621.2758.