Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[C:4]([C:11]2[N:16]=[C:15]3[N:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[C:14]3=[N:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].CO.CC[O:38]C(C)=O>OS(O)(=O)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[C:4]([C:11]2[N:16]=[C:15]3[N:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=4)[C:14]3=[N:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]([NH2:9])=[O:38]
Reactant: N#Cc1cnc(-c2cnc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC(=O)c1cnc(-c2cnc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dissolve 5-(trifluoromethyl)-6-(8-(5-(trifluoromethyl)pyridin-2-ylamino)pyrido[2,3-b]pyrazin-3-yl)nicotinonitrile (25 mg, 0.0542 mmol) in 1 mL of conc. H2SO4 and stir at 25° C. for 20 hours under N2 atmosphere. Monitor the reaction by TLC (1% MeOH/EtOAc) and LC/MS for the disappearance of starting material. Quench the reaction mixture with ice (5 g), adjust the pH to 9.0 using 10.0 N aq. NaOH, extract the aq. layer with EtOAc (3×5.0 ml) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum. Purify by column chromatography using 1% MeOH/EtOAc as eluent to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.4 (s, 1H), 9.36 (d, 1H, J=0.6 Hz), 9.18 (s, 1H), 9.09 (d, 1H, J=1.4 Hz), 8.95 (d, 1H, J=1.3 Hz), 8.73 (s, 1H), 8.70(d, 1H, J=0.5 Hz), 7.89 (dd, 1H), 7.13 (d, 1H, J=2.2 Hz). MS=480.01 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]1[C:16](=[O:17])[N:12]([CH3:11])[C:13](=[O:18])[CH2:14]1
Reactant: CN1C(=O)C=CC1=O
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Yield: 74.7 %

Procedure:
To a solution of 5-bromoindole (5 g, 25.5 mmol) in glacial acetic acid (60 mL) was added N-methylmaleimide (6.1 g, 56.11 mmol) and the resulting mixture was heated to reflux for 4 days. The acetic acid was removed by distillation and the crude product was dissolved in diethyl ether (500 mL) and washed with saturated sodium bicarbonate (2×100 mL) and brine (3×100 mL). The solvent was evaporated and the residue chromatographed on silica gel using hexane/ethyl acetate (1:1) as the eluent to provide 3-(5-bromo-1H-indol-3-yl)-N-methylsuccinimide (5.85 g, 75%). Yellow solid, mp 194-195° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BH4-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-n2cc(C=O)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2cc(CO)cn2)cc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a solution of 1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbaldehyde (2.0 g, 8.0 mmol, 1.00 equiv) in methanol (10 mL) was added sodium borohydride (0.3 g, 8.0 mmol, 1.0 equiv) in one portion. After 30 min at rt, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (sodium sulfate) and concentrated affording [1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methanol (1.8 g). LCMS: (MH)+=253.1 (0.91 min).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:8]>>[Cl:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]2[C:11]=1[C:6](=[O:2])[C:7](=[O:8])[NH:9]2
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1cccc(Cl)c1
Product: O=C1Nc2cccc(Cl)c2C1=O
Temperature: 90 °C

Procedure:
To 775 ml of concentrated sulfuric acid, preheated to 70° C., was added, with stirring, 136 g of isonitroso-3-chloroacetanilide at such a rate as to maintain the reaction medium at a temperature between 75° and 85° C. When all the solid had been added, the reaction mixture was heated at 90° C. for an additional 30 minutes. The reaction mixture was then cooled, and poured slowly onto ca 2 liters of ice, with stirring. Additional ice was added as necessary to maintain the temperature below room temperature. A red-orange precipitate formed which was recovered by filtration, washed with water and dried. The resultant solid was slurried in 2 liters of water, and then it was brought into solution by the addition of ca 700 ml of 3 N sodium hydroxide. The solution was filtered, and then pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added. The solid which precipitated was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatin had been recovered was further acidified to pH 0 using concentrated hydrochloric acid, whereupon a further precipitate formed. It was recovered by filtration, washed with water and dried, to give 43 g of crude 6-chloroisatin.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:22]=[C:23]([C:30]#[N:31])[CH:24]=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:19]=2)[CH:26]=1)[C:30]#[N:31]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-fluoro-3-cyanobenzeneboronic acid generally according to the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.18 (s, 1H), 8.09 (s, 1H), 7.96 (dt, J=9.8, 2.4 Hz, 1H), 7.80 (dt, J=8.3, 1.5 Hz, 1H), 7.76 (dd, J=8.3, 2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.55 (dd, J=5.4, 1.5 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.99 (dd, J=4.9, 3.4 Hz, 1H), 6.89 (dd, J=3.4, 1.5 Hz, 1H), 4.17 (d, J=16.1 Hz, 1H), 4.04 (d, J=16.1 Hz, 1H), 2.12 (s, 3H); MS (ES) m/z 379 (M+H)+.
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=O)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].O.[NH2:32][NH2:33]>O1CCOCC1>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:33][N:32]=2)[C:9]=1[F:25])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2cccnc2F)c1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncccc23)c1F

Procedure:
[4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (159 g, 429.2 mmol) was dissolved in dioxane (1.6 L) and calcium carbonate (85.91 g, 858.4 mmol) was added. The reaction was in an ice bath and hydrazine hydrate (107.4 g, 104.4 mL, 2.146 mol) was added dropwise over 30 minutes. The resultant mixture was stirred overnight, after which time the thick suspension became a heterogeneous red solution. The reaction mixture was filtered through a pad of Celite, washing copiously with EtOAc/MeOH 7:1 (2×500 mL) and a small amount of water (100 mL). The filtrate was partitioned between EtOAc (1 L) and water (500 ml). The organic phase was washed with a sat aq NaHCO3 (500 mL). The combined aqueous layers were back-extracted with EtOAc (2×200 ml) and the combined organics were washed with brine (400 ml), dried over MgSO4 and filtered and concentrated to an orange solid. The solid was triturated with dichloromethane and filtered, washing with dichloromethane and petrol. This gave the title compound as an off-white solid. (103.8 g). The filtrate was concentrated under reduced pressure. The resulting solid was again triturated and filtered, washing with more petrol to give an off-white solid (36.7 g). The title compound was obtained as an off-white solid (total weight 140.5 g, 90%); 1H NMR (CDCl3) 0.55 (6H, s), 1.02 (9H, s), 7.21 (1H, m), 8.69 (1H, m), 8.91 (1H, s), 11.69 (1H, brs); MS ES (+) 365.18 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1Br.[Cu][C:16]#[N:17]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[C:16]#[N:17]
Reactant: COC(=O)Cc1ccc(OC)cc1Br
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(OC)cc1C#N
Temperature: 170 °C
Yield: 75.9 %

Procedure:
To a microwave vial was added (2-bromo-4-methoxy-phenyl)-acetic acid methyl ester (200 mg, 0.77 mmol), copper (I) cyanide (138 mg, 1.54 mmol), a stir bar and 1 mL of N-methyl-pyrrolidinone. The vial was capped and heated at 170° C. for 15 minutes in a microwave reactor. The resulting dark solution was purified directly on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g column using a 0-20% MeOH in dichloromethane gradient. The desired product eluted in 100% dichloromethane to give 120 mg (76%) of (2-cyano-4-methoxy-phenyl)-acetic acid methyl ester as an orange oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37]>C(Cl)Cl>[O:1]([CH2:8][C:9]([N:11]([CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16]([CH3:18])([CH3:19])[S:17][C@H:13]12)[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N(C(=O)COc3ccccc3)C(=O)OCC(Cl)(Cl)Cl)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 4.855 gms. (10 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate, 16.94 gms. (80 mmol.) of 2,2,2-trichloroethyl chloroformate, 18 ml. of N,O-(bis-trimethylsilyl)trifluoromethylacetamide, and 20 ml. of methylene chloride was prepared. The mixture was permitted to stand at room temperature overnight. The mixture then was heated at reflux for 7 hours after which it was again permitted to stand at room temperature overnight. Heating then was continued for an additional 6 hours. The mixture then was evaporated to a residue, and the residue was dissolved in benzene which then was added to a large excess of heptane. The resulting insoluble material was filtered off, dissolved in benzene, and chromatographed over silica gel using a benzene-ethyl acetate elution gradient. p-Nitrobenzyl 6-[N-(phenoxyacetyl)-N-(2,2,2-trichloroethoxycarbonyl)amino]-2,2-dimethylpenam-3-carboxylate (4.76 gms.; 72 percent) was obtained as product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:20].[C:21]([CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:23])[CH3:22].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[C:21]([CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:20])[CH2:27]1)(=[O:23])[CH3:22]
Reactant: CC(=O)CNC1CCNC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(N3CCC(NCC(C)=O)C3)c(F)cc2c1=O
Yield: 86.7 %

Procedure:
A mixture containing ethyl 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (2.99 g), 3-(N-acetylmethylamino)pyrrolidine (2.13 g), triethylamine (1.52 g), and chloroform (30 ml) was heated to reflux for 4 hours with stirring. After cooling the mixture, 5% hydrochloric acid (20 ml) was added with stirring. The chloroform layer was separated off and the solvent was evaporated. To the residue was added 20 ml of acetonitrile and the mixture was cooled. The resulting precipitate was collected and recrystallized from acetonitrile to give 3.51 g of ethyl 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 212°-213° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)nc1

Procedure:
To a solution of 2-(6-chloropyridin-3-yl)acetic acid (2 g, 117 mmol) in methanol (40 ml) was added SOCl2 (1.38 g, 117 mmol). The reaction mixture was concentrated after two hours to give the desired product. LC-MS: m/z (M+H)=186.6
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[S:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NC(=S)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
To a solution of 4-cyanophenyl isothiocyanate (1.00 g, 6.24 mmol) in THF (25 mL) at room temperature was added a solution of tert-butylamine (1.31 mL, 12.5 mmol) and the reaction was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.37 g (94%) of 1-(4-cyanophenyl)-3-(tert-butyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)(CC)C>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=c1cc(Cl)nc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of 6-chloro-3H-pyrimidin-4-one (˜0.23 mol) in sec-butanol (525 mL) was added ethyldiisopropylamine (49.7 mL, 0.3 mol) and BOC-piperazine (available from Aldrich; 55.9 g, 0.3 mol). The reaction was stirred at 80° C. for 8 hours, and then allowed to cool to room temperature. The crude reaction mixture was filtered, and washed with sec-butanol to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester (47.8 g, 74%) LCMS Purity=100% (Rt=1.42). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 5.34 (s, 1H), 3.56-3.46 (m, 4H), 3.46-3.38 (m, 4H), 1.38 (s, 9H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C@@H:7]2[CH2:6][N:5]([CH3:19])[C@H:4]([C:1]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)=[O:3])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
700 mg of N,N'-carbonyldiimidazole were added to a suspension of 1.0 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine in 15 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 30 minutes. At the end of this time, the reaction mixture was ice-cooled, and 440 μl of N-methylpiperazine were added to the mixture. The temperature was then allowed to rise to room temperature over a period of 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography using LiChroprep RP-8 (trade mark) as stationary phase and 70% v/v aqueous methanol as the eluent, to give 1060 mg of the title compound as an oil.
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1C=CC(C=O)=CC=1>>[CH:10](=[O:9])[C:3]1[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: [Na]
Product: O=Cc1ccccc1O
Yield: 32 %

Procedure:
The phenol aldehyde mixture is in a form combined with sodium. It is neutralized and acidified to a pH of 5. Thereupon the salicylaldehyde is recovered by the conventional carrier vapor distillation of the aqueous phases (following methanol recovery). A yield of 32% (3.9 g) of salicylaldehyde and of 27% (3.2 g) in p-hydroxybenzaldehyde relative to the initial phenol are obtained.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Yield: 83.9 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino)acetate are suspended in 27 ml of methanol, and 4.9 ml of 2N sodium hydroxide solution are added thereto. The mixture is refluxed for 20 minutes under heating. After cooling, the mixture is concentrated under reduced pressure to remove methanol. The residue is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove solvent. Then, the residue thus obtained is crystallized with ether and collected by filtration. 2.15 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[N:14]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13])=[N+:15]=[N-:16]
Reactant: CCOC(=O)N1CCC(Br)C(O)C1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (5.1 g) was dissolved in anhydrous DMF (20 mL) under an argon atmosphere, followed by the addition of 18-crown-6 (0.27 g) and sodium azide (2.89 g). The reaction was heated at 90° C. for twenty-three hours, then stirred overnight, slowly cooling to room temperature. The reaction was then added to deionised water (150 mL) to quench it, saturated with solid sodium chloride, and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo, yielding the title compound (4.3 g, 100%). MS (GC-EI)[(M-N2)+]: 186 for C8H14BrN4O3.
Reaction SMILES: [C:1]1([S:7]([CH2:9]P(=O)(OCC)OCC)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH:9]=[C:32]([C:27]2[CH:28]=[C:29]([Cl:31])[CH:30]=[C:25]([Cl:24])[CH:26]=2)[C:33]([F:36])([F:35])[F:34])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CS(=O)c1ccccc1)OCC
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Diethyl [(phenylsulfinyl)methyl]phosphonate (5.00 g, 96% purity, 17.4 mmol) was dissolved in toluene (20 mL) and cooled to 0° C. To the solution potassium tert-butoxide (2.05 g, 18.2 mmol) was added in one portion. This solution was added over 45 minutes to a solution of 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone (4.26 g, 99% purity, 17.4 mmol) in toluene at 0° C. The reaction mixture was stirred for additional 15 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was poured onto hydrochloric acid (3.6%) and the phases were separated. The aqueous phase was extracted with toluene and the combined organic phases were washed with water, dried over sodium sulfate and the solvents evaporated. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide was obtained (6.26 g, 94% purity, 93% yield, E/Z=38/62).
Reaction SMILES: C([N:8]([CH2:32][C@H:33]([OH:54])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42]CC2C=CC=CC=2)=[C:38]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:37]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][CH2:32][C@H:33]([OH:54])[CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:37]=4)[CH2:14][CH2:13]3)=[CH:31][CH:30]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1O
Reaction time: 48 h

Procedure:
A mixture of 0.166 g of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N-(4-fluorobenzyl)benzamide (0.226 mmol) and of 0.117 g of 10% palladium-on-charcoal (50% in water) in a mixture of ethanol (5.3 ml) and tetrahydrofuran (4.02 ml) is placed under a hydrogen atmosphere and stirred for 48 hours. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.92 g, 52%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).