Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.0 g of 1-(2,4-dimethoxy-benzyl)-2,3-dioxopiperazine, 1.66 g of sodium hydride (60%, oil) and 100 ml of N,N-dimethylformamide was stirred at 50° C. for 30 minutes and then cooled to room temperature. To the reaction mixture was added 3.6 ml of methyl bromoacetate, after which the resulting mixture was stirred at the same temperature for 30 minutes and added to a mixed solvent of 200 ml of ethyl acetate and 200 ml of ice water, and the pH was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layer was washed with 50 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=10:1) to obtain 10.7 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]S(C)(=O)=O)[CH:18]=[CH:17][C:16]=2[F:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[F:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2F)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2F)C(=O)C1

Procedure:
A solution of product from Step C (3.88 g, 9.65 mmol), potassium t-butoxide (2.16 g, 19.3 mmol) in ethanol (100 mL) and H2O (5 mL) was heated at reflux for 3 hours. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with H2O, and brine and then dried over magnesium sulfate and concentrated in vacuo to give title product which was sufficiently pure for use in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].F[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[O:10][C:16]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:17]=2[C:18](=[O:19])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)oc2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105° C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116–120.1° C. 1H NMR (CDCl3/300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14H8F6O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
Reaction SMILES: CO[C:3]1[C:4]([N:53]=[C:54]=[O:55])=[C:5]([CH:32]=[CH:33][C:34]=1C1C2N=C(CNC(OC(C)(C)C)=O)NC=2C=CC=1)[C:6]([N:8](C)C1C=CC(C)=CC=1OCCCCCC(N1CCC(=O)CC1)=O)=[O:7].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[C:54](=[N:53][C:4]1[CH:3]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH2:8])=[O:7])=[O:55]
Reactant: COc1c(-c2cccc3[nH]c(CNC(=O)OC(C)(C)C)nc23)ccc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)c1N=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1N=C=O
Reaction time: 1 h
Yield: 464.3 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]-carbonylaminobenzamide (150 mg) in methanol (5 ml) was added sodium borohydride (7.52 mg) under an ice bath cooling and the mixture was stirred at the same temperature for 1 hour. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-[2-[5-(4-hydroxypiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]-3-methoxy-N-methyl-4-[2-tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:10]1([CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)[CH2:22][C:21]2=[O:23]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of (±)-6-bromo-4-oxo-spiro(chromane-2,3′-piperidine)-1′-carboxylic acid tert-butyl ester (6.0 g, 15.19 mmol), Pd(OAc)2 (68.1 mg, 0.304 mmol), P(o-tol)3 (184.7 mg, 0.608 mmol), TEA (6.33 ml, 45.6 mmol), methyl acrylate (4.10 ml, 45.57 mmol) in dry DMF (15 ml) was heated under N2 atmosphere to 100° C. for 3 h. After cooling down to RT, the solution was filtered on a celite pad and washed 3 times with EtOAc (100 ml). The filtrate was washed with water and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 8:2 to 7:3) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (6.0 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[Br:42][CH2:43][CH2:44][CH2:45][CH2:46]Br>C1COCC1>[Br:42][CH2:43][CH2:44][CH2:45][CH2:46][C:7]1[N:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:9]2[C:5]([N:6]=1)=[C:4]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: BrCCCCBr
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(CCCCBr)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (Example 118) (5.0 g, 15 mmol) and N,N,N′,N′-tetramethylethylenediamine (3.5 mL, 23 mmol) in THF (110 mL) was cooled to −42° C. and treated with a solution of 2.5M n-Butyllithium in hexane (22 mL, 54 mmol) drop-wise over 5 minutes. After 30 minutes at −42° C., 1,4-dibromo-butane (8.9 mL, 75 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr and then warmed to ambient temperature for 90 minutes. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(8-(4-bromobutyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine as a white solid (1.1 g, 15%). LC/MS (ESI+): m/z 459 (M+H)
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[O:9]C)[CH3:3].ClCl.[OH-].[Na+]>CO.O>[CH3:3][C:2]1[O:1][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:5]
Reactant: COc1ccoc1C(C)O
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 90 °C

Procedure:
2-(1-hydroxyethyl)-3-methoxy-furan (0.350 g, 2.5 mmole) in 4 ml of methanol and 1 ml of water was added to a solution of 2 ml of methanol and 5 ml of water as chlorine gas (2.5 mmoles) was added to the well stirred reaction. The temperature of the reaction was kept below -10° C. at all times. Following the addition the reaction was heated to 90° C. for 3 hours. After cooling, the reaction was adjusted to a pH 2.2 with 50% NaOH solution, the reaction was extracted with chloroform and the chloroform concentrated to yield maltol.
Reaction SMILES: [OH:1][CH:2](CC#N)[CH2:3][C:4]#[N:5].CC[O:11][C:12]([CH3:14])=[O:13].Cl>N#N>[OH:1][C@H:2]([CH2:3][C:4]#[N:5])[CH2:14][C:12]([OH:11])=[O:13]
Reactant: N#CCC(O)CC#N
Reactant: CCOC(C)=O
Agent: Cl
Agent: N#N
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 22 h

Procedure:
3-hydroxyglutaronitrile (1 g, 9 mmol) was suspended in 37.5 mL of N2 (g) sparged, room temperature, 100 mM sodium phosphate buffer at pH 7. To this 240 mM solution of HGN was added 150 mg of cell lysate normalized for protein content. As assessed by PAGE, the nitrilase content was established to be 20% of the total protein. Therefore effectively, 30 mg of nitrilase is used in this reaction. The reaction was agitated at 100 rpm. Reaction progress was monitored by TLC (1:1 EtOAc:Hexanes, Rf=0.32, nitrile; Rf=0.0, acid) and GC. After 22 h, the reaction was filtered through a 10,000 MW cutoff filter and then concentrated in vacuo. The concentrated hydrolysis solution was acidified with 1M HCl and the product was continuously extracted with MTBE (30 mL). The acid product (R)-3-hydroxy-4-cyanobutyric acid was isolated as a yellow oil (1.15 g, 98% yield). 1H NMR (d6-DMSO, 500 MHz) δ12.32 (s, 1H), 5.52 (s, 1H), 4.10 (m, 1H), 2.70 (dd, 1H, J=16.8, 4.1 Hz), 2.61 (dd, 1H, J=16.9, 6.3 Hz), 2.44 (dd, 1H, J=15.4, 5.3 Hz), 2.37 (dd, 1H, J=15.6, 7.8 Hz). 13C NMR (DMSO, 298K, 125 MHz) δ171.9, 118.7, 63.4, 41.2, 25.2 MS calc'd for [C5H7NO3]: 129.0, found: 130.0 [M+H+], (ESI+). ee=95% [HPLC]. Based on the isolated yield a productivity of 40 g g−1 d−1 is calculated.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>ClCCl>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)=[O:23]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (5.75 g, 0.05 moles) in dry dichloromethane (50 ml) was added dropwise with stirring to N-[2-(3-amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (13.1 g, 0.05 moles) and triethylamine (10.1 g, 7.5 ml, 0.1 mole) in dry dichloromethane (250 ml). Stirring was continued at 20° for 18 hr and the solution was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried and evaporated. The residue on recrystallisation from benzene gave the sub-title compound (15.9 g) as ivory-coloured plates mp 129°-130°.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH3:26]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH3:26])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CNCCOC
Product: COCCN(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and (2-methoxy-ethyl)-methyl-amine (276 mg; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (61 mg, 59%) as an off-white powder. ES-HRMS m/e calcd for C19H31N4O2 (M+H+) 347.2442, found 347.2438.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27](O)=O)[CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cccc2cccnc12
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc3cccnc23)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using quinoline-8-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 160 mg, 49%) which was obtained as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: C([C:4]1[NH:16][C:15]2[C:14](=[O:17])[N:9]([CH2:10]C(O)=O)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[N:5]=1)CC.ON1C(=O)CCC1=O.O>CN(C=O)C>[N:9]1([C:14](=[O:17])[C:15]2[NH:16][CH:4]=[N:5][C:6]=2[N:7]([CH3:19])[C:8]1=[O:18])[CH3:10]
Reactant: CCCc1nc2c([nH]1)c(=O)n(CC(=O)O)c(=O)n2C
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mg of 8-propylcarboxytheophylline was dissolved in 1 ml of DMF, and added with 3 mg of N-hydroxysuccinimide and 5 mg of water-soluble carbodiimide, followed by stirring at room temperature for 2 hours, to obtain activated theophylline. 10 mg of bovine serum albumin (BSA) was dissolved in 1 ml of a 0.1M aqueous solution of sodium hydrogencarbonate and added with 500 μl of the aforementioned activated theophylline solution. The mixed solution was allowed to stand at room temperature for an hour, and then unreacted substances were removed through a SEPHADEX G-25 (produced by Pharmacia Co.) column preliminarily equilibrated with PBS to obtain 9 mg of the objective large molecule antigen (theophylline-BSA conjugate)
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][NH2:15])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)/[CH3:27])[CH:25]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 41.8 %

Procedure:
3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (105 mg, 0.390 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (66.5 mg, 0.390 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (70 mg, 0.163 mmol, 41.7% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.18 (m, 1H), 8.13 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.41 (m, 1H), 7.21 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.23 (m, 4H), 2.39 (s, 3H), 1.75 (m, 4H). Mass [M+H]+:422.1
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:11][C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][C:13]1=[O:19]>>[CH3:11][C:12]1([CH3:20])[C:13]2[O:19][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:14]=2[C:15](=[O:18])[CH2:16][CH2:17]1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=C(CO)c1ccccc1
Product: CC1(C)CCC(=O)c2c(-c3ccccc3)coc21

Procedure:
The subtitle compound was prepared according to the procedure of example 2 using hydroxyacetophenone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step1.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:19][CH:20]([SH:22])[CH3:21]>CN(C=O)C>[CH:20]([S:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:21])[CH3:19]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C=O
Temperature: 55 °C

Procedure:
2-chloro-5-nitrobenzaldehyde (2.99 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and propane-2-thiol (1.35 g, 17.7 mmol) were dissolved in 10.0 ml, DMF in a 50 mL, round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 24 h. After cooling the mixture was added to 150 mL of saturated potassium carbonate solution. The yellow-brown solid was filtered, washed with water and further purified by chromatography on silica gel using 10:1 petroleum ether 60-80 and ether as eluent. Yield: 1.81 g, 50%, yellow solid. 1H NMR (200 MHz, CDCl3): δ 1.46 (d, J=6.9 Hz, 6H), 3.67 (septet, J=6.9 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 8.32 (dd, J=2.5, 8.7 Hz, 1H), 8.66 (d, J=2.5 Hz, 1H), 10.3 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ 22.5, 36.6, 127.2, 127.4, 127.9, 133.4, 144.7, 150.8, 189.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=1)=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)Nc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O

Procedure:
A mixture comprising (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid tert-butyl ester (Intermediate L) (226.7 mg, 0.82 mmol), 2-bromo-N-(2,6-dichloro-pyridine-4-yl)-acetamide (Intermediate N) (256.5 mg, 0.902 mmol) and Cs2CO3 (545.1 mg, 1.64 mmol) in DMF (5 ml) is stirred at RT for 3 hours. The resulting mixture is treated with water and the precipitate is filtered under vacuum. The solid is washed with water, iso-hexane and then dried to give the title compound, [M+H]+ 479
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.[CH3:14][C:15]([CH3:17])=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[CH:15]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1)([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: COc1cccc2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc2c1C[C@@H](NC(C)C)CO2
Reaction time: 72 h

Procedure:
(R)-3-Amino-5-methoxychroman (1.0 g; 6mmol) and acetone (2.5 g; 40 mmol) were mixed with methanol (820 ml), acetic acid (0.4 g; 6.6 mmol) and NaCNBH3 (1.2 g; 19 mmol), pH was adjusted to 6.0 with acetic acid. Stirring was continued at room temperature for 3 days. The mixture was evaporated and the residue was made alkaline and extracted with CH2Cl2. After drying (Na2SO4) and evaporation the title compound as base was transformed to the HCl-salt. Yield: 1.1 g (83%). Mp: 289° dec. [α]D25 =-29° (C=0.015; MeOH)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22]C=C)[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:52])([F:25])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:46])([F:47])[F:45])[C:30]([OH:32])=[O:31])[C@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1
Product: C[C@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@H]1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman resolved as Peak 1 in Example 17 and the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared in Example 3, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]([O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5].[C:15]1([C:21]2[NH:22][C:23](=[S:32])[O:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[N:22]=[C:23]([S:32][CH2:3][C:4]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[O:5])[O:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: S=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C(CCl)OCCN1CCOCC1
Agent: Cl
Product: O=C(CSc1nc(-c2ccccc2)c(-c2ccccc2)o1)OCCN1CCOCC1

Procedure:
A 7.3 g aliquot of the thus prepared 2-morpholinoethyl chloroacetate hydrochloride was then reacted according to the procedure of Example 1 with 7.6 g 4,5-diphenyl-4-oxazolin-2-thione to give 2.4 g of the title compound.