Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.O.P(=O)(O)(O)O.[CH3:12][C:13]1[C:18]([CH2:19]Cl)=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH2:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1CCl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Yield: 93.6 %

Procedure:
A mixture of 3,200 parts of concentrated sulfuric acid (98% strength by weight), 400 parts of water and 1,800 parts of 85 per cent strength by weight phosphoric acid is circulated in a reactor by pumping with a centrifugal pump. A solution of 1,680 parts of o-xylyl chloride and 4,680 parts of benzene is added in the course of 31/2 hours at from 75° to 77° C; an emulsion forms. A part of the emulsion is fed continuously from an overflow into a receiver. The inorganic phase is returned to the circulation system and the organic phase is distilled. 2,023 parts (93.6% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[OH-].[Na+].Br[CH2:11][CH2:12][OH:13]>C(O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][CH2:12][OH:13]
Reactant: OCCBr
Reactant: CN(C)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSCCO

Procedure:
2-(Dimethylamino)ethanethiol hydrochloride (Aldrich) is treated with NaOH (0.2N) in ethanol (95%). To this slurry, 2-bromoethanol (1.2 eq.) is added and the mixture is refluxed for 2 hours. The reaction mixture is cooled, filtered and concentrated. The resultant residue is purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:15]([CH3:18])[C:16]#[N:17].[I-].[K+]>CC(CC)=O.O>[O:7]([CH:15]([CH3:18])[C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cl)C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C#N)Oc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of phenol (18.8 g.) and anhydrous potassium carbonate (25 g.) in dry ethyl methyl ketone (35 ml.) was stirred and heated to reflux, during the dropwise addition of a solution of 2-chloropropionitrile (19.7 g.) in dry ethyl methyl ketone (15 ml.) containing finely-powdered potassium iodide (0.5 g.). The addition took 20 minutes. Stirring and heating were continued for a total of 2 hours after which the mixture was cooled, poured into water (200 ml.) and extracted with ether (200, 75 and 75 ml.). The combined ether extract was washed several times with 2N-sodium hydroxide to remove phenol, dried over anhydrous sodium sulphate, and evaporated. The residue was distilled under water-pump vacuum to give pure 2-phenoxypropionitrile, b.p. 117°-118°/13 mm.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH:23]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C.C(#N)C>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 47.5 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of the 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (26.7 g, 39.1 mmol) in THF (200 mL) and ethanol (200 mL) was added aqueous 1.0 N sodium hydroxide (200 mL) at room temperature. The resulting suspension was heated to 45-50° C. and the mixture was stirred for 30 min and then cooled to room temperature and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (200 mL) and extracted with diethyl ether (150 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×200 mL). The combined ethyl acetate extracts were washed with brine solution (300 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded the crude product which was dissolved in acetonitrile (270 mL) at hot condition and was stored in the refrigerator. The resulting white solids were collected by filtration and washed with acetonitrile. After air-drying, 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (19.7 g, 80.5%) was isolated as a white solid. ES(+)-HRMS m/e calcd for C33H38O10S (M+Na)+ 649.2078, found 649.2076.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23](O)[CH2:24][CH3:25])[CH:14]=[CH2:15].B(F)(F)F.CCOCC>O1CCOCC1>[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24][CH3:25])[CH:14]=[CH2:15]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: C=CCOc1ccccc1C(O)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=CCOc1ccccc1C(CC)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a flame-dried flask containing a near-solution of 4-hydroxycoumarin (337mg) and 1-(2-allyloxyphenyl)propanol of Preparation 36 (500 mg) in anhydrous dioxane (10 mL) under nitrogen is added boron trifluoride etherate (1.31 mL). The resulting solution is stirred at RT for 25 hrs. concentrated to remove solvent, diluted with aqueous sodium hydroxide (5%, 20 mL) and extracted with methylene chloride (2×25 mL). The organic phase is discarded and the aqueous phase is adjusted to pH 1 using 6M hydrochloric acid and extracted with methylene chloride (2×25 mL). The organic phase is washed with saline (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a viscous residue which is then chromatographed on silica gel (230400 mesh, 45g), eluting with a gradient of ethyl acetate/hexane (5/95-10/90). Pooling of fractions having an Rf =0.44 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent gives the title compound.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12](O)=O.[OH-].[Na+]>O>[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1-c1nc2ccccc2[nH]1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
Benzene-1,2-diamine (2.60 g, 25 mmol) and 2-methyl-5-nitrobenzoic acid (5.0 g, 27.6 mmol) were suspended in polyphosphoric acid (30 ml, 11 vol) and heated to 140° C. overnight. Once the reaction had gone to completion (monitored by LCMS), the crude green mixture was dissolved in water, basified with NaOH (pH=14) and extracted into EtOAc (×2). The organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 7 (4.70 g, 74%) as an orange/brown solid: 1H NMR (C2D6SO) δ 13.20 (s, 1H), 8.80 (app d, 1H), 8.84 (dd, 1H), 7.89-7.87 (m, 2H), 7.74 (d, 1H), 7.40-7.45 (m 2H), 2.90 (s, 3H); MS (ES, positive mode): 254 [M++1].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Na].[K].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>[Cu]>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10]
Reactant: CC(=O)c1ccccc1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: [K]
Agent: [Na]
Product: O=C(COc1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
Hitherto this compound has been prepared by reacting o-chloroacetophenone with the sodium or potassium salt of 2,4-dichlorophenol at a temperature of at least 120° C. in the presence of a copper catalyst to produce 2-(2,4-dichlorophenoxy)acetophenone. This is then reacted with sulphur and morpholine to afford a thioacetmorpholide which is thereafter hydrolysed.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:14]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=3[N:16]=[C:17](Cl)[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:80][N:81]1[CH:85]=[C:84]([NH2:86])[CH:83]=[N:82]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:14]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=3[N:16]=[C:17]([NH:86][C:84]3[CH:83]=[N:82][N:81]([CH3:80])[CH:85]=3)[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: Cn1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2nc(N[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 140 °C

Procedure:
A microwave tube fitted with a stir bar was charged with tert-butyl((trans)-3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate (260 mg, 0.55 mmol), 1,4-dioxane (3 mL), Cs2CO3 (452 mg, 1.4 mmol), Pd2(dba)3 (16 mg, 0.03 mmol), Xantphos (34 mg, 0.056 mmol) and 1-methyl-1H-pyrazol-4-amine (60 mg, 0.58 mmol). The tube was flushed with nitrogen gas and heated at 140° C. in a Biotage microwave reactor for 40 min. The product was purified via flash chromatography eluting with a gradient of 30%-100% EtOAc in heptanes to afford the title compound (115 mg, 39% yield) as an orange foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([OH:26])=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:24](=[O:26])[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 10.3 %

Procedure:
To a solution of 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (100 mg, 0.262 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (110 mg, 0.262 mmol), EDC (151 mg, 0.786 mmol) and DMAP (64.1 mg, 0.524 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1N HCl (10 ml) and EtOAc; the aqueous phase was extracted with EtOAc, the combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum. Three flash chromatographic column on silica gel (DCM/MeOH 97/3) were required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (21.4 mg, 0.027 mmol, 10.4% yield, MS/ESI+ 783.19 [MH]+, [αD]=+14.1, c=0.2 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.50 (s, 2H), 7.34 (d, 1H), 7.07-7.21 (m, 5H), 6.90 (dd, 1H), 7.06 (t, 1H), 6.55 (d, 1H), 6.02 (dd, 1H), 5.25 (d, 1H), 5.10 (d, 1H), 3.91 (d, 2H), 3.80 (t, 2H), 3.46-3.54 (m, 4H), 3.41 (dd, 1H), 3.21 (dd, 1H), 3.09 (s, 3H), 2.32 (dd, 2H), 2.23-2.31 (m, 4H), 1.07-1.36 (m, 1H), 0.54-0.65 (m, 2H), 0.29-0.47 (m, 2H).
Reaction SMILES: [C:1]([C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2].CO.[H][H]>[Pd].CC#N>[C:1]([CH:3]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2]
Reactant: CCC(=O)C(C#N)=Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC#N
Product: CCC(=O)C(C#N)Cc1ccc(C#N)cc1
Yield: 99.1 %

Procedure:
To a hydrogenation reactor was charged with 4-(2-cyano-3-oxopent-1-enyl)benzonitrile (24) (20 g, 95.1 mmol), Pd/C (2 g, 10%, wet), MeOH (100 ml) and MeCN (100 ml). The mixture was stirred at 25° C. under 50 psi hydrogen for 2 h until absorption of hydrogen was stopped. The mixture was filtered through a celite pad to remove catalyst. It was concentrated under reduced pressure to give product 25 (20 g, 99%) as an oil. The product was directly used for the next step reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.S(C1C=CC(C)=CC=1)(O[CH2:13][C@@H:14]1[CH2:28][C@H:27]2[C@@H:17]([CH2:18][C:19]3[C:29]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]2=4)[NH:21][CH:20]=3)[N:16]([CH3:30])[CH2:15]1)(=O)=O>CN(C)C=O>[CH3:3][C:4]1[N:5]([CH2:13][C@@H:14]2[CH2:28][C@H:27]3[C@@H:17]([CH2:18][C:19]4[C:29]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]3=5)[NH:21][CH:20]=4)[N:16]([CH3:30])[CH2:15]2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
0.8 g of 50% sodium hydride in an oil was added in small portions to a mixture of 1.2 g of 2-methylimidazole and 16 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 3 hours. After allowing the mixture to cool, ice-water was added to the reaction mixture, and the precipitated crystals were separated by filtration, washed with water and purified by silica gel column chromatography (eluted with chloroform). The product was recrystallized from ethanol to obtain 1.1 g of the titled compound as colorless needles having a melting point higher than 300° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12])#[N:2].[ClH:13]>CO.[Pd]>[ClH:13].[NH2:2][CH2:1][C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: Cc1c(C#N)sc(C(N)=O)c1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(CN)sc(C(N)=O)c1C

Procedure:
19 g (105.42 mmol) of 5-cyano-3,4-dimethylthiophene-2-carboxamide were suspended in 760 ml of methanol and 110 ml of 2N hydrochloric acid solution and, after addition of 9.5 g of Pd on carbon (10%), hydrogenated at room temperature. After uptake of 4.7 l of hydrogen (4 h), methanol was distilled out under reduced pressure, and the aqueous phase was extracted three times with ethyl acetate and then freeze-dried. 16.3 g of the required product were obtained as a white solid (70.4% of theory).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].[OH-].[NH4+]>ClCCl>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 25 mg (0.07 mmol) of (RS)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride in 1 ml of dichloromethane is treated with 22 μl (0.16 mmol) of triethylamine and cooled to 0° C. To this solution, 6 μl (0.08 mmol) of acetylchloride are added and stirring at 0° C. is continued for 30 min. For the working-up, the reaction mixture is treated with 2 ml of ammonium hydroxide solution, the organic phase separated, thereafter dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 95:5 mixture of dichloromethane and methanol as the eluent. There are obtained 20 mg (78% of theory) of (RS)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=343 (M+H)+.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4]O[C:2]=1[CH2:9][OH:10].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: Cl
Product: O=c1cc(CO)n(-c2ccccc2)cc1O
Reaction time: 8 h
Yield: 49 %

Procedure:
To a suspension of kojic acid (1.421 g, 10.00 mmol) in diluted hydrochloric acid (0.52 mL of concentrated hydrochloric acid diluted with 25 mL of water) was added aniline (1.40 mL, 15.4 mmol). The resulting mixture was heated under reflux for 20 h. The mixture, while warn (60° C.), was washed with dichloromethane two times and the organic phase was discarded. The aqueous phase was neutralized with solid sodium carbonate, upon which much off-white precipitate appeared. The mixture stood in a hood overnight. The crude product was isolated by filtration and purified by recrystallization with methanol to give a pale solid (1.064 g, 49%). Mp: 236-238° C. (lit.85 237-240° C.). 1H NMR (d6-DMSO): δ 4.20 (2H, s), 6.47 (1H, s), 7.35 (1H, s), 7.5-7.6 (5H, m). 13C NMR (d6-DMSO): δ 70.9, 102.5, 114.8, 118.2, 118.9, 130.5, 138.7, 146.7, 165.3, 179.5.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=[O:14])[CH2:12][CH3:13])(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(=O)C(CO)NC(=O)OC(C)(C)C
Yield: 97.2 %

Procedure:
tert-butyl 1-(tertbutyldimethylsilyloxy)-3-oxopentan-2-ylcarbamate (26) (900 mg, 2.7 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (14 mL). The mixture was stirred and glacial acetic acid (21 mL) was added to the reaction flask. The reaction stirred for 22 h at rt. The reaction was transferred to a 250 mL separatory funnel with sat. NaCl (50 mL) and sat. NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (3×75 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 825 mg of crude oil. The residue was purified by flash column chromatography (50% EtOAc/hexanes) to give 570 mg (96%) of 27 as a colorless oil. Rf=0.31 (50% EtOAc/hexanes); IR (film) 3420, 2976, 2937, 1686, 1498, 1365, 1163, 1056 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.78 (d, J=6.0 Hz, 1H, carbamate-NH), 4.34 (br s, 1H, Boc-NH—CH), 3.97 (d, J=10.0 Hz, 1H, CH—CH2), 3.87 (d, J=10.0 Hz, 1H, CH—CH2), 3.34 (br s, 1H, CH2—OH), 2.66 (m, 1H, O═C—CH2), 2.59 (m, 1H, O═CCH2), 1.45 (s, 9H, t-butyl-CH3), 1.09 (t, J=7.0 Hz, 3H, O═C—CH2CH3); 13C NMR (125 MHz, CDCl3) δ 209.0, 156.1, 80.3, 63.1, 61.5, 33.4, 28.4, 7.5.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]>[CH:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([O:6][C:5]3[CH:24]=[CH:25][C:2]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]4=[O:32])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: O=C1CCCCN1
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(I)cc3)CC2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(N4CCCCC4=O)cc3)CC2)CC1

Procedure:
To a mixture of 1.04 g (4.09 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 1.50 g (6.82 mmol) of 4-iodephenol, 1.25 g (4.77 mmol) of triphenylphisphine in 5 ml THF, 1.1 g (4.78 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.67 g (14% yields, about 67% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone. A mixture 100 mg (0.15 mmol) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 87 mg (0.88 mmol) of 2-piperidone, 41 mg (0.3 mmol) of potassium carbonate and 37 mg (0.58 mmol) of copper was stirred at 175 degree for 6 hr. The mixture was diluted with AcOEt, filtered through celite. The filtrate was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 1:3. The combined product fractions were evaporated to dryness to yield 30 mg (32%) of the title compound. MS (m/e): 428.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([O:25][CH2:26][CH3:27])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[C:21]([F:24])([F:23])[F:22])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([O:25][CH2:26][CH3:27])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C(F)(F)F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 c], (2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.