Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOCCn1cc(-c2ccccc2)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCOCCN1CC(c2ccccc2)NC1=O

Procedure:
A solution of 1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one in ethanol with 10% palladium on carbon catalyst is reduced in an atmosphere of hydrogen. After the theoretical amount of hydrogen is absorbed, the catalyst is filtered and filtrate concentrated to give the title compound.
Reaction SMILES: [OH-].[K+].[O:3]([CH2:10][CH2:11][CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:42])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)[C:13]([O:15]CC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[O:3]([CH2:10][CH2:11][CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:42])[C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:34][CH:35]=2)=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCOc1ccc(CC(CCOc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
An aqueous solution of potassium hydroxide (85%, 0.13 g) was added to a solution of ethyl 2-(2-phenoxyethyl)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (350 mg) in ethanol (8 ml). The mixture was stirred at 80° C. for 3 hours. At the end of this time the ethanol was evaporated under reduced pressure. An aqueous solution of hydrogen chloride (1N, 2.0 ml) and ethyl acetate was added to the residue. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (260 mg) as a mass of foam.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reactant: CC(C)CCBr
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CCC(C)C)c2ccc(C(C)C)cn2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a stirred solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (150 mg, 0.37 mmol) in acetonitrile (4 mL) was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (128 mg, 0.75 mmol). The reaction mixture was stirred at 20° C. for 1 hour. 1-Bromo-3-methylbutane (0.09 mL, 0.75 mmol) was then added and the reaction vessel sealed and heated by microwaves to 150° C. for 30 minutes. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic phase was washed with water, dried using a hydrophobic frit and evaporated in vacuo to give the crude product. The crude was then purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (48 mg) as a yellow oil. LCMS (2 min, HpH) Rt 1.50 min, m/z (ES+) 472 (M+H).
Reaction SMILES: C([N:9]1[C:22]2[CH:21]=[CH:20][C:19]([NH:23][CH2:24][CH3:25])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([NH:26][CH2:27][CH3:28])[CH:14]=2)(=O)C1C=CC=CC=1.C([BH-](CC)CC)C.[Li+].[OH:37][C:38]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][C:39]=1[C:51]([CH3:54])([CH3:53])[CH3:52].O>O1CCCC1>[C:51]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:38]=1[OH:37])[C:42]([N:9]1[C:22]2[CH:21]=[CH:20][C:19]([NH:23][CH2:24][CH3:25])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([NH:26][CH2:27][CH3:28])[CH:14]=2)=[O:43])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCNc1ccc2c(c1)Oc1cc(NCC)ccc1N2C(=O)c1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)Oc1cc(NCC)ccc1N2C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
A solution containing 4.29 g of 10-benzoyl-3,7-diethylaminophenoxazine in 15 ml of tetrahydrofuran was added to 26 ml of 1M lithium triethylborohydride in tetrahydrofuran. After the addition was complete, the mixture was stirred for one hour. To this was added, over 15 minutes, 3.1 grams of 4-hydroxy-3,5-di-t-butylbenzoyl chloride. The mixture was stirred for one hour. Water was added and the product extracted into ethyl acetate. The solvent was removed and the product filtered through a pad of silica gel, and eluted with 1:3 ethyl acetate-hexane. Additional chromatography over alumina and elution with 1:4 ethyl acetate-hexane followed by recrystallization from etherhexane and finally from methanol gave 0.6 gm of the color forming developer.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([NH:17]C=O)/[CH:6]=[CH:7]/[CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])C>Cl>[NH2:17][CH:5](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:14])([OH:11])=[O:10])[C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)C(/C=C/CP(=O)(OCC)OCC)NC=O
Agent: Cl
Product: NC(/C=C/CP(=O)(O)O)C(=O)O

Procedure:
8.22 g of E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester are dissolved in 170 ml of 6 N hydrochloric acid and the whole is heated under reflux for 22 hours. After concentration in vacuo, the oily residue is taken up in a small amount of ethanol and the mixture is again concentrated by evaporation in vacuo. This procedure is repeated a further twice. The resulting residue is dissolved in 15 ml of ethanol and 20 ml of ethanol/propylene oxide (1:1) are added dropwise. The resulting brownish-coloured precipitate is filtered off and purified by ion exchange chromatography (Dowex 500W×8/H2O). After concentration and lyophilisation, E-2-amino-5-phosphono-3-pentenoic acid is obtained in the form of a white amorphous powder, 1H-NMR (D2O): 2.39 (dd, 2H, C(5)-H); 4.27 (d, 1H, C(2)-H); 5.53 (m, 1H, C(3)-H); 5.87 (m, 1H, C(4)-H), m.p. after recrystallisation from ethanol/water 191°-192° .
Reaction SMILES: [CH2:1]([C:3]([C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:16][O:14][C:13]([C:11]1[S:12][C:8]([C:3]([CH2:4][CH3:5])([CH2:6][OH:7])[CH2:1][CH3:2])=[CH:9][CH:10]=1)=[O:15]
Reactant: CCC(CC)(CO)c1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(CO)c1ccc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of 5-(1-ethyl-1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid (0.750 g, 3.28 mmol) in DMF (16.0 mL) is treated with K2CO3 (0.684 g, 6.00 mmol), iodomethane (0.27 mL, 4.34 mmol), and stirred at rt overnight. The mixture is poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 5-(1-ethyl-1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid methyl ester (0.571 g, 72%) as a clear syrup. MS (ES): 243.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]2[C:21](C)=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:26])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:29]C1C=CC=C(C)C=1NC1C=CC=CC=1CC(O)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1

Procedure:
[o-(3-chloro-o-toluidino)-phenyl]-acetic acid-p-nitrophenyl ester, starting with [o-(3-chloro-o-toluidino)-phenyl]-acetic acid, M.P. 124° - 125° (from ether/petroleum ether).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: CNC(=O)c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CNC(=O)c1ccc2c(ccn2-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
The title compound can be synthesized from 1H-indole-5-carboxylic acid methylamide and 4-fluoronitrobenzene in the same manner as in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.N1C=CC=CC=1.[OH-].[Na+]>CN(C)C(=O)C.[Cu]I.O>[CH:13]1([NH:16][C:2]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cc(F)c(F)cc1NC1CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a 10 ml resealable pressure reaction flask equipped with a magnetic stirrer and teflon septum cap was charged a solution of 1.0 g (5.19 mmol) 2-chloro-4,5-difluorobenzoic acid, 792 μl (11.43 mmol) cyclopropylamine, 800 mg (4.15 mmol) copper (I) iodide and 630 μl (7.79 mmol) pyridine in 8.0 ml of N,N-dimethylacetamide. The flask was sealed and was heated to 70° C. during stirring for a period of 16 hours. The reaction mixture was allowed to cool to room temperature and was then added to 100 ml of water. The suspension was adjusted to pH 13 with sodium hydroxide solution and was stirred for 15 minutes at room temperature. The suspension was filtered and the filtrate was adjusted to pH 4.5 with concentrated aqueous HCl. Filtration of the resulting slurry provided 451 mg (41%) of 2-cyclopropylamino-4,5-difluorobenzoic acid; m.p.: 175°-176° C.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].[CH2:34]1C2C(=CC=CC=2)CC1CCO.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:34][CH:19]1[CH2:18][CH2:17][N:16]([C@H:27]1[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: OCCC1Cc2ccccc2C1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC2Cc3ccccc3C2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-indan-2-yl-ethanol and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([I:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH:24]=[O:25]>C1COCC1>[I:11][C:5]1[C:4]([O:12][CH3:13])=[CH:3][C:2]([CH:24]([OH:25])[C:23]([CH3:27])([CH3:26])[CH3:22])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: COc1cc(I)c([N+](=O)[O-])cc1I
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of crude 3,6-diiodo-4-nitroanisole (770 mg, 80% purity, 1.52 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 0.46 mL, 0.92 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethylacetaldehyde (0.22 mL, 1.97 mmol). The mixture was stirred at minus 30° C. for two hours and then at room temperature for another one hour. The reaction was then quenched with brine (1.0 mL), diluted with CH2Cl2 (100 mL), and the solution was washed with CH3COOH (0.1 N, 50 ml) and brine (50 ml) sequentially. The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (399 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H, Ph-H), 7.17 (s, 1H, Ph-H), 5.60 (d, 1H, J=4.0 Hz, PhCH), 3.98 (s, 3H, OCH3), 2.12 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H,C(CH3)3).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[CH3:13][C:14]1[C:15]([CH3:26])=[CH:16][C:17]2[NH:22]C(=O)[O:20][C:19](=O)[C:18]=2[CH:25]=1.Cl.[OH-].[Na+]>CCCCCC.O1CCCC1.O>[NH2:22][C:17]1[CH:16]=[C:15]([CH3:26])[C:14]([CH3:13])=[CH:25][C:18]=1[C:19](=[O:20])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: Cc1cc2[nH]c(=O)oc(=O)c2cc1C
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(N)c(C(=O)Cc2nnnn2C)cc1C
Reaction time: 1 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 9.8 ml) was added to a stirred solution of 1,5-dimethyltetrazole (2.6 g) in dry tetrahydrofuran (25 ml) at 0° under nitrogen. After 1 hour, 6,7-dimethyl-1H-3,1-benzoxazine-2,4-dione (1.69 g) was added and stirring was continued for 4 hours. The mixture was poured into water (200 ml), acidified with hydrochloric acid (5N) to pH 1, neutralised with aqueous sodium hydroxide (5N) and extracted with dichloromethane (3×100 ml). The combined extracts were dried and evaporated under reduced pressure. The residue was triturated with water to give a yellow solid which was collected by filtration and dried to give the novel compound 1-(2-amino-4,5-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 162°-165°.
Reaction SMILES: NCC1CCC(N(C)C)(C2C=CC=CC=2)CC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.N1C2C(=CC=CC=2)C(CCC(O)=O)=C1.[CH3:50][N:51]([CH3:79])[C:52]1([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:57][CH2:56][CH:55]([CH2:58][NH:59][C:60](=[O:72])[CH:61]([C:63]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][CH:64]=2)[CH3:62])[CH2:54][CH2:53]1.[Cl:80][Si](C)(C)C>CC(=O)CC.CO>[ClH:80].[CH3:79][N:51]([CH3:50])[C:52]1([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:57][CH2:56][CH:55]([CH2:58][NH:59][C:60](=[O:72])[CH:61]([C:63]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][CH:64]=2)[CH3:62])[CH2:54][CH2:53]1
Reactant: C[Si](C)(C)Cl
Agent: CC(C(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1)c1c[nH]c2ccccc12
Agent: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CO
Solvent: CCC(C)=O
Product: Cl
Reaction time: 20 h

Procedure:
The non-polar diastereoisomer of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (232 mg, 1.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmol.) were added to a solution of 3-(1H-indol-3-yl)propionic acid (189 mg, 1.0 mmol.) in abs. methanol, and stirring was carried out for 20 h at RT. For working up, the mixture was concentrated, the residue was taken up in water (10 ml) and ether (10 ml), and the phases were separated. The aqueous phase was adjusted to pH 11 with 5M NaOH and extracted with EE (4×10 ml). The combined organic extracts were washed with 1M NaOH (2×3 ml), dried, filtered and concentrated. For the preparation of the hydrochloride, the resulting non-polar diastereoisomer of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-2-(1H-indol-3-yl)propionamide (220 mg, 0.54 mmol.) was dissolved in 2-butanone; chlorotrimethylsilane (104 μl, 0.82 mmol.) was added thereto, and stirring was carried out for 1 h at RT. After 1 h at 4° C., the resulting precipitate was filtered off with suction, washed with cold 2-butanone (1 ml) and cold ether (2×1 ml) and dried in vacuo. The target compound was obtained in a yield of 168 mg (colourless solid, m.p. 163–168° C. with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](I)[CH2:9][S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)CC(I)c2ccc(Cl)cc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-Chloro-4-(1-iodo-2-tosylethyl)benzene (28.5 g, 67.7 mmol) was dissolved in dry MeCN (376 mL) followed by addition of Et3N (18.83 mL, 135 mmol) and the mixture was stirred at room temperature for 1 h. Then the solvent was evaporated under reduced pressure and the residue partitioned between DCM (400 mL) and 1M aqueous KHSO4 (300 mL). The layers were separated and the organic phase was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to afford 19 g (96%) of the desired product.
Reaction SMILES: ON[C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28]C3C=CC=CC=3)=[CH:23][CH:22]=2)(=O)=O)CCN(CC2C=CC=CC=2)CC1)=[O:4].C[O:36][C:37]1C=CC(S)=C[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:37]([O:36][C:3](=[O:4])[CH2:5][S:18][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:38]
Reactant: COc1ccc(S)cc1
Reactant: O=C(NO)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OC)cc1

Procedure:
1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous K2CO3 (10 gm, excess) in dry acetone (100 ml), α-bromo ethyl acetate (3.3 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O and 0.5N NaOH solution. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. (4-methoxy- phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[C:16]([F:22])[CH:15]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:22])[CH:15]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(OC)c2)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2cc(O)cc(F)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A −78° C. solution of 3-[4-(3-fluoro-5-methoxy-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (0.715 g, 2.15 mmol) in dry CH2Cl2 (10 mL) is treated with a 1 M CH2Cl2 solution of boron tribromide (6.5 mL, 6.5 mmol). The mixture is warmed to 0° C. and stirred for 1 hour under N2. Upon completion, the mixture is poured into ice water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 1/1 to hexanes/ethyl acetate to afford 0.558 g (81%) of the title compound. Rf=0.36 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3). MS (ES−) m/z mass calculated for C18H19O4F 318, found 317 (M−1, 100%).
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH3:8][C:9]1[S:10][C:11]2[C:17](=[O:18])C[CH2:15][CH2:14][C:12]=2[N:13]=1.Cl>CCOCC.CO.CCCCCC>[CH3:8][C:9]1[S:10][C:11]2[C:17](=[O:18])[CH:7]([CH:6]=[O:5])[CH2:15][CH2:14][C:12]=2[N:13]=1
Reactant: CCOC=O
Reactant: Cc1nc2c(s1)C(=O)CCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CO
Product: Cc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a suspension of hexane-washed NaH (1.1 g, 44.8 mmol) in dry Et2O (70 mL) was added dry MeOH (6.1 mL). After evolution of H2 had subsided, freshly distilled ethyl formate (7.3 mL, 6.7 g, 89.7 mmol) was added, followed by 2-methyl-5,6-dihydro-4H-benzothiazol-7-one (3.0 g, 17.9 mmol) in dry Et2O (12 mL). The reaction mixture was stirred at room temperature for 16 h. 10% aq HCl solution was added (150 mL) and the product was extracted with EtOAc (5×150 mL). The combined organic extracts were dried, filtered, and concentrated under vacuum to leave a brown oily crude product. Purification by flash column chromatography (20% EtOAc:hexane) afforded the pure title product as a yellow solid (2.30 g, 66%): mp 107-108° C. Anal. RP-HPLC: tR 12.6 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 9.90 (s, CHO), 7.20 (s, 1H, CH), 2.91 (t, 2H, J 7.1, CH2), 2.67 (s, 3H, CH3), 2.58 (t, 2H, J 7.1, CH2). 13C-NMR (CDCl3): δ 198.6, 186.3, 174.2, 165.7, 162.6, 131.0, 108.4, 27.0, 24.5, 20.7. MS: (ESI−) m/z 193.98 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.[CH2:18]([O:25][CH2:26][C:27](Cl)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([O:25][CH2:26][C:27]([NH:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)COCc2ccccc2)sc1C(=O)O
Temperature: 80 °C

Procedure:
300 mg (1.90 mmol) 2-Amino-4-methylthiazole-5-carboxylic acid and 0.67 mL (6.07 mmol) N-methylmorpholine are added to 20 mL DMF. After adding 0.32 mL (2.09 mmol) benzyloxyacetyl chloride the resulting mixture is stirred at 80° C. over night. Then the mixture is callowed to cool to r.t. and slightly acidified with aq. HCl solution (c=1 mol/L). The solvent is removed in vacuo, water is added and the suspension is stirred for 10 min before the precipitate is filtered off and dried.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C(N(CC)CC)C.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(OCC)(=O)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:8][C:1](=[O:9])[C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 97.5 %

Procedure:
10.45 g of D-leucic acid was dissolved in 150 ml of ethyl acetate. 11 ml of triethylamine and 18.78 g of 4-nitrobenzyl bromide were added and the mixture was heated under reflux for 3 hours. The mixture was washed in sequence with water, 10% citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation, there were obtained 20.6 g (98%) of D-leucic acid 4-nitrobenzyl ester as a gum. Rf (chloroform) 0.37.