Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:46][OH:47]>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH:46][OH:47])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 36.5 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide was prepared by the procedure of example 8 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.6 g, 1.3 mmol), CDI (0.32 g, 2.0 mmol) and hydroxylamine hydrocloride (0.19 g, 2.6 mmol) in THF (30 ml) to give 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide as white solid (0.22 g, 40% yield): mp 121-123° C.; 1HNMR (DMSO-d6): 1.34 (t, J=7.5 Hz, 3H, OCH2CH3), 2.16 (s, 3H, CH3), 2.89 (d, J=7.5 Hz, 2H, CH2), 4.10 (q, J=7.0 Hz, 2H, OCH2CH3), 4.24 (d, J=17.5 Hz, 1H, CH2N), 4.59 (d, J=17.5 Hz, 1H, CH2N), 5.69 (m, 1H, CHN), 6.93 (m, 1H, Ar), 7.03 (t, JH-F=75 Hz, 1H, CF2H), 7.15 (m, 3H, Ar), 7.52 (t, J=7.5 Hz, 1H, Ar), 8.26 (d, J=8 Hz, 1H, Ar), 8.85 (s, 1H, NHOH), 10.26 (s, 1H, NHOH), 10.35 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ14.4, 24.4, 34.5, 51.5, 64.2, 93.9, 113.0, 116.6, 117.3, 117.5, 120.7, 121.3, 122.5, 132.8, 134.0, 137.0, 137.8, 142.2, 149.8, 165.7, 168.0, 168.5; Anal. Calcd. for C22H23F2N3O6+0.13 H2O: C, 56.73; H, 5.03; N, 9.02. Found: C, 56.35; H, 4.89; N, 8.75; H2O 0.34.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[C:24](Cl)=[O:25]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:24]([CH:18]3[CH2:19][CH:20]4[CH2:23][CH:17]3[CH:22]=[CH:21]4)=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CC2C=CC1C2
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CC2C=CC1C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][Cl:26])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][Cl:26])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCOc1cc(C(=O)OC)ccc1N(CCCl)CCCl
Agent: Cl
Product: CCCCCCCCOc1cc(C(=O)O)ccc1N(CCCl)CCCl
Yield: 89.9 %

Procedure:
A suspension of methyl 4-bis(2′-chloroethyl)amino-3-octoxybenzoate (1.8 g, 4.5 mmol) in concentrated HCl (37% w/w in H2O, 50 mL) was heated to reflux under N2 for 0.5 hours. The reaction mixture was treated with ice/H2O (100 mL), extracted with chloroform (3×50 mL). The organic solution was concentrated to give a brown oil. Flash chromatographic purification (silica gel, 2% methanol in chloroform) gave the product as an off-white solid (1.58 g, 88%). 1H NMR (300 MHz, CDCl3): 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.40 (d, J=6.6 Hz, 2H), 3.65 (m, 8H), 1.85 (J=7.8 Hz, 2H), 1.35 (m, 10H), 0.90 (t, J=6.6 Hz, 3H). ESMS calcd for C29H29Cl2NO3: 389.2; Found: 390.2 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][CH:7]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.Cl>ClC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: c1ccsc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
33.8 g of aluminium trichloride were suspended in 217 g of chlorobenzene, and a solution of 40.3 g of 4-fluorobenzoyl chloride in 37.4 g of chlorobenzene was added dropwise to this at 0° C. over the course of 15 minutes. The mixture was then stirred for 1 hour and then, at 0° C., 21.8 g of thiophene were added dropwise over the course of 20 minutes. The resulting hydrogen chloride was drawn off and absorbed in sodium hydroxide solution. The mixture was subsequently heated to 80° C. and the remaining hydrogen chloride was removed. The resulting solution was added dropwise to a suspension of 7.2 g of sodium borohydride in 47.2 g of digylme while stirring at 70° C. over the course of 45 minutes. The reaction mixture was then stirred for 90 minutes and then cooled to room temperature and discharged into a mixture of 250 g of ice, 44.6 g of concentrated aqueous hydrochloric acid and 500 g of water. The organic phase which formed thereby was separated off, the aqueous phase was extracted by shaking with chlorobenzene, and the combined organic phases were distilled. 35.0 g of product with a boiling point of 83° C./1.0 mbar and a purity of 99.7% (GC) were obtained. This corresponds to 73.9% of theory. The product contained less than 0.1% by weight of defluorinated compounds (GC).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26]([C:6]3[NH:5][C:4](=[O:7])[NH:3][C:2]=3[CH3:1])=[O:27])=[CH:24][C:23]=2[O:22]1
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc2c(c1)OCO2

Procedure:
To 5.13 g. of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 7.98 g. of anhydrous aluminum chloride in 80 ml. of nitrobenzene is added dropwise 10.60 g. of 3,4-methylenedioxybenzoyl chloride and the mixture is poured on 500 ml. of 2N-HCl and ice, washed 3 times with ethyl ether, the resulting solid is collected to give the title compound. M.p. 293°-296° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([N:41]1[CH2:42][CH2:43][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][CH2:40]1)=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)N2CCN(c3ccccn3)CC2)cc(OC)c1OC
Yield: 67.8 %

Procedure:
8 g of 3',4',5'-trimethoxy-flavone-3-carboxylic acid with 5.5 g 4-dimethylaminopyridine and 2.2 ml mesylchloride in 100 ml absolute dichloromethane were converted into the mixed anhydride analogously to Example 1 (a), and this was then reacted with 3.6 g 1-(2-pyridyl)-piperazine analogously to Example 1 (b). The working up of the reaction mixture and the purification of the crude title compound obtained were carried out analogously to Example 1 (b). 7.5 g of 3',4',5'-trimethoxy-3-{[4-(2-pyridyl)-piperazin-1-yl]-carbonyl}flavone were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C(C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)Cl)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-methyl-2-phenylbutyric acid (891 mg; 5.0 mmol) and a catalytic amount of dry dimethylformamide (ca. 10 uL) in 10 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (0.65 mL; 7.5 mmol) dropwise. After 1 hour, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: [OH-].[CH3:2][CH:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([O:29][C:30]([O:32][CH2:33][CH2:34][O:35][P:36]([OH:45])([O:38][CH2:39][CH2:40][N+:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])=[O:31])[CH2:20][CH2:21]2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:4]>CO.[Pd]>[OH-:29].[CH3:4][CH:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@H:17]([CH2:18][C@@H:19]([O:29][C:30]([O:32][CH2:33][CH2:34][O:35][P:36]([OH:45])([O:38][CH2:39][CH2:40][N+:41]([CH3:44])([CH3:42])[CH3:43])=[O:37])=[O:31])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)OCCOP(=O)(O)OCC[N+](C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)OCCOP(=O)(O)OCC[N+](C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 119.6 %

Procedure:
1 g of O-[[2-[(cholest-5-en-3β-yloxy)carbonyloxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt is hydrogenated in 100 ml of methanol with 1 g of Pd/C 5% under 30 bar of H2 at 80° C. After filtration the solution is evaporated and the residue is dissolved in chloroform-methanol-dioxan. By adding ether there is obtained 0.6 g of O-[[2-[(5α-cholestan-3β-yloxy)carbonyloxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt as a hygroscopic powder, m.p. 225° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:12]
Reactant: CCI
Reactant: OCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCO
Reaction time: 8 h
Yield: 60.5 %

Procedure:
4.4 g of 2-hydroxyphenethyl alcohol was dissolved in 80 ml of N,N-dimethylformamide, and 15.3 g of ethyl iodide and 4.7 g of potassium carbonate were added. After stirring was continued at 70° C. overnight, the solution was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 3.2 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:23]=[C:24]1[C:29]2=[CH:30][NH:31][C:32]([CH:33]=O)=[C:28]2[CH2:27][CH2:26][O:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:33][C:32]2[NH:31][CH:30]=[C:29]3[C:24](=[O:23])[O:25][CH2:26][CH2:27][C:28]=23)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-methyl-amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH2:1])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Solvent: CO
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
An autoclave was cooled with an acetone/dry ice bath, and an ammonia gas was blown to pool 64 cc of liquid ammonia (corresponding to 25 equivalent of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine). Thereto were added 30 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (108.4 mmol, optical purity: 100% e.e.) and 118 g of methanol, which was heated to 100° C. whereby an internal pressure of 10 barr was observed. After allowing the reaction for 7 hrs, the reaction mixture was cooled to room temperature, and ammonia and methanol were removed by distillation under reduced pressure. As the residue, 26.6 g of a pale yellow oily material was obtained (reaction yield: 67%, optical purity: 85.8% e.e.).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[NH:14][CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].CN(C)C=O.[H-].[Na+].Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[N:14]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C1NCC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)OC1=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a solution of 243 mg (0.5 mmol) 9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one in dimethylformamide 24 mg (0.5 mmol) of a 55% sodium hydride suspension in mineral oil was added at room temperature under argon. After 15 min, 126 mg (0.8 mmol) of 2-chloro-N,N-dimethylacetamide was added. The reaction mixture was stirred at 80° C. under argon overnight. After evaporation of the solvent in vacuum water (1 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane/ethylacetate=1:1) to yield 154 mg (54%) of the title compound.
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].CS(C)=O>CCOCC>[C:21]([S:23][CH:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)[CH3:7])(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)SC(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a 500 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (19 g, 61.8 mmol), potassium thioacetate (8.47 g, 74.2 mmol) and 90 ml dimethyl sulfoxide. The resulting reaction mixture was heated at 60° C. under nitrogen for 2 hours then at 45° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 300 ml ether, washed with 400 ml water and then 150 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:10 ethyl acetate/hexane to give 15 g tert-butyl 4-[1-(acetylthio)ethyl]piperidine-1-carboxylate as dark yellow sticky material. This material was dissolved in 100 ml MeOH. A solution of KOH (17.3 g, 309 mmol) in 150 ml water was added. The reaction mixture was flushed with nitrogen and stirred at 50° C. for 2 hours. After cooling to room temperature, the volume of reaction was reduced to 150 ml. Hexane (300 ml) was added. The layers were separated, and the aqueous portion was poured into an Erlenmyer flask with 250 ml saturated NH4Cl, and pH of the mixture was adjusted to 7 by addition of 3N HCl. This solution was extracted with 250 ml ether. The extracts were washed with 100 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:9 ethyl acetate/hexane to give 8.3 g desire product as light yellow sticky material.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>CC(O)C>[C:6]1([C@@H:3]([OH:5])[CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
The catalyst solution was added to a degassed 0.1M solution of KOH in 2-propanol, followed by a solution of acetophenone in 2-propanol. The mixture was stirred at ambient temperature under nitrogen for 2 h, then worked up by neutralising with dilute hydrochloric acid and concentrating by vacuum distillation. The residue was diluted with ethyl acetate and washed with an equal volume of saturated aqueous sodium chloride. The organic layer was separated, dried over magnesium sulphate, separated from the solid and freed of solvent to give crude (S)-1-phenylethanol (1.76 g). Yield 84%, ee 89%. The turnover number, integrated over 1 h, was 324 h−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]([OH:14])[CH2:10][N:11]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@H:9]([OH:14])[CH2:10][NH2:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN

Procedure:
(1S,2R)-(3-azido-1-benzyl-2-hydroxy-propyl)-carbamic acid t-butyl ester (2.5 g, 8.17 mmol) prepared in Step A was dissolved in methanol (15 mL), to which was added Pd/C (100 mg). The mixture was reacted for 12 h in a hydrogen reactor (50 psi), and filtered through a cellite. The solvent was removed under reduced pressure, and the residue was used in the next reaction without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:24]C(=O)C(C)(C)C)=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.C[O-].[Na+].Cl.[NH2:35][CH2:36][C:37]([OH:39])=[O:38]>CO>[CH2:17]([N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:5])[C:7]([OH:24])=[C:8]2[C:14]([CH3:15])=[C:13]1[CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)n(Cc2ccccc2)c2cnc(C(=O)NCC(=O)O)c(O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (70 mg, 0.171 mmol), NaOMe in MeOH (1.02 mL, 0.51 mmol, 0.5 M), and methanol (3 mL) was stirred overnight at 60° C.; then the reaction was cooled to room temperature and acidified to pH=6 with 2 M HCl aqueous solution. The solvents were then removed, and the residue was oil pumped to dryness. The left residue was then refluxed with glycine (257 mg, 3.42 mmol), NaOMe in MeOH (5.13 mL, 2.57 mmol, 0.5 M) overnight; the solvent was removed, the residue was dissolved in water and then extracted once with MTBE, the aqueous layer was acidified with HCl (2 M) aqueous solution to pH=1-2; the precipitated solids were collected by filtration, washed briefly with water and freeze-dried to give powder, the desired title compound (53 mg, 88%); ESI MS (m/z): 354 (M+H+).
Reaction SMILES: [NH3:1].[C:2]([C:5]1[C:19]([OH:20])=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])=[C:7]([CH2:21][CH:22]=[CH2:23])[CH:6]=1)(=[O:4])[CH3:3]>C(Cl)Cl>[C:2]([C:5]1[C:19]([OH:20])=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH2:1])=[O:16])=[C:7]([CH2:21][CH:22]=[CH2:23])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: N
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)Cl
Solvent: ClCCl
Product: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(N)=O
Reaction time: 0.17 h

Procedure:
Ammonia gas was bubbled into a solution of approximately 3 millimoles of the acid chloride from Example 95 in 25 ml of methylene chloride. After 10 minutes, gas introduction was discontinued and the reaction was stirred overnight. The reaction mixture was concentrated in vacuo and then partitioned between ethyl acetate and dilute hydrochloric acid to which sodium chloride had been added. The organic layer was separated, washed with a potassium carbonate solution, dried over sodium sulfate, and concentrated to dryness. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate to provide 110 mg of the desired title product, m.p.=122°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]=[C:18]([CH3:20])[CH3:19]>S(=O)(=O)(O)O.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:4]
Reactant: C=C(C)C
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Temperature: -78 °C
Reaction time: 144 h
Yield: 62 %

Procedure:
Concentrated sulfuric acid (10 drop) was added to a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 2,15 mmol) in 20 ml of dioxane/chloroforme (2:3) in a sealed tube. After cooling the solution at −78° C., put 20 ml of isobutene gaz. The sealed tube was closed and then the reaction mixture was stirred for 6 days at 60° C. The solvant was removed and then partitioned between 15 ml of sat. Na2CO3 solution and 15 ml of EtOAc. The organic layer was separated, the aqueous phase was washed twice with ethyl acetate and the combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (5% EtOAc/Hexane) to obtain 385 mg (62%) of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65 ppm (d, 2H, Haro); 7.44-7.38 ppm (m, 3H, Haro); 7.07 ppm (s, 1H, Haro); 3.86 ppm (s, 3H); 1.48 ppm (s, 9H).