Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:4].C(=O)(O)[O-].[K+].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1OS(C)(=O)=O.O>C(#N)C>[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:26]3[CH2:25][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(C3Cc4ccccc4C3)CC2)cc1
Yield: 33.4 %

Procedure:
To a suspension of 4-piperazin-1-yl-benzoic acid ethyl ester dihydrochloride (1 g) and potassium bicarbonate (1.57 g) in acetonitrile (10 ml) was added methanesulfonic acid indane-2-yl ester (0.69 g) and the mixture was stirred under refluxing for 8 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried over under reduced pressure. The powder was purified by column chromatography on silica gel using methanol/dichloromethane (50:1) as the eluent to give 4-(4-indan-2-yl-piperazin-1-yl)benzoic acid ethyl ester (0.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:21].C([O-])(O)=O.[Na+].Cl[C:28]([O:30][C:31]([CH3:33])=[CH2:32])=[O:29]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:21][C:28](=[O:29])[O:30][C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of Example A1 (2.0 g, 7.04 mmol) and saturated aq NaHCO3 (100 mL) in EtOAc (100 mL) was cooled in an ice bath and treated with isopropenyl chloroformate (1.6 mL, 14.64 mmol). The reaction mixture was allowed to slowly warm to RT overnight. The organic layer was separated and washed with sat aq NaHCO3 (25 mL) and brine (25 mL), dried (MgSO4), concentrated in vacuo and was re-crystallized (diethylether) to provide prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate (2.32 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (br s, 1 H), 8.38 (d, J=5.6 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J=0.8 Hz, 1 H), 7.67 (br t, J=8.4 Hz, 1 H), 7.27 (d, J=2.4 Hz, 1 H), 7.22 (dd, J=11.2, 2.4 Hz, 1 H), 7.00 (m, 1 H), 6.69 (dd, J=5.6, 2.4 Hz, 1 H), 4.74 (m, 1 H), 4.72 (s, 1 H), 3.84 (s, 3 H), 1.92 (s, 3H); MS (ESI) m/z: 369.1(M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(I)c(OCC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(OCC)c1
Yield: 97.6 %

Procedure:
3-Ethoxy-4-iodo-benzoic acid ethyl ester (0.500 g, 1.56 mmol, CAS No. 741699-04-7) was dissolved under Ar in 12 ml of abs. DMF and treated successively with 4-(trifluoromethyl)phenyl boronic acid (0.356 g, 1.2 eq.), K3PO4 (0.564 g, 1.7 eq.), and Pd(PPh3)4 (0.054 g, 0.03 eq.). The mixture was allowed to react for 16 h at 80° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=95/5) afforded finally 0.515 g of the title compound as white solid.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:48]>>[NH2:48][C:5]1[C:4]2[N:3]=[CH:2][N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCCNC(=O)CCCCCn1cnc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
6-(1H-Imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide (7.0 g, 26 mmol) was treated with mCPBA (8.68 g, 37.7 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (8.01 g, 42.1 mmol) according to the method described in Part D of Example 8. The crude product was triturated with ethyl acetate and recrystallized twice from methanol:water to provide 2.00 g of 6-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide as brown needles, mp 128-130° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=4)[NH:17][C:16]3=[O:21])=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Brc1ccc2c(c1)OCO2
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccc2c(c1)OCO2
Yield: 74.6 %

Procedure:
With 3.00 g of 5-bromo-1,3-benzodioxol and 1.86 g of 5-chloroisatin as starting materials, 2.32 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[OH:22])[OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[CH2:1]([O:8][CH2:9][C@H:10]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:24][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=1)[OH:22])[OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O[C@@H]([C@H](O)[C@@H](COCc1ccccc1)OCc1ccccc1)[C@H](O)COCc1ccccc1
Product: O=[N+]([O-])c1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccccc2)cc1

Procedure:
The product of example 71 was further alkylated with 4-nitrobenzyl bromide affording after purification by flash chromatography the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[S:10][CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=[CH2:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[S:10][CH2:9][CH2:8]1
Reactant: [Li]CCCC
Reactant: CCCCCC(=O)c1ccc2c(c1)SCCC2(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CCCCC)c1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl triphenylphosphonium bromide (2.293 g, 6.42 mmole) in 40 mL of THF at 0° C., was treated dropwise with 2.6 mL of 2.5M butyllithium. The mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. A solution of 1-(4,4-dimethyl-thiochroman-7-yl)-hexan-1-one (1.183 g, 4.28 mmole) in 10 mL of THF was added to the ylide solution. The reaction mixture was stirred at room temperature for one hour, quenched by the addition of 50 mL water and was extracted with three 50 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The product was purified by flash chromatography (SiO2, 1% ethyl acetate in hexanes) to yield 0.939 g of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>CN(C=O)C>[OH:15]/[C:13](/[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=1)=[CH:14]\[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(/C(O)=C/C(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
NaH (60% dispersion, 0.388 g, 16.2 mmol) was added to a solution of methyl benzoate (0.629 g, 4.62 mmol) and 1,1-dimethylethyl (4-acetylphenyl)carbamate (N-BOC-4-aminoacetophenone 1.09 g, 4.62 mmol) in anhydrous DMF (20 mL) at 0° C. The reaction was allowed to warm to room temperature overnight then quenched with saturated aqueous NH4Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 mL) and the organic layer washed successively with saturated aqueous NaHCO3 and brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo to provide the condensation product as a yellow oil (1.31 g, 83% yield). The product was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH:20]=[CH:19]4)[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH2:20][C@H:19]4[CH3:1])[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Reactant: C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.35 g of copper(I) iodide is added to an ice-cooled solution of 11.9 ml of a 3-molar methylmagnesium bromide solution in 68 ml of tetrahydrofuran under a nitrogen stream. Then, a solution of 4.26 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one (see Example 6b) in 50 ml of tetrahydrofuran is added in drops and stirred for 30 minutes at a bath temperature of 0° C. Then, the excess reagent is decomposed with saturated ammonium chloride solution, diluted with ethyl acetate, washed with ammonium chloride solution and water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 3.6 g of 3-benzyloxy-7α-(5-hydroxypentyl)-15β-methyl-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+66.4°(c=0.515% in chloroform).
Reaction SMILES: [CH2:1](N(CC)CC)C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([N:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32][OH:33])[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.CI>CN(C=O)C>[CH3:1][N:28]1[CH2:27][CH2:26][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:31][CH2:32][OH:33])[C:23]=2[CH2:29]1
Reactant: CCN(CC)CC
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
Triethylamine (0.038 ml, 0.27 mmol) was added to 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.058 g, 0.14 mmol, Example 1) in DMF (2 mL). Methyl iodide (9.28 μl, 0.15 mmol) was added and the reaction mixture was stirred for 1 h at 25° C. The solution was concentrated under reduced pressure and the product purified by preparative HPLC to give 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.022 g, 36.7%). MS (ESI+)/(ESI−) m/z 443/441
Reaction SMILES: [N+:1]([C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:13](Br)[C:14]#[CH:15]>O1CCCC1>[N+:1]([C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([CH2:15][C:14]#[CH:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1c[nH]cc1[N+](=O)[O-]
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1cc(C=O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
826 mg of 3-nitro-1H-pyrrole-4-carboxaldehyde [prepared by the process in Bull. Soc. Chim. p. 283-29 (1972)] were poured into 40 ml of tetrahydrofuran and then, at +5° C., 280 mg of sodium hydride as 50% in oil were added. After leaving the temperature at 20° C. for one hour, 1.19 g of propargyl bromide were added. The mixture was stirred for 18 hours at 20° C. and then was filtered and concentrated. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (1-1) to obtain 800 mg of 3-nitro-1-(2-propynyl) 1H-pyrrol-4-carboxaldehyde melting at 120° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[S:31][CH:32]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:27][C:28]1[N:29]=[C:30]([S:33]([NH:4][C:5]2[CH:13]=[C:12]3[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][C:6]=2[O:14][CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=2)(=[O:35])=[O:34])[S:31][CH:32]=1
Reactant: CCOC(=O)c1cnc(COc2cc3c(cc2N)CCC3)cn1
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NS(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 712 mg of ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate trihydrochloride were added 35.6 mL of pyridine and 35.0 mL of a 0.21 M 4-methyl-1,3-thiazole-2-sulfonyl chloride/tert-butyl methyl ether solution, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 95:5) to obtain 256 mg of ethyl 5-{[(6-{[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C1CCCC(=O)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Racemic 3-oxocyclohexanecarboxylic acid (1.0 g, 7.03 mmol) was dissolved in THF (27.1 mL). To this solution was added triethylamine (1.9 mL, 13.5 mmol) followed by pivaloyl chloride (0.8 mL, 6.5 mmol) at −20° C. The resulting mixture was stirred at −20° C. for 1 h. After that, LiCl (0.252 g, 5.9 mmol) and (4R,5S)-4-methyl-5-phenyloxazolidin-2-one (0.959 g, 5.4 mmol) were added to the solution at −20° C. The reaction mixture was warmed to room temperature and stirred overnight, before the reaction was quenched with 0.2 N HCl. The THF was removed and the resulting mixture was partitioned by 0.2 N HCl and EtOAc. The organic layer was collected and washed with brine, dried (MgSO4) and concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, isocratic elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 51% B over 30 min, 25 mL/min, 220 nM: the first peak (retention time=15.3 min) was (4R,5S)-4-methyl-3-((S)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8A, (LCMS=302.0 [M+H]+), and the second peak (retention time=19.6 min) was (4R,5S)-4-methyl-3-((R)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8B, LCMS=324.1 [M+Na]+ by comparison to the R-3-oxocyclohexanecarboxylic acid case (Aust. J. Chem., 34:2231 (1981)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C(OC(C)(C)C)=O)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]>ClCCl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)n1N(Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)n1NCc1ccccc1
Yield: 100.9 %

Procedure:
1-(Benzyl-tert-butoxycarbonyl-amino)-3,4,5-trichloro-1H-pyrrole-2-carboxylic acid methyl ester (509 mg, 1.17 mmol) was stirred in a mixture of dichloromethane (5 mL) and TFA (5 mL) at rt for 30 m in; then concentrated, the residue was dissolved in EtOAc, washed with diluted sodium bicarbonate, and saturated NaCl solution, dried over sodium sulfate, filtered, concentrated to give the crude product (394 mg) as white solid. ESI (m/z): 334 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:9]1([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]1)#[CH:8].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH:7]([C:9]1([O:14][Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:20][CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[CH2:8]
Reactant: C#CC1(O[Si](CC)(CC)CC)CCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C=CC1(O[Si](CC)(CC)CC)CCCC1

Procedure:
Lindlar catalyst (250 mg) was prehydrogenated in hexane (40 ml) and pyridine (0.25 ml) for 30 min.; after addition of 1-Ethinyl-1-triethylsilanyloxy-cyclopentane (11.22 g; 50.0 mmole) dissolved in hexane (80 ml) hydrogenation was continued at ambient temperature and normal pressure until the uptake of hydrogen ceased; the catalyst was removed by filtration through a plug of neutral alumina (act. 3); after removal of the solvent under reduced pressure the crude product was purified by distillation. 1-Vinyl-1-triethylsilanyloxy-cyclopentane (B1) was obtained as a colourless oil; bp.: 100° C. (0.2 mbar), Kugelrohr.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])[CH3:11].[C:23]([O:27][C:28](=[O:56])[NH:29][C:30]([C:32]1[S:33][C:34]([S:54][CH3:55])=[C:35]([S:37]([C:40]2[CH:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=3[CH3:53])[CH:43]=[CH:44][CH:45]=2)(=[O:39])=[O:38])[CH:36]=1)=[NH:31])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:52][C:49]1[CH:50]=[CH:51][C:46]([C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([S:37]([C:35]3[CH:36]=[C:32]([C:30]([NH:29][C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:56])=[NH:31])[S:33][C:34]=3[S:54][CH3:55])(=[O:39])=[O:38])[CH:41]=2)=[C:47]([CH3:53])[CH:48]=1)=[O:21])[CH3:11]
Reactant: CCOC(=O)CCCCCN=C=O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Yield: 42.7 %

Procedure:
Diisopropylethylamine (35 μL, 0.2 mmol), 6-isocyanato-hexanoic acid ethyl ester (40 μL, 0.2 mmol), and {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 220: step b) 20 mg, 0.04 mmol) were stirred for 24 h in DCM (1 mL). The solution was partitioned between EtOAc (40 mL) and 0.1 N HCl (10 mL) and was washed with additional 0.1N HCl (2×10 mL), NaHCO3 (10 mL), and brine (20 mL). The solution was dried, concentrated in vacuo, and purified by SiO2 preparative TLC to yield the product (12 mg, 43%). 1H-NMR (CDCl3): δ 8.06 (s, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.46 (m, 2H), 7.23 (br t, 1H, J=5.4 Hz), 7.15 (m, 1H), 7.07 (m, 2H), 6.97 (m, 1H), 5.32 (br t, 1H), 4.15 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 2.30 (t, 2H, J=7.3 Hz), 2.11 (s, 3H), 1.54–1–70 (m, 4H), 1.51 (s, 9H) 1.35 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.30 g), 5% palladium-carbon (28.00 g), ethanol (150 ml), and tetrahydrofuran (150 ml) was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (9.01 g, yield: 83%). This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.C[OH:31].O>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH:16]=[CH:15][C:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[OH:31]
Reactant: CO
Reactant: O=C(C=Cc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(C=Cc1ccccc1O)c1ccccc1Cl

Procedure:
To a solution of 740 mg (2.12 mmol) of 1-4 in 15 mL of CH2Cl2 at −78° C. was added dropwise 2.75 mL (2.75 mmol) of a 1M solution of BBr3 in CH2Cl2. After stirring for 30 min at that temperature, 1 mL of MeOH was added, and the mixture was dumped into water, extracted twice with 50 mL of CH2Cl2, washed again with water, and dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel with a gradient of 2 to 70% EtOAc in hexanes over 30 min to provide 1-5 as a beige solid. Data for 1-5: 1HNMR (500 MHz, CDCl3) δ 7.5-7.3 (m, 5H), 7.25 (m, 1H), 7.2-7.0 (m, 3H), 6.9 (m, 1H), 5.1 (bs, 1H) ppm.