Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH:13]C1C=CC=C2C=1N=CC=C2.[OH-].[K+].C(O)(C)(C)C>[Cu]I.O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1cccc2cccnc12
Reactant: Cc1c(I)cc(Cl)cc1C(=O)O
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(O)cc(Cl)cc1C(=O)O
Temperature: 100 °C
Reaction time: 24 h
Yield: 404.9 %

Procedure:
To 5-chloro-3-iodo-2-methylbenzoic acid (10.0 g, 33.7 mmol), copper(I) iodide (0.70 g, 3.68 mmol), 8-hydroxyquinoline (1.0 g, 6.89 mmol), and potassium hydroxide (9.5 g, 169 mmol) was added tert-butanol (30.0 mL), dimethyl sulfoxide (30 mL) and water (3.0 mL). The reaction was purged with nitrogen, then heated to 100° C. and stirred for 24 h. The reaction was allowed to cool to room temperature and poured into 1 N HCl (200 mL) and EtOAc (250 mL). The flask was rinsed with water. The mixture was stirred for 30 min, filtered through a pad of Celite®, and rinsed with EtOAc. The EtOAc layer was removed, washed with aqueous sodium bisulfate and brine, dried (MgSO4), filtered and evaporated under vacuum to give 5-chloro-3-hydroxy-2-methylbenzoic acid (6.5 g, 27.9 mmol, 83% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s., 1H), 10.18 (s, 1H), 7.17 (d, J=2.27 Hz, 1H), 6.98 (d, J=2.02 Hz, 1H), 2.26 (s, 3H). MS(ES) [M+H]+ 186.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1>CS(C)=O.CCOC(C)=O>[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1.[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: CC(N)c1ccc(-n2cccc2)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(-n3cccc3)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2ccc(-n3cccc3)cc2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (44 mg, 0.18 mmol) and 1-(4-(1H-pyrrol-1-yl)phenyl)ethanamine (33.9 mg, 0.182 mmol, 1 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-3-(2-((R)-1-(4-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(4-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][N:18]1[C:25]2[N:21]([N:22]=[CH:23][CH:24]=2)[CH:20]=[CH:19]1)=[O:6])[CH:2]=[CH2:3].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].C(OCC)(=O)C.[Cl-].[Na+]>C(#N)C>[C:26]([S:28][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][N:18]2[C:25]3[N:21]([N:22]=[CH:23][CH:24]=3)[CH:20]=[CH:19]2)[CH2:9]1)(=[O:29])[CH3:27]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccn2nccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccn2nccc12
Yield: 81 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-2-(imidazo [1,2-b]pyrazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (3.04 g) and potassium thioacetate (1.41 g) in acetonitrile (60 ml) was stirred under refluxing for 4 hours. To the reaction mixture were added ethyl acetate (100 ml) and aqueous sodium chloride (50 ml) with stirring and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl -2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (2.33 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH2:9])=[O:8].CO.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+]>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([NH2:9])=[O:8])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
To a stirred solution of cis-2-amino-cyclopentanecarboxylic acid amide (1 g, 0.008 mol) in methanol (20 mL, 0.5 mol) and water (10 mL, 0.6 mol) at 0° C. in an ice bath was added 2,4,5-trichloropyrimidine (1.7 g, 0.0094 mol) followed by sodium bicarbonate (1 g, 0.02 mol). The reaction mixture was warmed to room and stirred at room temperature for 24 h. The reaction mixture was diluted with water (25 mL) and washed with ethyl acetate (3×50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid amide as a white solid (1.8 g, 80% yield). No further purification was needed. 1HNMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 6.73 (d, 1H, J=6.8 Hz), 5.56 (broad s, 1H), 5.44 (broad s, 1H), 4.66 (p, 1H, J=7.5 Hz), 2.97 (q, 1H, J=7.5 Hz), 2.05-2.15 (m, 3H), 1.83-1.98 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].O1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N:11]1[C:12]2[C:10](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:7]=1[NH:4][CH2:3][CH2:2][CH2:1][NH2:5]
Reactant: NCCCN
Reactant: c1ccncc1
Reactant: C1CCOC1
Product: NCCCNc1ccc2ccccc2n1
Yield: 82 %

Procedure:
To a solution of propane-1,3-diamine (65.1 ml, 0.764 mol) in dry pyridine (25 ml) kept under an atmosphere of nitrogen 2-chloro-quinoline (25 g, 0.153 mol) was added. The reaction mixture was heated at reflux temperature for 18 h. To the cooled reaction mixture was added tetrahydrofuran (100 ml) and the precipitate was filtered off and washed with tetrahydrofuran (2×50 ml). The solvent was evaporated in vacuo and the residue purified by distillation at 154° C. and 2.5×10-2 mbar affording 25.34 g (82%) of N-(quinolin-2-yl)propane-1,3-diamine as a crystallising oil.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[I-].[K+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1n[nH]c(Br)n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Cn2nc(Br)nc2Br)cc1
Yield: 78 %

Procedure:
3,5-dibromo-1H-1,2,4-triazole (1.5 g, 6.61 mmol, Eq: 1.00), potassium iodide (110 mg, 661 μmol, Eq: 0.10), 4-methoxybenzyl chloride (1.14 g, 990 μl, 7.27 mmol, Eq: 1.1) and N,N-diisopropylethylamine (1.71 g, 2.31 ml, 13.2 mmol, Eq: 2.0) was stirred in acetonitrile (23.0 ml) overnight at room temperature. The crude material was applied on silica gel and purified by column to give 3,5-Dibromo-1-(4-methoxy-benzyl)-1H-[1,2,4]triazole (1.79 g, 78%) as white solid. MS: m/z=348.1 (M+H+)
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:3]1([CH2:2][CH2:1][NH:9][C:17](=[O:19])[CH3:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
After phenethylamine (37.8 ml, 0.3mol) and triethylamine (42 ml, 0.3mol) were dissolved in dichloromethane (200 ml), acetyl chloride (20.7 ml, 0.3mol) was dropwise added thereto, while maintaining the reaction temperature below 0° C. The resulting solution was stirred for 10 minutes at room temperature, washed with water dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 45.8 g of the titled compound as a white solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([C@@H:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[C@H](c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the racemic product as an off-white solid. The desired enantiomer (>99% ee) was obtained via SFC. MS m/z=359.0 [M+1]+ Calc'd for C20H14N4OS: 358.4
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36]([O:43][CH2:44][CH2:45]I)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:43][CH2:44][CH2:45][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: ICCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86(eee)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988),2039] there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 625 (M+NH4)+.
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]([NH2:39])=[O:38])=[CH:34][CH:33]=[C:32]([C:40]#[C:41][Si](C(C)C)(C(C)C)C(C)C)[CH:31]=2)=[O:26].O>O1CCCC1>[NH2:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]([NH2:39])=[O:38])=[CH:34][CH:33]=[C:32]([C:40]#[CH:41])[CH:31]=2)=[O:26]
Reactant: CC(C)[Si](C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
1.0 M Tetrabutylammonium fluoride tetrahydrofuran solution (15 mL, 15 mmol) was added to a solution of 2-aminocarbonylamino-6-triisopropylsilylethynylindole-3-carboxamide (Compound 9-15, 4.0 g, 10 mmol) in anhydrous tetrahydrofuran (180 mL), and the mixture was stirred at 75° C. for 2.5 hours. Water (180 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (180 mL). The organic layer was washed with brine (180 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with a solution mixture of ethanol and chloroform (ethanol/chloroform=1/3, 55 mL) and dried under reduced pressure to give the title compound (2.2 g) as a slightly brown solid (yield 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[C:11](=[O:36])[NH:10][C:9]1=[O:37].[CH2:38]([O:45][CH2:46]Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:38]([O:45][CH2:46][N:10]1[C:11](=[O:36])[C:12]2[N:13]([C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:37])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: ClCOCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(COCc2ccccc2)c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1.3 g (9.44 mmol) of potassium carbonate were added at 60° C. to a solution of 2.4 g (5.9 mmol) of 3-methyl-7-tritylxanthine from stage a) in 50 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.06 ml (7.67 mmol) of benzyloxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 7 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (3/2).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8])=[CH:2][CH:3]=1)=[O:14]
Reactant: CC(=O)NC(C)c1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-(1-phenylethyl)acetamide (5.0 g) in dichloromethane (100 ml) was added dropwise titanium tetrachloride (16.7 ml) at below 5° C. over 30 min. Thereto was added dropwise a solution of dichloromethyl methyl ether (14.1 ml) in dichloromethane (30 ml) solution at below 5° C. over 30 min. The mixture was stirred at 25° C. for 3 hr, at room temperature for 12 hr, and then at 25° C. for 3 hr, and poured into ice water (800 ml) and extracted with ethyl acetate. The extract was washed successively with a saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=1:3) to give the title compound (0.35 g) as a colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35]([OH:37])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29](=[O:30])[NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35](=[O:37])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reactant: CC(C)(C=CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C=CC(C)(C)NC(=O)OC(C)(C)C)n1
Yield: 94.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42 g, 2.18 mmol) and 1-hydroxybenzotriazole monohydrate (0.33 g, 2.18 mmol) were added to a solution of 4-tertbutoxycarbonylamino-4-methylpent-2-enoic acid (0.50 g, 2.18 mmol) in N,N-dimethylformamide (7 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (0.68 g, 1.56 mmol) and triethylamine (0.16 g, 1.56 mmol) in N,N-dimethylformamide (8 ml) were added. After 18 h at 20° C. the reaction mixture was poured on ice water (90 ml) and extracted several times with ethyl acetate (total 90 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (95 g) using ethyl acetate and heptane (1:1) as eluent to give 0.90 g of {1,1-dimethyl-3-[(1R)-1-((1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl]allyl}carbamic acid tertbutyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:30](=[O:31])[O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1(O)CCc2ccccc2C12CCCC2)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of the product from Example 9 (0.88 g, 3.59 mmol) and triethylamine (0.40 g, 3.78 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and treated dropwise with 2,2,2-trichloroethylchloroformate (0.80 g, 3.78 mmol) in 2 mL CH2Cl2. The resulting solution was stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was washed with saturated aq. NaHCO3 solution (10 mL). The aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 10:1 heptane/ethyl acetate) to give the title compound (1.18 g, 78%) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19].[OH-].[K+].S(=O)(=O)(O)O>C(O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
10.0 g of (+/−)-trans-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene and 20.0 g of potassium hydroxide are dissolved in 150 ml of ethanol and 35 ml of dimethyl formamide. A solution of 17.5 ml of conc. sulfuric acid in 60 ml of ethanol is then added dropwise such that the internal temperature does not exceed 4° C. After stirring for 1 h, the mixture is added to 1 l of ice water, the precipitate is filtered off with suction, washed with water and dried, and the crude product is recrystallized from ethanol. 8.6 g of the title compound of m.p. 82.5-84° C. are obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-:21].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][C:2]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:21])=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)=[O:19]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C(Cl)CCCCl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 23.6 g (0.142 mole) of fluorene and 50.0 g (0.35 mole) of 4-chlorobutyryl chloride in 1500 ml of methylene chloride chilled to -20°C., is added 39.8 g (0.298 mole) of aluminum chloride with rapid stirring. The reaction mixture is refluxed for 4 hours, stirred at room temperature for 16 hours and is poured onto an ice/concentrated HCl mixture. The organic layer is separated, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. The methylene chloride solution is filtered, evaporated to dryness, and the solid residue recrystallized from acetone to yield the desired 2,7-bis(4-chlorobutyryl)fluorene.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: BrC/C=C/c1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CBr)C1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.4 %

Procedure:
To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%).
Reaction SMILES: C[C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=C)CC=1.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14].[OH2:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:12]([F:20])([F:19])[C:13]1([C:15]([F:18])([F:17])[F:16])[O:21][CH:5]([CH:8]=[CH2:10])[CH:6]([CH:7]=[CH2:2])[O:14]1
Reactant: O
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC1OC(C(F)(F)F)(C(F)(F)F)OC1C=C
Temperature: 120 °C
Yield: 779.5 %

Procedure:
2,3-Divinylethylene oxide was prepared according to E. L. Stogryn et al., J. Org. Chem., , 1275 (1964). This compound (60 g, 0.625 mole) was mixed with d-limonene (2 g), tetra-n-butylammonium bromide (0.6 g), water (0.6 g) and hexafluoroacetone (108 g, 0.65 mole) in a 360 ml Shaker tube. The tube was sealed and was heated at 80° C./1 h4, 100° C./1 hr and 120° C./6 hrs. The product mixture unloaded from the tube was distilled to give the desired product 30 g as a clear, colorless liquid. Bp. 50° C./30 mmHg. The structure was supported by its NMR spectroscopic data.