Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:34][C:7]2[CH:8]=[CH:9][C:10]3[C@@:15]4([C:27]([CH3:29])([CH3:28])[C@@H:26]5[C@@:17]6([N:32](C)[C:30](=[O:31])[C@:24]7([CH2:25]5)[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]7)[CH2:18]6)[CH2:16]4)[C:13](=[O:14])[NH:12][C:11]=3[C:6]=2[O:5][CH:4]=[CH:3]1.C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1([CH3:35])[O:34][C:7]2[CH:8]=[CH:9][C:10]3[C@@:15]4([C:27]([CH3:28])([CH3:29])[C@H:26]5[C@@:17]6([NH:32][C:30](=[O:31])[C@:24]7([CH2:25]5)[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]7)[CH2:18]6)[CH2:16]4)[C:13](=[O:14])[NH:12][C:11]=3[C:6]=2[O:5][CH:4]=[CH:3]1
Reactant: CN1C(=O)[C@@]23CCCCN2C[C@@]12C[C@@]1(C(=O)Nc4c1ccc1c4OC=CC(C)(C)O1)C(C)(C)[C@H]2C3
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C=COc2c(ccc3c2NC(=O)[C@@]32C[C@@]34CN5CCCC[C@]5(C[C@H]3C2(C)C)C(=O)N4)O1
Temperature: 28 °C
Reaction time: 48 h

Procedure:
The contents of 100 flasks, each containing 100 ml fermentation as described in the protocol for biotransformation and which had been shaken at 28° C. for 24-72 hours following addition of Marcfortine A (0.010 g per flask, 1 g total) in DMF (0.2 ml per flask, 20 ml total) are each treated with CH2Cl2 (100 ml). The contents are combined and stirred in a waring blender for 5 minutes. The mixture is centrifuged and the resulting aqueous layer is decanted. The organic layer is collected, dried (sodium sulfate), filtered and concentrated. The components of the crude mixture are separated by a series of column chromatographies using a silica gel--solid extract ratio of 50-125:1. Columns are eluted with either 2-5% methanol in CH2Cl2 or 15-60% acetone in C2Cl2. From these chomatographic separations there is isolated Marcfortine B. HRMS (FAB); mle, found, 464.2563; calculated for C27H33N3O4 +H1, 464.2549.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([CH2:22][C:23]([O:25]CC)=[O:24])=[N:12]3)=[N:7][C:6]=2[CH:28]=1.O1CCOCC1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([CH2:22][C:23]([OH:25])=[O:24])=[N:12]3)=[N:7][C:6]=2[CH:28]=1
Reactant: CCOC(=O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(5-bromobenzothiazol-2yl- methyl)-4-oxo-3-H-phthalazin-1-ylacetate (15.0 g) and dioxane (150 ml) was brought to solution by warming on a steam bath and to this solution was added a solution of 10% potassium hydroxide (20 ml) in ethanol (50 ml.). The resulting dark purple solution was stirred at room temperature for 2 hours and concentrated to remove excess dioxane and ethanol. The concentrate was diluted with water (100 ml) and the resulting solution was washed with ether (2×100 ml). The aqueous layer was collected and acidified to pH 2.0 by addition of concentrated HCl. The precipitated solid was crystallized from methylene chloride/ethanol (400 ml/40 ml) to obtain the product (Yield 7.65 g; m.p. 214° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].[Cs].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[N:9]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2C
Reactant: COc1cccc(CBr)c1
Agent: [Cs]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(CN2C(C)c3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35.3 %

Procedure:
To a solution of 240 (170 mg, 0.45 mmol) in acetone (1.5 ml) was added cesium C(Ar)bonate (162 mg, 0.5 mmol) followed by 3-methoxy benzyl bromide (0.063 ml, 0.54 mmol). The reaction mixture was stirred at rt for 23 h. The resulting solution was diluted with water and extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification (Flashmaster; 10 g, 100% hex to 95% hex:5% EtOAc over 25 min) afforded the title compound (79 mg, 35%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 0.94 (3H, s, CH3), 1.07 (18H, d, J=6.7 Hz, 6×SiCHCH3), 1.09 (3H, s, CH3), 1.15-1.29 (3H, m, 3×CH), 1.20 (3H, d, J=6.2 Hz, CH3CH), 2.37 (1H, d, J=15.3 Hz, one of CH2), 2.94 (1H, d, J=15.3 Hz, one of CH2), 3.50 (1H, d, J=17.3 Hz, one of CH2), 3.71 (1H, q, J=6.2 Hz, CHCH3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.09 (1H, d, J=17.3 Hz, one of CH2), 6.48 (1H, s, CH), 6.59 (1H, s, CH), 6.71 (1H, dd, J=7.7, 2.2 Hz, CH), 7.0 (1H, d, J=7.7 Hz, CH), 7.09 (1H, brs, CH), 7.19 (1H, t, J=7.9 Hz, CH). 13C NMR (100 MHz; CDCl3) 12.85 (CH3), 17.92 (CH3), 18.69 (CH3), 24.35 (CH3), 30.03 (CH3), 44.29 (CH2), 53.29 (CH2), 53.72 (C), 55.08 (OCH), 55.47 (OCH3), 57.40 (OCH3), 111.06 (CH), 111.84 (CH), 112.92 (CH), 118.13 (CH), 119.34 (CH), 126.70 (C), 128.81 (CH), 132.34 (C), 143.23 (C), 146.35 (C), 148.81 (C), 159.46 (C). LC/MS (ES+) tr=7.09 min, m/z 498.42 (M++H). HPLC tr=7.03 min (>98%).
Reaction SMILES: C([O:4][C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35]CC=C)=[O:34])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:6]=1[C:7]([OH:9])=[O:8])C=C.[F:39][C:40]([F:45])([F:44])[CH:41](O)[CH3:42]>>[OH:4][C:5]1[C:6]([C:7]([O:9][CH:41]([CH3:42])[C:40]([F:45])([F:44])[F:39])=[O:8])=[C:10]([CH:11]=[CH:12][C:13]=1[C:14]([F:15])([F:16])[F:17])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)O)cc2)cc1
Reactant: CC(O)C(F)(F)F
Product: CC(OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O)C(F)(F)F
Yield: 43 %

Procedure:
According to a method similar to Example (72-1) and Example (13-5), from 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoic acid (150 mg, 0.29 mmol) and 1,1,1-trifluoro-2-propanol (31 μl, 0.34 mmol), the title compound was obtained as a yellow crystal (68 mg, two-step total yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccnc(Cl)n2)C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A flask was charged with a solution of 2,4-dichloropyrimidine (300 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL). tert-Butyl 3-hydroxyazetidine-1-carboxylate (349 mg, 2.0 mmol) and cesium carbonate (1.11 g, 3.42 mmol) were added and the resulting mixture was heated to 80° C. for 2 h. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-80% ethyl acetate in hexanes) afforded tert-butyl 3-[(2-chloropyrimidin-4-yl)oxy]azetidine-1-carboxylate (550 mg, 1.9 mmol, 96%). MS ESI: [M+H]+ m/z 286.1.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:31][CH2:30]1
Reactant: Cc1cccc(C)c1CC1(N)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1CC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
The compound is prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 52 mg (11%, trifluoroacetate); mass spectroscopy: [M+H]+=383.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])[C:8]([C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2].C.[H][H]>[Pd].C(O)C>[CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:34])([F:35])[F:33])[C:8]([C:16]([OH:18])=[O:17])=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2]
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Reaction time: 0.5 h

Procedure:
Three g (6.2 mMol) Benzyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate are hydrogenated at normal pressure and at ambient temperature with the use of 1.5 g. 10% palladium on active charcoal in 100 ml. ethanol. The take up of hydrogen is finished after 30 minutes. The catalyst is filtered off, the solvent is distilled off in a vacuum and the colorless, crystalline residue is recrystallized from diisopropyl ether/ethyl acetate. There is obtained (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid in the form of colorless crystals with a melting point of 164°-166° C. (decomp.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Br:16])=[CH:11][CH:10]=2)=[O:5])C.[NH2:18][C@@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][C@@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:15]2
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Br)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Br)ccc2nc1N[C@H](Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 6-bromo-2-chloroquinoline-3-carboxylic acid ethyl ester is reacted with D-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (Yield 61%) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm: 4.45 (3H, s) 7.03–7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ ppm: 39.86, 116.28, 118.66, 118.76, 130.13, 135.73, 161.74, 163.53; LC/MS m/z 257/259.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:32][CH2:31][C:15]2([CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].C1CCCCC=1>C(O)C.[Pd]>[CH2:16]1[C:15]2([CH2:31][CH2:32][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14]2)[CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 106.4 %

Procedure:
Suspend benzyl 9-[2-(isobutylcarbamoylamino)acetyl]-2,9-diazaspiro[5.5]undecane-2-carboxylate (239.78 mmoles; 106.60 g) in ethanol (852.80 mL) and cyclohexene (1.20 moles; 121.90 mL), and add 5% palladium on charcoal (24 g; 55.4% moisture content). Heat the mixture to reflux and stir for 45 mins. Cool the mixture to room temperature, filter through a pad of diatomaceous earth washing the solid with ethanol, and concentrate under reduced pressure to give the final title compound, 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (79.2 g; 94% purity; 100% yield) mass spectrum (m/z):311.2 (M+1).
Reaction SMILES: [NH:1]1[C:5]([C:6](OC)=[O:7])=[C:4]([C:10](OC)=[O:11])[N:3]=[CH:2]1>O1CCCC1>[OH:7][CH2:6][C:5]1[N:1]=[CH:2][NH:3][C:4]=1[CH2:10][OH:11]
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Solvent: C1CCOC1
Product: OCc1nc[nH]c1CO

Procedure:
Reflux dimethyl 4,5 imidazole dicarboxylate (1.8 g) in THF (tetrahydrofuran) with 2.5 equivalents of LAH lithium aluminum hydride). Neutralize with NH4Cl solution and filter. Concentrate the filtrate under vacumm and extract the product with ethanol. Remove the solvent, filtrate through alumina using a THF solvent to give the title compound.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37].O>C1COCC1>[C:36]([O:25][CH2:24][CH2:23][C:21]1[NH:20][C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH:22]=1)(=[O:38])[CH3:37]
Reactant: Cc1ccc(-c2nc3cc(CCO)[nH]c3nc2-c2ccc(C)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethanol (step 2) (73 mg, 0.213 mmol) in dry THF (2 ml) at RT was treated with DIPEA (0.082 ml, 0.468 mmol) and acetyl chloride (0.018 ml, 0.255 mmol). After stirring for 16 hours at RT, the mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound, 2-(2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate;
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]2[C@@H:19]3[C@H:24]([CH2:25][CH2:26][C:17]=2[CH:16]=1)[NH:23][CH2:22][CH2:21][CH2:20]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@@H:19]([C:18]5[CH:27]=[CH:28][C:15]([O:14][CH3:13])=[CH:16][C:17]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 78 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 78% of theory; LC (method 1): tR=2.54 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:13]=[O:14].CC(=CC)C.[O-:20]Cl=O.[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([OH:20])=[O:14]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(-c2ccccc2)sc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-thiophene-2-carbaldehyde (0.200 g, 0.99 mmol) and 2-methyl-2-butene (2.77 g, 0.040 mol) in dimethylformamide (4 ml) at 0° C. was added NaClO2 (0.894 g, 9.89 mmol) and NaH2PO4 (1.09 g, 7.91 mmol) in water (5 ml). The solution was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed at reduced pressure and the residue partitioned between dichloromethane (10 ml) and 1N HCl solution (10 ml). The organic was separated, the aqueous layer extracted with dichloromethane (2×5 ml). The combined organic layers were dried (MgSO4) and the solvent removed at reduced pressure to give a yellow oil. Purification by flash column chromatography 50% ethyl acetate/petrol 40-60° C.) gave the sub-title compound as a white solid (0.14 g, 69% yield): 1H NMR (400 MHz, CDCl3) δH 2.65 (3H, s), 7.25 (1H, s) 7.35-7.80 (5H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=2)[NH:6]1)=[O:4].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][CH3:32])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:16])[F:17])[CH:11]=2)[N:6]1[C:28](=[O:29])[C@@H:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH3:32])=[O:4]
Reactant: COC(=O)C1Cc2cc(OC(F)(F)F)ccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-trifluoromethoxyindoline-2(R/S)-carboxylic acid methyl ester (1.95 g, 7.47 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (1.52 g, 7.47 mmol) dissolved in dried dichloromethane (15 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (1.00 ml, 7.96 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown oil which was purified by column chromatography on silica gel first by using 95:5 dichloromethane: diethyl ether as eluent, then another column on silica gel by using 7:3 petroleum spirit: diethyl ether. A yellow foam was obtained which was the mixture of two diastereomers.
Reaction SMILES: [CH2:1]([C@@H:8]1N[C@H](C(C)(C)C)N(C)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][N:21]([CH3:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[O:25][CH3:26].C(=O)C=CC1C=CC=CC=1.[BH4-].[Na+]>O1CCOCC1.C(O)C.C(Cl)Cl>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:27]([C@H:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:8][CH2:9][OH:18])=[C:24]([O:25][CH3:26])[CH:23]=1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Reactant: COc1cccc(N(C)C)c1
Agent: Cl
Agent: O=CC=Cc1ccccc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(N(C)C)ccc1[C@@H](CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a 50-mL roundbottom flask equipped with a magnetic stir bar was added (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (0.394 g, 1.60 mmol, 0.100 equiv), CH2Cl2 (16.0 mL), HCl (as a 4N solution in 1,4-dioxane, 0.400 mL, 1.60 mmol, 0.100 equiv), and N,N-dimethyl-m-anisidine (4.69 mL, 32.0 mmol, 2.00 equiv). The reaction vessel was cooled to 0° C. before the addition of cinnamaldehyde (2.06 ml, 16.0 mmol, 1.00 equiv). The solution was stirred for 12 h at 0° C. and then warmed to ambient temperature and stirred for an additional 6 h. At that time, the reaction mixture was added drop-wise to a stirring suspension of NaBH4 (0.750 g, 0.198 mmol, 1.24 equiv) in ethanol. After 5 min, the reduction was quenched with saturated aqueous NaHCO3 solution and diluted with CH2Cl2. The layers were separated and the organic was washed with saturated aqueous NaHCO3 and brine solutions. The resulting solution was dried over sodium sulfate and concentrated in vacuo to give a pale yellow residue, which was purified by silica gel chromatography. Gradient elution with 25–50% EtOAc in hexanes afforded the product as a colorless oil in 81% yield (3.70 g, 13.0 mmol); 74% ee. 1H NMR (300 MHz, CDCl3) δ 7.32–7.12 (m, 5H, ArH), 6.99 (d, J=8.2 Hz, 1H, ArH), 6.31 (dd, J=2.7, 8.8 Hz, 1H, ArH), 6.27 (d, J=2.2, Hz, 1H, ArH), 4.51 (dd, J=6.6, 8.8 Hz, 1H, ArCH), 3.83 (s, 3H, OCH3), 3.65–3.48 (m, 2H, CH2OH), 2.93 (s, 6H, N(CH3)2), 2.38–2.12 (m, 2H, CHCH2), 1.98 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3) δ 157.8, 150.5, 145.5, 128.8, 128.4, 128.2, 125.9, 121.3, 105.5, 96.6, 61.6, 55.9, 41.1, 38.7, 38.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][C@H:17]2[C@H:9]([CH2:10][C:11]3[C:16]2=[CH:15][C:14](Br)=[CH:13][C:12]=3[CH3:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][C@H:17]2[C@H:9]([CH2:10][C:11]3[C:16]2=[CH:15][C:14]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][C:12]=3[CH3:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(Br)cc3[C@H]2C1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(NCc4ccccc4)cc3[C@H]2C1
Temperature: 80 °C
Yield: 90 %

Procedure:
cis-6-Bromo-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (68 mg, 0.2 mmol), benzylamine (64 mg, 0.6 mmol), NaOt-Bu (58 mg, 0.3 mmol) and (2-biphenyl)di-t-butylphosphine (11 mg, 0.018 mmol) were dissolved in toluene (5.0 mL), and the solution was degassed. To the solution was added tris(dibenzylideneacetone)dipalladium (11 mg, 0.006 mmol), and the reaction mixture was heated at 80° C. for 15 h under Ar. The reaction mixture was cooled to 20° C. and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was filtered through short silica gel column (Hex/EtOAc 7/3) to obtain crude cis-6-benzylamino-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (66 mg, 0.18 mmol)
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].C[O-].[Na+].CO[CH:25]=[CH:26][C:27](=O)[CH3:28].[OH-].[Na+]>CCO.O>[CH3:25][C:26]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:28][CH:27]=1
Reactant: COC=CC(C)=O
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (19.2 g, 70 mmol) and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added 4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, the reaction mixture was refluxed for 2 h and then cooled. Water (50 ml) and 2M NaOH were added and the mixture was stirred at room temperature overnight. The organic solvents were removed and the reaction mixture was extracted (washed) with EtOAc. The water phases were acidified with hydrochloric acid to pH 3-4, an orange coloured precipitate appeared and was filtered off, washed with water and dried. Recrystallisation twice from heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as a white powder.