Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:14][OH:15])[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O>C1COCC1>[F:13][C:10]([F:11])([F:12])[C:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:15][N:14]=1
Reactant: ON=C(c1ccc(O)cc1O)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(C(F)(F)F)noc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of 1-(2,4-dihydroxyphenyl)-2,2,2-trifluoroethanone oxime (Example 70, 0.25 g, 1.13 mmol) in THF (15 mL) was added triphenylphosphine (0.63 g, 2.4 mmol) and the mixture was cooled to 0° C. A solution of DEAD (0.48 mL, 2.3 mmol) in THF (10 mL) was slowly added while the temperature was kept at 0° C., after which the reaction mixture was stirred at 0-5° C. for 4 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/hexane (v/v) 1:10 to 3:2 gradient) gave 0.23 g of the title compound with minor impurities. The material was used without further purification. GC-MS [M+H]+: 204.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5Br)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc2[nH]cc(-c3ccccc3)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 130 °C

Procedure:
Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130° C. in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-1H-indol-5-yl)cyclopropane carboxamide. ESI-MS m/z calc, 396.2, found 397.3 (M+1)+. Retention time of 3.52 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (d, J=1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:11][C:5]1([CH2:4][CH2:3][OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(C)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CCO)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Step C To a solution of (1-methyl-cyclohexyl)-acetic acid methyl ester (3.3 g, 19.4 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added a tetrahydrofuran solution (1 M) of LiAlH4 (29 mL, 29 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 2-(1-methyl-cyclohexyl)-ethanol as a colorless oil (2.2 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:9](=[N:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1cccnc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1ccc(C(=NCc2cccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 ml of 3-(aminomethyl)pyridine are added to a solution of 2.8 ml of benzophenoneimine in 50 ml of DCM, and the mixture is stirred overnight at RT. A further 0.28 ml of benzophenoneimine is added and the mixture is stirred for 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 4.56 g of the expected product are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:16]=[C:15]3[NH:17][CH:18]=[CH:19][C:14]3=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH:17]1[C:15]2=[N:16][C:11]([CH:8]([NH2:7])[CH2:9][CH3:10])=[CH:12][CH:13]=[C:14]2[CH:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc[nH]c3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(N)c1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 140.9 %

Procedure:
To a solution of [1-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-cyclopropyl]-carbamic acid tert-butyl ester (80 mg, 0.32 mmol) in dioxane (1 mL) was added 4N HCl in dioxane (500 uL, 2.00 mmol). The reaction was stirred at room temperature for 1 h. Solvents were removed and the resulting brown oil was suspended in Toluene (3 mL×2). Removal of solvents to dryness affords 79 mg of the title compound 1-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-cyclopropylamine as a HCl salt, m/z 174.40 [M+1]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (100 mg, 296 μmol), o-tolylboronic acid (40 mg, 296 μmol) and tetrakis(triphenylphosphine)palladium (17 mg, 15 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (444 μl, 888 μmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to RT and purified directly without work-up, via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound in (65 mg) as a pale yellow solid. Found MS (ES+): 394(M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([N:55]3[CH2:60][CH2:59][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:57][CH2:56]3)[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([N:55]5[CH2:56][CH2:57][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:59][CH2:60]5)[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 64.3 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.198 mmol), 5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 204, Step E) (0.081 g, 0.198 mmol) and HCl (4N,1,4-Dioxane, 0.099 mL, 0.395 mmol) in Trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. The reaction was quenched with 7N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide (0.112 g, 61%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.26-9.40 (m, 1H), 8.40 (s, 1H), 8.27 (d, J=5.22 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.77 (dd, J=8.57, 2.25 Hz, 1H), 7.71 (d, J=8.98 Hz, 1H), 7.59 (s, 1H), 7.33-7.51 (m, 2H), 7.27 (d, J=8.61 Hz, 1H), 7.15-7.24 (m, 2H), 6.88-6.98 (m, 1H), 6.81 (s, 1H), 6.60 (d, J=5.22 Hz, 1H), 4.21-4.34 (m, 2H), 4.07 (q, J=6.93 Hz, 2H), 3.07-3.17 (m, 4H), 2.97-3.06 (m, 2H), 2.87 (s, 3H), 2.59-2.77 (m, 6H), 2.55 (q, J=7.45 Hz, 2H), 2.37-2.46 (m, 1H), 1.79-1.90 (m, 2H), 1.53-1.68 (m, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.26 (t, J=6.97 Hz, 3H), 1.10 (t, J=7.51 Hz, 3H). MS (M-2H, ES−) 878.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1.B(Cl)(Cl)Cl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: COc1cccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC1c2cccn2-c2ccc(Br)cc2N1C(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A solution of 7-bromo-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (240 mg, 0.60 mmol) and tetrabutylammonium iodide (558 mg, 1.51 mmol) in methylene chloride (5 mL) at −78° C., under nitrogen, was treated with a 1 M solution of boron trichloride in methylene chloride (1.51 mL, 1.51 mmol). The reaction was then warmed to 0° C. and was stirred for 4 h. Ice and water was added to the reaction which was stirred to 30 min. The reaction was then diluted with a saturated aqueous solution of sodium bicarbonate, and the product was extracted with methylene chloride (3×25 mL). The product was purified via Biotage Horizon® (25S, silica, gradient from 15% EtOAc/hexane to 60% EtOAc/hexane) to yield 196 mg (85%) of 3-[(7-bromo-4-methylpyrrolo[1,2-a]quinoxalin-5(4H)-yl)carbonyl]phenol as a white foam. MS (ESI) m/z 383/385 ([M+H]+); MS (ESI) m/z 381/383 ([M−H]−); HRMS: calcd for C19H15BrN2O2, 382.0317; found (ESI+), 383.03805.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:10][CH2:11][N:12]([CH3:23])[CH2:13][C:14]=3[C:15]3[NH:20][C:19](=[O:21])[C:18](=O)[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:10][CH2:11][N:12]([CH3:23])[CH2:13][C:14]=3[C:15]3[NH:20][C:19](=[O:21])[C:18](=[N:25][OH:26])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(-c3ccc(Cl)cc3)cc3c(c2C1)NC(=O)C3=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN1CCc2c(-c3ccc(Cl)cc3)cc3c(c2C1)NC(=O)C3=NO
Reaction time: 0.25 h

Procedure:
A mixture of 5-(4-chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1-H-pyrrolo[3.2-h]isoquinoline-2,3-dione (0.50 g, 1.53 mmol), hydroxylamine hydrochloride (0.5 g, 7.2 mmol) and ethanol (5 ml, 96%) was stirred at room-temperature for 15 minutes. The colour shifted from yellow to red and the product precipitated. The product was filtered and 0.44 g (76%) was isolated. Mp decomp. 300-305° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].Cl>>[CH2:17]([N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)[CH2:18][CH2:19][CH3:20]
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: CCCCBr
Agent: Cl
Product: CCCCN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(3-Trifluoromethyl-phenyl)piperidine and n-Bu-Br: m.p. 222° C. (HCl), MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C:8]1([CH:14]([CH2:17][CH2:18][OH:19])[CH2:15][OH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[C:8]1([C@H:14]2[CH2:17][CH2:18][O:19][C:15]2=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCC(CO)c1ccccc1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1OCC[C@@H]1c1ccccc1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-Phenyl-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (R)-2-phenylbutyrolactone as a yellowish solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][N:17]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18]1>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]([CH3:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Cn1cc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c2ccccc21
Yield: 21 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 1-methyl-L-tryptophan to provide the title compound in 21% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [CH2:1](O)[C:2]#C.[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:6]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:1]#[CH:2])=[O:12])#[N:6]
Reactant: COC(=O)CCCCC#N
Reactant: C#CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: C#CCOC(=O)CCCCC#N
Yield: 79.3 %

Procedure:
15.1 g (269 mmol) of propargyl alcohol and 1.92 g (7 mmol) of titanium tetraisopropoxide were added to 18.0 g of the obtained methyl 5-cyanovalerate, and heated and stirred at 120° C. for 8 hours while methanol was removed. After the reaction, methanol and excessive propargyl alcohol were evaporated away under reduced pressure, and the residue was purified through column chromatography (Wakogel C-200, elution with hexane/ethyl acetate=1/9) to give 16.7 g (yield 75%) of 2-propynyl 5-cyanovalerate.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16]CCC.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccccc1)C1CCCCC1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
α-Cyclohexylstyrene was prepared from cyclohexyl phenyl ketone using standard Wittig chemistry (Gupta, P.; Fernandes, R. A.; Kumar, P. Tet. Lett. 2003, 44, 4231–4232.) Methyltriphenylphosphonium bromide (29.57 g, 82.77 mmol) was slurried in 600 mL THF in the glovebox. The mixture was cooled to 2° C., and nBuLi (1.6 M in hexanes, 52 mL) was added over 15 min. After 1 h, solid cyclohexyl phenyl ketone (15.18 g, 80.63 mmol) was added, and the solution was allowed to slowly warm to room temperature overnight. Water (200 mL) was added. The solution was extracted with Et2O (3×150 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give a tan liquid. Ph3PO crystallized upon standing and was removed by filtration and washed with hexane (200 mL). The hexane solution was filtered through a 2 in column of neutral alumina, washing with an additional 200 mL of hexane. The filtrate was evaporated to a colorless liquid which was distilled (46–49° C./0.1 mm Hg) to give 13.72 g of colorless liquid (89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][NH2:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:8])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N-(t-butoxycarbonyl)ethylenediamine are stirred at 130° for 15 hours. The mixture is cooled to room temperature, taken up in 100 ml of water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extract is washed twice with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered off under suction. There are obtained 3.9 g of t-butyl [2-(4-chlorobenzamido)ethyl]carbamate, m.p. 141°-143°.
Reaction SMILES: [CH3:1][N:2]([CH3:63])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@H:21]([O:27][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7].CO.C(Cl)Cl>Cl>[CH3:63][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@H:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C[C@@H](CCCCC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(=O)CCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C[C@H](O)CCCCC)OC(=O)CCCN(C)C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A solution of (6R,8Z,27Z,30Z)-6-(tert-butyldiphenylsilyloxy)hexatriaconta-8,27,30-trien-18-yl 4-(dimethylamino)butanoate (800 mg, 0.95 mmol) in the saturated HCl(g)/MeOH (50 mL) was stirred for 10 minutes. The starting material did not dissolve so anhydrous DCM (12 mL) was added, and the mixture was stirred for 30 minutes. Upon completion, the solution was concentrated in vacuo, saturated sodium bicarbonate (75 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (100 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (0.228 g, 39%). 1H NMR (400 MHz, CDCl3): δ5.61-5.52 (m, 1H), 5.45-5.29 (m, 4H), 4.91-4.83 (m, 1H), 3.66-3.58 (m, 1H), 2.81-235 (m, 2H), 2.75-2.44 (m, 7H), 2.42-2.36 (m, 2H), 2.24-2.18 (m, 2H), 2.10-1.93 (m, 7H), 1.56-1.41 (m, 6H), 1.40-1.20 (m, 36H), 0.93-0.85 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][SiH3:29])[CH:23]=1)[C:15]2=[O:20].O.ClCCl>CN(C)C1C=CN=CC=1.O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][SiH3:29])[CH:23]=2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1CN(Cc1cccc(C[SiH3])c1)C2=O
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1CN(Cc1cccc(C[SiH3])c1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon and at 0° C., 5-chloro-2-thiophenecarbonyl chloride (1.7 g, 9.2 mmol) and 4-dimethylaminopyridine (93 mg, 0.8 mmol) are added to a solution of 4-amino-2-[3-(silylmethyl)benzyl]-1-isoindolinone (2.9 g, 7.7 mmol) in tetrahydrofuran (26 ml) and pyridine (12 ml). The reaction mixture is stirred at room temperature for 12 h, and water is added. After addition of dichloromethane and phase separation, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (dichloromethane/methanol mixtures). Yield: 3.9 g, 97% of theory.