Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)/[CH:10]=[C:11]2\[CH2:12][CH2:13][C:14]3[NH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]\2=3)[CH:2]=1.[OH-].[Li+].CO>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[CH2:10][CH:11]2[C:18]3[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[NH:15][C:14]=3[CH2:13][CH2:12]2)[CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(-c2cccnc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2cccnc2)c1

Procedure:
The title compound was synthesized from (E)-methyl 4-(3-(pyridin-3-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.051 g, 0.15 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 15.0 mg, 31% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.21 (m, 1H), 2.52-2.63 (m, 3H), 2.79-2.94 (m, 2H), 3.33-3.36 (m, 1H), 6.34 (s, 1H), 7.28 (d, J=7.57 Hz, 1H), 7.39-7.44 (m, 2H), 7.46-7.51 (m, 2H), 8.04 (dt, J=8.02, 1.90 Hz, 1H), 8.49 (dd, J=4.88, 1.46 Hz, 1H), 8.76 (d, J=2.00 Hz, 1H); LCMS-MS (ESI−) 317.2 (M−H); HPLC (UV=96.4%), (ELSD=100%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C@H:9]3[C:11]4([CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH2:10]3)[N:7]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: Brc1cccc(N[C@@H]2CC23CCOCC3)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: Fc1cc(-c2cccc(N[C@@H]3CC34CCOCC4)n2)c(Cl)cn1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of (R)-6-bromo-N-(6-oxaspiro[2.5]octan-1-yl)pyridin-2-amine (C, 100 mg, 0.35 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (136 mg, 0.77 mmol), PdCl2(dppf).CH2Cl2 adduct (23 mg, 0.028 mmol) in DME (1 mL) and 2M Na2CO3 (97 mg, 0.92 mmol) in a sealed tube was heated at 103° C. for 2 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (˜25 mL) and MeOH (˜5 mL), filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=10/90 to 50/50]. Fractions were combined and concentrated in vacuo giving 105 mg of titled compound. LCMS (m/z): 334.0/336.0 [M+H]+, retention time=0.64 min.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.C1COCC1>CN(C)C1C=CN=CC=1.O>[C:5]([O:4][CH2:1][CH2:2][N:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])(=[O:7])[CH3:6]
Reactant: COC(=O)CCN(CCO)CCC(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCN(CCOC(C)=O)CCC(=O)OC
Reaction time: 5 h
Yield: 89.8 %

Procedure:
At 20 to 30° C., 2.56 g of acetic anhydride was added to a mixture of 5.00 g of N-(2-hydroxyethyl)bis[2-(methoxycarbonyl)ethyl]amine, 2.97 g of triethylamine, 50 mg of 4-dimethylaminopyridine and 25 g of THF. The resulting mixture was stirred for 5 hours. Water was added to terminate the reaction. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by distillation under reduced pressure, whereby 5.30 g of N-(2-acetoxyethyl)bis[2-(methoxycarbonyl)ethyl]amine was obtained (boiling point: 120° C./15 Pa, yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH3:12])[NH:4][N:3]=1.BrC[CH:15]([O:18][CH3:19])[CH2:16][CH3:17]>>[CH3:19][O:18][CH2:15][CH2:16][CH2:17][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([OH:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: CCC(CBr)OC
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Product: COCCCn1nc(C)c(C(=O)O)c1C
Yield: 12 %

Procedure:
Prepared by following the same method as the preparation of intermediate 42: ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (280 mg) was reacted with 1-bromo-2-methoxybutane (337 mg) to afford white solid (42 mg, 0.20 mmol, 10%). ESI-MS m/z 213.2 (M+H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22].CO.[H-].[Na+]>CN(C=O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:26][C:24](=[O:25])[C:23]([C:21]#[N:22])=[CH:3][C:4]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:11]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 95 °C

Procedure:
A solution of 3-dimethylamino-1-(4-chlorophenyl)-2-(phenyl)prop-2-en-1-one (43.3 mmol assumed) from Step A, cyanoacetamide (4.0 g, 47.6 mmol), and methanol (3.9 mL, 95 mmol) in DMF (100 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (4.3 g, 108 mmol) in DMF (50 mL) at rt. After the slow addition was complete, the reaction was heated to 95° C. for 2 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aqueous 18% citric acid solution. The mixture was extracted twice with methylene chloride and the organic layers were washed with a portion of brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The solid residue was triturated with ether, filtered, and air dried to afford 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-nitrile. HPLC/MS: 307 (M+1); Rt=3.0 min;
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: [H][H]
Reactant: Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add the 5-(2-methyl-benzylidene)-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (0.19 g, 0.64 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite, evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e) 298 (M+). Analysis for C23H22: Calcd: C, 91.99 H, 7.39. Found: C, 91.95 H, 7.39.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:16]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].[ClH:32]>O>[Cl:32][C:6]1[CH:7]=[C:8]([CH:16]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
A solution of NaNO2 (34 mg, 498 μmol) in H2O (0.8 mL) was added to a solution of 2-(3-amino-4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 171, 200 mg, 488 μmol) in 6M HCl (1.6 mL) at 0° C. The reaction was stirred at 0° C. for 35 min, before being added slowly to a stirred mixture of Cu powder (80 mg, 1.26 mmol) and 12M HCl (0.8 mL) at 0° C. The temperature was increased to 20° C., then stirring was continued for 1 h. The mixture was then heated at 60° C. for 1 h, before being cooled down to 20° C. and extracted with CH2Cl2 (3×15 mL). The organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by RP-HPLC to furnish the title compound: RTA=3.17 min; m/z (ES+)=429.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(OCc3ccccc3)ccc2o1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Under cooling in ice bath, 6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (514 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (20 ml), followed by addition of thioanisole (1.24 g, 10 mmol), with stirring at ambient temperature for 12 hours. The solvent was distilled off from the reaction solution; the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and was dried over anhydrous magnesium sulfate, from which the solvents were distilled off. The residue was purified by silica gel column chromatography (30 g of silica gel; elution solvents:hexane:acetone=5:1 to 5:2), to recover the objective compound (459 mg at a yield of 97%) as a pale red amorphous. IR (KBr) cm−1: 3247, 2963, 1649, 1445, 1153. 1H-NMR (d6-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.48-1.91 (6H, m), 2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1 Hz), 6.70 (1H, dd, J=8.8, 2.4 Hz), 6.92 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.3 Hz), 7.10 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, d, J=8.8 Hz), 8.68 (1H, br s), 8.92 (1H, s). EIMS m/z (relative intensity): 440 (M+, 100). Elementary Analysis: C25H32N2O3S Required: C, 68.15; H, 7.32; N, 6.36; S, 7.28. Found: C, 68.16; H, 7.45; N, 6.26; S, 6.86.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1>[Fe].CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(Br)nc1N
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
A mixture of 6-bromo-3-methoxy-2-nitropyridine (14.4 g, 61.8 mmol), AcOH (200 mL) and Fe powder (14.0 g, 0.25 mol) was stirred at 90° C. for 1.5 h. After cooling to rt and dilution with EtOAc the mixture was filtered through celite and the filtrate concentrated in vacuo. Purification by flash chromatography eluting with DCM yielded the title compound (10.2 g, 50.2 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][N:5]=[C:4]([N:15]2[CH2:20][C@H:19]([CH3:21])[O:18][C@H:17]([CH3:22])[CH2:16]2)[N:3]=1.[CH2:23]([Mg]Cl)[CH:24]([CH3:26])[CH3:25].[Cl-].[NH4+].Cl>O1CCCC1.ClCCl.[Cu]I.CO>[ClH:1].[CH3:22][C@H:17]1[O:18][C@@H:19]([CH3:21])[CH2:20][N:15]([C:4]2[N:3]=[C:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=3)=[CH:6][N:5]=2)[CH2:16]1
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
Reactant: CC(C)C[Mg]Cl
Agent: [Cu]I
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2CC(C)C)ccn1
Temperature: 0 °C
Yield: 40.6 %

Procedure:
A mixture of cis-4-[4-chloro-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.314 mmol) and copper (I) iodide (11.95 mg, 0.063 mmol) in tetrahydrofuran (1 ml) was stirred at 0° C. under argon and isobutyl magnesium chloride (2M solution in tetrahydrofuran) (0.314 ml, 0.627 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 90 minutes. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic extract was separated, washed with saturated ammonium chloride solution, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50-100% ethyl acetate in isohexanes. The product (61 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml) and methanol (0.5 ml) and hydrogen chloride (1M in ether, 0.2 ml) was added. The solvent was evaporated and the residue was co-evaporated with ether. The residue was triturated with ether and the resulting solid was collected and dried to give the title compound (48 mg, 41%). LC/MS [M+H]+=341. 1H NMR (400 MHz, d6-DMSO): δ 8.74 (1H, d), 8.36 (1H, s), 7.87-7.85 (1H, m), 7.81-7.78 (1H, m), 4.62-4.58 (2H, m), 3.61-3.54 (2H, m), 2.72 (3H, s), 2.63-2.58 (4H, m), 2.15-2.08 (1H, m), 1.18 (6H, d), 0.79 (6H, d).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:20][C:21](=O)[CH3:22])[CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=O)C.[CH3:24]I>>[CH3:1][O:4][CH2:5][CH:6]([N:20]([CH2:21][CH3:22])[CH3:24])[CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CI
Reactant: CC(=O)NC(CCOc1cccc2ccccc12)COC(C)=O
Product: CCN(C)C(CCOc1cccc2ccccc12)COC

Procedure:
2-(acetylamino)-4-(1-naphthyloxy)-1-butanol acetate, described in Example 5, with methyl iodide, followed by reduction, gives 1-methoxy-N-ethyl-N-methyl-4-(1-naphthyloxy)-2-butanamine, and
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Cl:14][C:15]1[CH:16]=[C:17]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([O:36][CH3:37])[N:30]=2)=[O:28])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].[Cl-].[NH4+]>CN(C)C=O>[Si:5]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([O:36][CH3:37])[N:30]=2)=[O:28])=[CH:16][C:15]=1[Cl:14])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: COc1nc(C(=O)c2ccc(OCCCCO)c(Cl)c2)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1nc(C(=O)c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
tert-Butyldimethylchlorosilane (240 mg) and imidazole (108 mg) were sequentially added to a solution of [3-chloro-4-(4-hydroxybutoxy)phenyl](5-chloro-6-methoxypyridin-2-yl)methanone (391 mg) in N,N-dimethylformamide (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→10:1) to give the title compound (389 mg, 76%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:27][CH2:28]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4c3C(=O)CCC4)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6c5C(=O)CCC6)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 16f and amine 14.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Cc1cc(CCl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)on1
Yield: 25.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (3 g) is alkylated using 5-chloromethyl-3-methyl-isoxazole (1.65 g; 12.5 mmol) and K2CO3 (3,3 g; 23.9 mmol) at RT for 3 days. After aqueous work-up and purification by RP chromatography the pure material (1.07 g) is de-acetylated in MeOH (50 ml) using DBU (220 μl) at 60° C. in 18 h. After aqueous work-up 5-amino-3,3-dimethyl-1-(3-methyl-isoxazol-5-ylmethyl)-6-nitro-1,3-dihydro-indol-2-one (0.93 g) is obtained and used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21](OCC)=[O:22])=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][C:16](/[C:19](/[CH3:26])=[CH:20]/[CH2:21][OH:22])=[CH:17][CH:18]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cccc(-c3ccccc3)c2)cc1

Procedure:
(E)-Ethyl 3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enoate (0.95 g, 2.77 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-en-1-ol as a colourless solid; 0.81 g (97%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C([O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])(=O)C.[CH3:37][C:38]1[O:42][C:41]([CH2:43]O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[OH:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:43][C:41]3[O:42][C:38]([CH3:37])=[CH:39][CH:40]=3)[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1OC(C)=O
Reactant: Cc1ccc(CO)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccc(C)o3)c2)cc1O
Reaction time: 16 h
Yield: 1.7 %

Procedure:
Diethylazodicarboxylate (1.13 mL 5.83 mmol) was added dropwise to a solution of (E)-3-(3-acetoxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.763 g, 2.33 mmol), (5-methyl-furan-2-yl)-methanol (0.392 g, 3.5 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in dry THF (20 mL) at 0° C. The resulting solution was allowed to reach RT and stirred for 16 hrs. The reaction mixture was then diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 15 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(5-methyl-furan-2-ylmethoxy)-phenyl]-acrylamide.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:36]#[N:37])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[C:11]([F:38])[CH:10]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:38])([C:36]#[N:37])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 58.4 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 68c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 59%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[Br:24][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:23])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
A stirred solution of 3α-hydroxy-5α-pregnan-20-one (5 g., 15.7 mmole) in AR methanol (350 c.c.) was treated at 0° with a solution of bromine (1 c.c.) in methanol (23 c.c.) at such a rate that the yellow colour disappeared before further addition. The resultant suspension was poured into water and stirred for 30 minutes, and the precipitate was collected by filtration and dried in vacuo. The product was purified by column chromatography on silica gel MFC, (700 g.). Elution with benzene:ethyl acetate, 1:1) gave 21-bromo-3α-hydroxy-5α-pregnan-20-one (5.2 g.) [α]D + 105.5°.