Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:21]3[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)ccc(F)c3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][C:29]([OH:31])=O)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([N:15]1[C:29](=[O:31])[CH2:28][CH2:27][N:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 15 h
Yield: 76.9 %

Procedure:
A solution of 8.20 g (15.77 mmol) of (S)-4-benzyloxy-2-{2-[(2-carboxy-ethyl)-(3,4-dichloro-phenyl)-amino]-ethylamino}-butyric acid methyl ester; HCl in 130 ml CH2Cl2 was treated with 2.20 (15.77 mmol) of triethylamine and at 0° C. with 3.70 g (18.93 mmol) of EDCI. The cooling bath was allowed to come to RT and after 15 h the reaction was extracted with aq. 10% KHSO4/Et2O (3×). The organic phases were washed with aq 10% KHSO4. solution, 10% NaCl and dried over Na2SO4 and purified by flash silica gel column (n-heptane:EtOAc 75:25 to 1:1) to yield 5.64 g (77%) of the title compound as a light yellow oil. MS: 465.1 (MH+, 2Cl).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1>CO.[C].[Pd]>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1O
Yield: 95.5 %

Procedure:
20.0 g of Ferulic acid was dissolved in 250 ml of methanol and subjected to catalytic reduction under normal pressure for 3 hours in the presence of 10% palladium carbon catalyst (50% wet type). After removing the catalyst by filtration, the resulting filtrate was concentrated to collect precipitated crystals by filtration, thereby obtaining 19.3 g of 3-(4-hydroxy-3-methoxy-phenyl)propionic acid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)(=O)C(Cl)=O.O[C:23]1[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C:23]2[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([OH:52])=[O:51])[C:29](=[O:48])[C:30]3[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:12])=[CH:14][CH:15]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(OCCC(C)C)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(isopentyloxy)benzoic acid (37 mg, 0.178 mmol) in DCM (0.5 mL) was added DMF (1 drop) and oxalyl chloride (0.016 mL, 0.190 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (60 mg, 0.119 mmol) and TEA (0.050 mL, 0.357 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 41.2 mg (54%) of 2-(N-(4-((4-(isopentyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 46. LCMS-ESI (m/z) calculated for C37H38N2O8: 638; found 637 [M−H]−, tR=8.44 min (Method 4). 1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 10.24 (s, 1H), 8.13-8.02 (m, 2H), 7.69-7.62 (d, J=8.4 Hz, 2H), 7.48-7.28 (m, 4H), 7.26-7.19 (dt, J=6.7, 1.9 Hz, 4H), 7.16-7.08 (m, 2H), 6.93-6.83 (m, 2H), 4.72-4.54 (d, J=31.5 Hz, 2H), 4.16-4.08 (t, J=6.6 Hz, 2H), 4.05-3.86 (d, J=27.0 Hz, 2H), 3.71 (s, 3H), 3.57 (s, 2H), 1.88-1.75 (dp, J=13.3, 6.7 Hz, 1H), 1.72-1.62 (q, J=6.7 Hz, 2H), 0.97-0.86 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([OH:39])=[N:37][CH:38]=2)O1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:33]2[CH:38]=[N:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccc(O)nc4)nc3s2)cc1
Yield: 21 %

Procedure:
The titled compound (yield=21%, tan solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 2F (Example 2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.48 (s, 2H) 6.48 (d, J=9.60 Hz, 1H) 7.58 (d, J=8.84 Hz, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.09 (d, J=8.59 Hz, 2H) 8.14 (d, J=8.59 Hz, 1H) 8.20 (d, J=2.27 Hz, 1H) 8.27 (dd, J=9.60, 2.78 Hz, 1H) 11.99 (br. s., 1H) 12.93 (br. s., 1H); ESI-MS: m/z 421.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:25]=[CH:24][C:7]3[N:8](COC)[C:9]([CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[N:10][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.C1(C2C=CC3N=C(CN(C)C(=O)OC(C)(C)C)N(COC)C=3C=2)CC1.[ClH:51].O1CCOCC1>C1COCC1.CCO>[ClH:51].[ClH:51].[CH:1]1([C:4]2[CH:25]=[CH:24][C:7]3[NH:8][C:9]([CH2:11][NH:12][CH3:13])=[N:10][C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(C3CC3)ccc21
Agent: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2ccc(C3CC3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCO
Product: CNCc1nc2cc(C3CC3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of a mixture (501 mg) of tert-butyl {[5-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and EtOH/water (1/1, 6 mL) was added 4 M hydrogen chloride/1,4-dioxane (6 mL), followed by heating and stirring at 80° C. for 5 hours and then concentrating under reduced pressure to obtain 1-(5-cyclopropyl-1H-benzimidazol-2-yl)-N-methylmethanamine dihydrochloride (328 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([S:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:6])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Sc1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1ccccc1)Sc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (2.44 g, 10 mmol), in THF (100 ml) at −4° C., lithium bis(trimethylsilyl)amide (1 M solution, 15 ml, 15 mmol) was added slowly. The orange colored reaction mixture was stirred at room temperature for 15 minutes and then it was cooled to 0° C. at which time it was stirred for an additional hour. The temperature of the mixture was again brought to −40° C. and benzylbromide (1.72 gm, 10 mmol) was added dropwise in THF. The reaction was warmed to room temperature and stirred overnight before it was quenched with ice water, extracted with chloroform and washed with water. The organic layer was dried over MgSO4, filtered and concentrated and chromatographed on a silica-gel column with 10% ethyl acetate:hexane to afford 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield: 860 mg, (26%); MS: 331 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.ClCCl.C[SiH](C)C.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:60])[C@@H:31]([O:57][CH2:58][CH3:59])[C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=2)=[CH:36][CH:35]=1)O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:60])[C@@H:31]([O:57][CH2:58][CH3:59])[CH2:32][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]([CH3:56])[C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=2)=[CH:36][CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Agent: C[SiH](C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
320 μl (2.6 mmol) of boron trifluoride etherate and 5 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 800 μl (5 mmol) of trimethylsilyl hydride are added dropwise, followed by portionwise addition of 380 mg (0.64 mmol) of N-{4′-[(1R,2S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide. After one hour at room temperature, the mixture is heated at 50° C. for 20 hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 280 mg (76%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:29]([O:31]C)=[O:30])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:29]([OH:31])=[O:30])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)OC)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)O)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 7 (100.0 mg, 0.23 mmol, 1 equiv) was dissolved in THF/MeOH/H2O (3:1:1 2.3 mL) and the solution was cooled to 0° C. followed by addition of solid lithium hydroxide (5.4 mg, 0.23 mmol, 1 equiv). The reaction mixture was allowed to reach rt and stirred for 1 hour. It was acidified with 0.1 M aqueous HCl solution to pH 3 and extracted three times with ethyl acetate. The combined organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure and the remaining crude product was purified by chromatography (SiO2; toluene/EtOH/AcOH 95:4:1). Yield 23.7 mg, 24.5%. 1H NMR (DMSO; 200 MHz) δ 13.05 (brs, 1H); 8.59 (s, 1H); 7.72 (s, 1H); 7.05 (d, 1H); 7.41-7.22 (m, 3H); 7.17-7.03 (m, 3H); 6.91 (d, 1H); 6.22 (dd, 1H); 4.49-4.81 (m, 1H); 4.30-4.19 (m, 2H); 4.0 (q, 2H); 3.04 (q, 2H); 1.49 (sextett, 2H); 1.19 (t, 3H); 0.94 (t, 3H). MS (EI) 430 (M+H), 345, 210.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[Cl:11])[C:6]#[N:7].[C-:13]#[N:14].[K+]>C(O)C.O.C(OCC)(=O)C>[Cl:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: Cc1cc(C#N)cc(CBr)c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)cc(CC#N)c1Cl
Yield: 47.9 %

Procedure:
3-Bromomethyl-4-chloro-5-methyl-benzonitrile (0.9938 g, 4.06 mmol), potassium cyanide (0.529 g, 8.12 mmol) in ethanol (5.0 mL) and H2O (2.5 mL) was heated at 85° C. for 3 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexane) to give 4-chloro-3-cyanomethyl-5-methyl-benzonitrile as a white solid (0.3707 g, 48%). 1H NMR (300 MHz, CDCl3): 7.61 (s, 1H), 7.51 (s, 1H), 3.83 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C=O.CN(C1C=CN=CC=1)C>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccccc21
Reaction time: 0.02 h
Yield: 52.6 %

Procedure:
To a stirred solution of 486 mg (2.0 mmole) of 3-(2-thenoyl)-2-oxindole in 4 ml of N,N-dimethylformamide was added 538 mg (4.4 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting mixture was cooled in an ice-bath, and then a solution of 225 mg (2.2 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise, with stirring during about 1 minute. The cooling bath was removed and stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 50 ml of water and 1.7 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and the solid was recovered by filtration. This afforded 528 mg of a yellow solid. The yellow solid was recrystallized from ca. 15 ml of ethanol, giving 300 mg of the title compound as yellow crystals, m.p. 139°-140° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:40]([C:39]3[C:38]([CH3:37])=[N:46][CH:45]=[CH:44][CH:43]=3)=[O:41])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 75 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 2-methyl-nicotinic acid in 75% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][C:10]2[N:9]=[C:8]([CH:12]([OH:14])[CH3:13])[C:7]3[C@@H:15]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[O:16][C:17]4([CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:6]=3[C:5]=2[C@@H:4]([O:33][C:34]([CH3:40])([C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35])[CH2:3]1.[CH3:42]I>O1CCCC1>[CH3:42][O:14][CH:12]([C:8]1[C:7]2[C@@H:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[O:16][C:17]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[C@@H:4]([O:33][C:34]([CH3:40])([C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35])[CH2:3][C:2]([CH3:1])([CH3:41])[CH2:11][C:10]=2[N:9]=1)[CH3:13]
Reactant: CI
Reactant: CC(O)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](OC(C)(C)C(C)(C)C)CC(C)(C)C2
Solvent: C1CCOC1
Product: COC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](OC(C)(C)C(C)(C)C)CC(C)(C)C2
Reaction time: 0.08 h

Procedure:
70 mg 1-((3R,9S)-7,7-Dimethyl-3-(4-(trifluoromethyl)phenyl)-9-(2,3,3-trimethylbutan-2-yloxy)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)ethanol are dissolved in 1.5 ml tetrahydrofurane. 27 mg Potassium-tert.-butylate are added, the mixture is stirred for 5 minutes and the 11 μl methyliodide are added. The mixture is stirred for 20 minutes and then partitioned between 0.1 M hydrochloric acid and dichloromethane. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried with sodium sulphate. The solvents are evaporated in vacuo and the residue is purified by preparative HPLC (Gemini C18, water/methanol/ammonia 90:10:0.1 to 0:100:0.1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C=O>[ClH:48].[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]4[N:18]=[C:17]([CH2:19][O:20][C:21]5[CH:34]=[CH:33][C:24]([CH2:25][CH:26]6[S:30][C:29](=[O:31])[NH:28][C:27]6=[O:32])=[CH:23][CH:22]=5)[N:16]([CH3:35])[C:15]=4[CH:36]=3)=[CH:37][CH:38]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNS(=O)(=O)c4ccc(Cl)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 118.3 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.4 g), N,N-diisopropylethylamine (0.27 g) and anhydrous N,N-dimethylformamide (15 ml) was added 4-chlorobenzenesulfonyl chloride (0.15 g) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and diluted with water and tetrahydrofuran and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To a solution of the residue in tetrahydrofuran (10 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added diethyl ether (10 ml) and this mixture was stirred at room temperature for 30 minutes and then was irradiated with ultrasound for 30 minutes. The precipitate was isolated by filtration and washed with acetone, ethyl acetate and n-hexane to afford the title compound (0.3 g, mp 155-160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2F)cc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
As shown in Scheme 1, a well stirred mixture of 4-chloro-2-fluorophenol (1) (14.62 g, 99.8 mmol), 1-fluoro-4-nitrobenzene (2) (12.80 g, 90.72 mmol) and sodium carbonate (19.23 g, 181.43 mmol) in DMF (100 mL) was heated at 100° C. for 12 h. LC/MS showed that the reaction was complete. The cooled reaction mixture was poured into 350 mL of water with stirring and extracted with 2×100 mL of dichloromethane. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by chromatography yielded 24.2 g (99%) of 4-chloro-2-fluoro-1-(4-nitrophenoxy)benzene (3) as a pale yellow solid. 1H NMR CDCl3: 8.25-8.18 (m, 2H); 7.28-7.15 (m, 3H); 7.08-6.97 (m, 2H). Unless otherwise indicated all NMR chemical shifts reported herein are denoted by the delta (δ) scale.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: N#Cc1ccc(NC(=O)CCCCC(=O)O)cc1
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCC(=O)Nc3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 1 and 9-ethyl-9H-carbazol-3-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:9])[CH2:7][SH:8])[CH3:4].[C:10]([C:13]([CH2:24][C:25]([CH3:27])=[CH2:26])=[C:14](OS(C(F)(F)F)(=O)=O)[CH3:15])(=O)[CH3:11].[OH-].[Na+]>CCCCC.C1COCC1.C(Cl)Cl.O>[CH2:3]([O:5][C:6]([C:7]1[S:8][C:10]([CH3:11])=[C:13]([CH2:24][C:25]([CH3:27])=[CH2:26])[C:14]=1[CH3:15])=[O:9])[CH3:4]
Reactant: CCOC(=O)CS
Reactant: C=C(C)CC(C(C)=O)=C(C)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Solvent: ClCCl
Product: C=C(C)Cc1c(C)sc(C(=O)OCC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
Sodium hydride (60% in petrolether, 404 mg, 10 mmol) is washed with dry pentane (3×10 mL), then dry THF (30 mL) is added and the suspension is cooled at 0° C. A solution of mercaptoacetic acid ethyl ester (0.445 mL, 4 mmol) in THF (4 mL) is slowly added. After stirring for 0.5 h at 0° C. a solution of trifluoromethanesulfonic acid 2-acetyl-1,4-dimethyl-penta-1,4-dienyl ester (1.16 g, 4 mmol) in THF (4 mL) is slowly added. The mixture is stirred at 0° C. for 0.5 h, then slowly warmed to rt during 15 h. The reaction mixture is partioned between H2O (75 mL) and DCM (100 mL), the aq. phase is basified with 1M aq. NaOH (50 mL) and extracted with DCM (50 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The crude product is purified by reversed phase MPLC (H2O-MeOH gradient) to give 450 mg of 3,5-dimethyl-4-(2-methyl-allyl)-thiophene-2-carboxylic acid ethyl ester; LC-MS: tR=1.10 min, [M+1]+=239.05.