Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:5].[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccccc2)c(Cl)c1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)c(Cl)c1
Yield: 70 %

Procedure:
Proceeding as in Reference 5, but substituting 3-chloro-4-phenoxyaniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(3-chloro-4-phenoxyphenyl)propanamide (470 mg, 70%).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[F:13][C:14]([C:17]1[N:22]=[C:21]([C:23]2[S:27]C(N)=NC=2C)[CH:20]=[CH:19][N:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl>[F:13][C:14]([C:17]1[N:22]=[C:21]([C:23]2[S:27][C:4]([NH:3][C:6]([N:8]3[CH:9]=[CH:10][N:11]=[CH:12]3)=[O:7])=[N:5][C:1]=2[CH3:2])[CH:20]=[CH:19][N:18]=1)([CH3:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)F)n1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C(C)(C)F)n1
Reaction time: 56 h

Procedure:
CDI (0.10 g) was added to a stirred solution of 5-[2-(1-fluoro-1-methyl-ethyl)-pyrimidin-4-yl]-4-methyl-thiazol-2-ylamine (Step 9.2) (0.15 g) in CH2Cl2 (4 mL) at rt. The reaction mixture was then stood for 56 h at 25° C. and the title compound isolated by filtration.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([S:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>ClCCl>[C:12]1([S:16]([OH:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([S:8][S:7][C:1]2[CH:2]=[CH:3][C:4]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: c1ccc(SSc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(SSc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of phenyl disulfide (4.36 g, 20 mmol) in dichloromethane (40 mL) at 0° C. is added a solution of chlorosulfonic acid (4.64 g, 2.95 mL, 40 mmol) in dichloromethane (60 mL) dropwise. The mixture is stirred at 0° C. for 1 hour followed by 1.5 hours at room temperature. The reaction mixture is concentrated to dryness in vacuo and the residue is partitioned between diethyl ether and water. The water phase is separated, made basic with 2N aqueous sodium hydroxide and concentrated in vacuo to half the volume. The resulting solution is refrigerated overnight. The precipitate formed overnight is discarded, the filtrate is concentrated further in vacuo until a solid started to appear. The mixture is placed in the refrigerator for 2 hours. The mixture is treated with ethanol, the solid formed is filtered, washed with ethanol twice and dried under high vacuum overnight at room temperature to give 6.0 g of 4,4′-dithiobisbenzenesulfonic acid as a white solid: [M−1]−=398.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Solvent: ClP(Cl)Cl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12

Procedure:
Following the chlorination procedure of Example 19 p-nitrobenzyl 7-phenoxyacetamido-3-chloro-3-cephem-4-carboxylate was prepared with phosphorus trichloride. The p-nitrobenzyl ester group was removed by the acidic hydrogenolysis procedure described by Example 18 to provide the 3-chlorocephalosporanic acid antibiotic compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35]C)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:29]([O:28][C:26]([N:24]1[CH2:25][C@@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][CH:7]=2)=[O:18])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:21][C@@H:22]([C:33]([OH:35])=[O:34])[CH2:23]1)=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1,3-dicarboxylate (1.08 g) was dissolved in methanol (25 ml) and THF (12 ml), 2 M aqueous sodium hydroxide solution (4.79 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(OC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 66.3 %

Procedure:
cis-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid amide (200 mg, 0.63 mmol), CsCO3 (250 mg, 0.76 mmol), and 1-bromomethyl-4-trifluoromethoxy-benzene (155 mg, 0.69 mmol) was stirred in acetonitrile (15 mL) at room temperature for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over Na2SO4 and concentrated to give a crude white wax. Further purification by flash chromatography (silica gel, 0.5%–1% MeOH/CHCl3) afforded the titled compound (205 mg) as a white solid in 67% yield: 1H NMR (DMSO-d6) δ 7.75 (d, 2 H, J=8.0 Hz), 7.59 (d, 2 H, J=8.0 Hz), 7.36 (m, 3 H), 7.21 (d, 2 H, J=8.0 Hz), 6.69 (s br, 1 H), 4.58 (AB2, 2 H, Δv=17, Jab=64 Hz), 3.89 (m, 1 H), 2.79 (s, 1 H), 2.44 (m, 1 H), 1.78 (m, 1 H), 1.66 (m, 2 H), 1.31 (m, 3 H), 0.98 (m, 1 H); MS m/e 491.03 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:42]=[CH:41][C:31]([CH2:32][NH:33]C(=O)OC(C)(C)C)=[C:30]([CH2:43][CH3:44])[CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[NH2:33][CH2:32][C:31]1[CH:41]=[CH:42][C:28]([CH2:27][CH2:26][C:6]2([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)=[CH:29][C:30]=1[CH2:43][CH3:44]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1CN
Yield: 96 %

Procedure:
tert-Butyl 4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylbenzylcarbamate (35 mg, 0.06 mmol, example A(126)) was dissolved in dichloromethane (1 mL) and 4N HCl in dioxane (0.5 mL) and stirred at room temperature 2 h. The solution was concentrated to give an off-white solid (30 mg, 96%). 1H NMR (300 MHz, CDCl3): δ ppm 1.14 (t, J=7.54 Hz, 3H) 1.37-1.49 (m, 1H) 1.52-1.66 (m, 6H) 1.67-1.77 (m, 2H) 2.05-2.16 (m, 2H) 2.58 (s, 4H) 2.60-2.70 (m, 6H) 2.74-2.80 (m, 1H) 3.80 (d, J=14.51 Hz, 2H) 4.02 (q, J=5.78 Hz, 2H) 7.07 (s, 1H) 7.13 (s, 1H) 7.16-7.21 (m, 1H) 7.32 (d, J=7.72 Hz, 1H) 8.15 (s, 3H). MS (ESI): 504 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[N:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][NH2:43])=[NH:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[N:42][N:43]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reactant: N=C(NN)c1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCc2nnc(-c3ccncc3)[nH]2)CC1

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 255 mg, 0.952 mmol) and triethylamine (138 μl, 0.982 mmol) in toluene was cooled to 0° C. and isobutylchloroformate (127 μl, 0.982 mmol) added. After stirring at rt for 45 min 4-pyridinecarboximidic acid hydrazide (100 mg, 0.82 mmol) and 3 Å powdered molecular sieves (0.82 g) were added and the reaction heated under reflux for 18 h. On cooling, the mixture was filtered through celite, the filtrate evaporated and the residue dissolved in EtOAc (50 ml). After washing with saturated aqueous Na2CO3 (10 ml) and brine (10 ml), the solvent was removed and the residue purified by flash chromatography (EtOAc then 5% MeOH in EtOAc) to afford the title compound: RT=2.81 min; m/z (ES+)=360.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=3)[CH:9]=2)[C:4]1=[O:22])[CH3:2].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:22])[C:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:1][CH3:2])[CH2:12][CH2:11]3)=[N:14][CH:15]=1
Reactant: CCOC(=O)CC1(CC)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(CC)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 85.3 %

Procedure:
Iron powder (1.533 g, 27.5 mmol) was added to a solution of 4F (2.1 g, 5.49 mmol) in 30 mL of ethanol-water mixture (5:1) followed by NH4Cl (0.015 g, 0.275 mmol), and the mixture was refluxed for 5 h. The solvent was removed under reduced pressure, and residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 40% ethyl acetate in hexane to afford the title compound (1.65 g, 85%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=2.7 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.06 (dd, J1=2.7 Hz, J2=8.4 Hz, 1H), 4.11 (q, J=5.7 Hz, 2H), 3.84 (bs, 2H), 3.23-3.12 (m, 1H), 3.06-2.93 (m, 2H), 2.56-2.46 (m, 2H), 2.14-2.07 (m, 1H), 1.85-1.61 (m, 2H), 1.24 (t, J=6.9 Hz, 3H), 0.92 (t, J=7.8 Hz, 3H). ESI-MS m/z=353 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(F)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (98%, 530 mg, 0.74 mmol) was added to a mixture of (5-fluoro-2-methoxyphenyl)boronic acid (10.0 g, 58.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (6.75 mL, 65.0 mmol) and potassium carbonate (16.3 g, 118 mmol) in tetrahydrofuran (100 mL) and water (30 mL), and the reaction mixture was stirred for 18 hours at room temperature. The aqueous layer was extracted with diethyl ether (100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo, while keeping the bath temperature at <30° C. Pentane (200 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure; the residue was subjected to silica gel chromatography (Eluent: pentane) to afford the product as a colorless oil. Yield: 9.08 g, 41.2 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 5.69-5.70 (m, 1H), 6.12-6.13 (m, 1H), 6.88 (dd, J=9.0, 4.5 Hz, 1H), 6.98 (br dd, J=8.8, 3.1 Hz, 1H), 7.05 (ddd, J=9.0, 7.8, 3.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:12]([S:13]CC2C=CC(OC)=CC=2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(SCc2ccc(OC)cc2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(S)c1F
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A stirred solution of compound A3 (30.0 g, 93.75 mmol) in TFA (54.5 mL) was heated to 80° C. and stirred for 12 h under inert atmosphere. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was dissolved in ice-cold water (100 mL), basified with solid sodium bicarbonate and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3% EtOAc/Hexanes to afford compound 6 (11.7 g, 62%) as a pale brown syrup. 1H NMR (500 MHz, CDCl3): δ 7.70-7.66 (m, 1H), 7.48-7.44 (m, 1H), 7.08-7.04 (m, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.67 (s, 1H), 1.40 (t, J=7.5 Hz, 3H); LC-MS (ESI): 91.8%; m/z 199.0 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 2.60 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(Oc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 89.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetate (0.016 g, 0.029 mmol) and LiOH (7.03 mg, 0.294 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. The, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetic acid (0.0132 g, 0.026 mmol, 87% yield) as solid. 1H NMR (500 MHz, CDCl3) δ 7.35-7.40 (m, 2H), 7.22-7.27 (m, 1H), 7.08-7.18 (m, 4H), 7.03-7.08 (m, 2H), 6.01 (br. s., 1H), 3.35-3.70 (m, 1H), 2.80-3.08 (m, 1H), 2.65 (s, 3H), 2.28-2.38 (m, 1H), 2.26 (s, 3H), 2.06-2.21 (m, 1H), 1.18-1.42 (m, 4H), 1.26 (s, 9H), 0.82 (br.s., 3H), 0.75 (br.s., 3H). LCMS (M+H)=517.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:33]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:34])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CCC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclobutanecarbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([N:17]3[C@@H:18]4[C@@H:23]([C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[CH2:20][CH2:19]4)[CH2:14][CH2:15][CH2:16]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1nc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc2s1
Yield: 24 %

Procedure:
The title compound is prepared from 2-amino-benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 24% of theory; LC (method 4): tR=1.80 min; Mass spectrum (ESI+): m/z=364 [M+H]+.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[OH:15])([O-])=O>[Pd].[Rh].O>[NH2:3][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[OH:15]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Rh]
Solvent: O
Product: Nc1ccc(O)c(N)c1
Temperature: 116 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
Onto the bottom of a cylindrical reactor a chamber is placed which is made of a 100μ-thick foil having the working surface area of 50 cm2. The foil is manufactured of an alloy consisting of 95% by mass of palladium and 5% by mass of rhodium. Hydrogen is continuously fed inside the chamber under the pressure 2.5 atm at the rate of 10 ml/min. Outside the chamber in the reactor there are placed 22 g of 2,4-dinitrophenol, whereafter 250 ml of distilled water are added thereto. The reactor is heated to the temperature of 116° C., pressure inside the reactor is increased to 4 atm; under these conditions the process of hydrogenation is conducted under stirring for 3 hours. Then the reactor is cooled and the precipitated crystals are filtered-off to give 15.2 g of 2,4-diaminophenol. The product is recrystallized from acetone to give 10.3 g of 2,4-diaminophenol with the melting point of 80° C. The yield of 2,4-diaminophenol is 71.6% of the theoretical (i.e. as calculated for the initial 2,4-dinitrophenol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-c1c(C)oc2ccc(Br)cc2c1=O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
Intermediate 11 (5.5 g, 16.38 mmoles) was taken in a RB flask and to this acetic anhydride (50 ml) and sodium acetate (9.40 g, 114.69 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (1.8 g, 30% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35 (d, J=1.7 Hz, 1H), 7.75 (d, J=6.7 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.35-7.26 (m, 3H), 7.09 (d, J=6.9 Hz, 1H), 2.20 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CS(C)=O.O>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])[CH2:19][CH2:20]1
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
10% sodium hydroxide aqueous solution (7.21 g) was added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (2.60 g) obtained in Example 5(1) in dimethylsulfoxide (36 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.97 g) was added thereto. After being stirred for 2.5 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1 to 30:1), thereby yielding the entitled compound (1.99 g) as white solid.