Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:40])([F:41])[C:36]([F:37])([F:38])[F:39]
Reactant: CN(CCCCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCCCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
92 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is dissolved in 2 ml of methanol and mixed with 23 mg of sodium borohydride. After 1 hour of stirring at room temperature, the solvent is drawn off in a vacuum for the most part, the residue is mixed with common salt solution, extracted 3 times with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative thin-layer chromatography with methylene chloride/methanol=9/1 as a mobile solvent provides 42 mg of 11β-fluoro-7α-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol as a foam, [α]D=+44° (c=1.0 in chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([O:33]CC)=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[F:45])[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[F:45])[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3F)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 172 mg of the crude ethyl 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(2-fluorophenyl)piperidin-1-yl]benzoate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was stirred at 85° C. for 1 hour. 0.50 mL of a 1 M aqueous sodium hydroxide solution was added thereto, for followed by stirring at 85° C. for 1 hour. The reaction mixture was cooled to room temperature, then neutralized by addition of 1.50 mL of 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oily compound of 161 mg of 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(2-fluorophenyl)piperidin-1-yl]benzoic acid as a crude product. ESI+: 583
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>ClCCl>[F:11][C:3]1[C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(C(=O)O)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-2-fluoro-benzoic acid (29, 1.70 g, 11 mmol) in 34 mL of dichloromethane, pyridine (2.2 mL, 27 mmol) and 4-trifluoromethyl-benzenesulfonyl chloride (30, 6.7 g, 27 mmol) were added. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound 31 as a white solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(C(CCCC)CO)C.N(OCCCCC)=O.[C:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])(=[O:35])[CH:33]=[CH2:34]>O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:34]=[CH:33][C:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[O:35])=[CH:5][CH:4]=1
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CCCCCON=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
12.3 g of 4-anisidine (4-methoxyaniline) are mixed while stirring with 10 ml of concentrated sulphuric acid and 60 ml of 2-ethylhexanol and the mixture is cooled to about 10° C. Subsequently 11.7 g of amyl nitrite are added and after addition is complete the mixture is stirred for a further 40 minutes. The reaction mixture is subsequently admixed with 20.2 g of 2-ethylhexyl acrylate and 100 mg of Pd (5% Pd on activated carbon) and heated to 65° C. over a period of 1 hour and stirred for a further 12 hours at this temperature. The mixture is diluted with 100 ml of water and extracted with 200 ml of dichloromethane. As examination by thin-layer chromatography and gas chromatography shows, 2-ethylhexyl p-methoxycinnamate has not been formed in even the smallest amounts. The 2-ethylhexyl acrylate employed is essentially present in unchanged form.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:9]([O:11][CH3:12])=[O:10])=O.C(O)(=O)C(C)(C)C>ClCCl>[C:2]([C:3]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=2[N:5]=1)([CH3:25])([CH3:24])[CH3:1]
Reactant: COC(=O)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
A mixture of methyl 3-[(2,2-dimethylpropanoyl)amino]-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzoate (step C, 455 mg, 1.31 mmol) and pivalic acid (2.20 g, 21.5 mmol) was stirred at 120° C. for 12 h. After cooling to room temperature, the mixture was diluted with dichloromethane. The solution was washed with 1N sodium hydroxide aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 as eluent) to afford the title compound (327 mg, 76%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH:15]1([C:12]2[C:13]3[C:8](=[C:7]([O:18][CH3:19])[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=3)[CH:9]=[CH:10][N:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1cc(OC)c2ccnc(C3CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Cyclopropyl-5-methoxy-isoquinoline-7-carboxylic acid methyl ester (4.87 g, 18.9 mmol) was dissolved in THF (50 ml) and MeOH (50 ml), and 5N NaOH aq. (18.9 ml) was added thereto. After stirred at 60° C. for 2 h, the mixture was concentrated in vacuo. The residue was triturated with H2O and 5N HCl aq. (18.9 ml) and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-(3-chlorophenyl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(3-chlorophenyl)-2-(4-fluoroanilino)benzoic acid 19 mg of pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=O.C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[S:24])[NH2:9]
Reactant: Cc1occc1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1occc1C(N)=S

Procedure:
A reaction mixture of N-[4-chloro-3-[dimethylhydrazono)methyl]phenyl]-2-methyl 3-furancarboxamide (1 g), sodium bicarbonate (1.8 g) and Lawesson's reagent (0.9 g) in toluene (20 mL) was refluxed for 3 hours. The reaction mixture was then cooled and filtered through a plug of neutral aluminum oxide and eluted with ether. Evaporation of the solvent produced 0.6 g of N-[4-chloro-3-[dimethylhydrazono)methyl]phenyl]-2-methyl-3-furancarbothioamide, m.p. 90-92° C.
Reaction SMILES: [OH-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH2:41][C:42]([O:44]CC)=[S:43])([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)[CH3:22])=[CH:17][CH:16]=1>O1CCOCC1.C(O)C>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH2:41][C:42]([OH:44])=[S:43])([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:17][CH:16]=1
Reactant: CCOC(=S)CC(C)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(CC(O)=S)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1N sodium hydroxide (0.5 mL) was added to a solution of ethyl 1,1-bis(4-(2-quinolylmethoxy)phenyl)eth-1-ylthioacetate from above in dioxane (10 mL) and ethanol (5 mL), and the resulting mixture was stirred at ambient temperature for 3 hours. The organics were removed in vacuo, the residue was diluted with water and acidified to pH 3. The solid was filtered, washed with water, dried under reduced pressure and recrystallized from methylene chloride-hexane to provide 170 mg of the title compound: mp 92°-94° C.; 1H NMR (300 MHz, DMSO-d6)δ 2.00 (s, 3 H), 3.32 (s, 2 H), 5.34 (s, 4 H), 7.02 (d, J=9 Hz, 4 H), 7.30 (d, J=9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J=8 Hz, 2 H); MS (DCI-NH3) m/z 587 (M+H)+. Anal. Calc'd. for C36H30N2O4S: C, 73.70; H, 5.15; N, 4.77. Found: C, 74.24; H, 5.28; N, 4.34.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(O)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>CO.[Pd]>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCCCC(c1ccccc1)c1ccccc1

Procedure:
11.2 g (46.2 mmol) of 1,1-diphenyl-1,4-butanediol was hydrogenated (45° C., 5 atm) in 100 ml of methanol in the presence of 0.5 ml of concentrated sulfuric acid and 10% palladium/carbon to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:40])[CH:37](Br)[CH3:38]>O>[CH3:34][O:35][C:36](=[O:40])[CH:37]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2)[CH3:38]
Reactant: COC(=O)C(C)Br
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.18 g), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.092 g) and 2-bromopropionic acid methyl ester (0.11 g) was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 to 1:4 by volume) to afford title compound, 0.092 g.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=O)=[CH:4]2.ON1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:39][CH2:40][CH2:41][N:42]1[C:47](=[O:48])[CH2:46][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][C:43]1=[O:58].C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)Cl>[O:58]=[C:43]1[CH2:44][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:46][C:47](=[O:48])[N:42]1[CH2:41][CH2:40][NH:39][C:13]([C:5]1[S:6][C:7]2[N:12]3[C:3](=[CH:2][N:1]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:4]=1)=[O:15]
Reactant: NCCN1C(=O)CN(CCCc2ccccc2)CC1=O
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCN1C(=O)CN(CCCc2ccccc2)CC1=O)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 0.8 g (3.67 mmol.) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate and 0.84 g (7.30 mmol.) of N-hydroxysuccinimide in acetonitrile (10 ml) was added, at room temperature, 1.41 g (7.36 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide. The mixture was stirred for 2 hours. To the reaction system was added a solution of 1.66 g (4.77 mmol.) of 1-(2-aminoethan-1-yl)-2,6-dioxo-4-(3-phenylpropan-1-yl)piperazine.dihydrochloride and 2.7 ml (19.4 mmol.) of triethylamine in chloroform (5 ml). The mixture was stirred for further one hour. The solvent was distilled off under reduced pressure. To the residue was added water, and the mixture was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate. The concentrate was purified by means of a column chromatography (methanol/ethyl acetate 20%) to afford the object compound as a reddish amorphous product. The yield was 1.56 g (89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].Cl>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-nitrophenol (30.0 g) and 1,1′-carbonyldiimidazole (47.34 g) were dissolved in THF (300 mL). The mixture was refluxed over night. The reaction mixture was cooled, poured into ice/water and acidified with 1M aqueous HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Methanol (150 mL) was added to the resulting precipitate and the mixture was stirred for 30 minutes at r.t. The resulting solid was filtered off and dried in vacuo. The title compound was obtained as a yellow solid (32.32 g, 88%). MS (neg. ion, m/e)=179.0 [(M−H)−].
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[Cl:17])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 27.7 %

Procedure:
This compound was prepared according to the procedure used in Preparation 1. A mixture of 44.6 g (0.25 mol) of bis(2-chloroethyl)amine hydrochloride, 40.5 g (0.25 mol) of 3,4-dichloroaniline and 50.0 g (0.362 mol) of potassium carbonate in a total volume of 500 mL of n-butanol gave an oil as residue. Trituration of the oil with petroleum ether (30°-60°) gave 16.0 g (28%) of white solid, mp 62°-65° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2C=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:30]2[CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 93.8 %

Procedure:
6-amino hexanoic acid (39a) (13.1 g, 100 mmol) and phthalic anhydride (40) (14.8 g, 100 mmol) were mixed in toluene (150 mL.). To the suspension was added triethyl amine (13 mL) The suspension was refluxed using Dean-stark for 16 h. When collection of water ceased, the reaction was cooled and evaporated to dryness. The residue was suspended in water and conc. hydrochloric acid (1.5 mL) was added. The suspension was stirred for 30 mins and filtered. The precipitate was washed with water and dried over sodium sulfate to afford compound 41a (24.5 g, 93%) which was used as such for the next step.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].Br.[OH2:16]>CS(C)=O>[F:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[O:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O
Reactant: COC(=O)c1ccc(C(C)=O)cc1F
Agent: Br
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=O)C=O)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-acetyl-2-fluorobenzoate (1.6 g, 8.2 mmol) and 8.8M hydrogen bromide in water (2.8 mL) in dimethyl sulfoxide (20 mL) was stirred at 60° C. overnight. After cooling, the mixture was poured into ice-water. The reaction mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the desired product which was used in the next reaction step without further purification. (1.60 g, 93.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH2:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: C=C1CN(C(=O)C(F)(F)F)CCc2nc(OC)ccc21
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of 2-methoxy-5-methylene-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (495 mg, 1.73 mmol), 10% Pd/C (60 mg) and MeOH (40 ml) was stirred under a H2 atmosphere (1 atm) for 2 h at ambient temperature. Filtration and concentration of the filtrate in vacuo gave 490 mg (98%) of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.52 (d, 1H), 6.65 (m, 1H), 3.94-3.73 (m, 5H), 3.65-3.44 (m, 2H), 3.24-3.05 (m, 3H), 1.20 (m, 3H) ppm. A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (97.0 mg, 346 μmol) and K2CO3 (100 mg) in MeOH (10 ml) was heated at reflux for 2 h. The reaction mixture was parted between EtOAc and NaHCO3.The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 63 mg (95%) of 2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.35 (d, 1H), 6.51 (d, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 3.04-2.93 (m, 4H), 2.75 (dd, 1H), 1.30 (d, 3H) ppm.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.C(O)(C)(C)C.[CH2:36]1[CH2:46]CN2C(=NCCC2)[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH2:46][CH2:36][CH2:37][CH3:38])=[O:28])[CH:17]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CCCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
CDI (1.29 g, 7.99 mmol) was added to a solution of diflunisal (2.02 g, 8.07 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (1.50 mL, 14.97 mmol) and DBU (2.40 mL, 16.064 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 20 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.677 g of ten-butyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (colourless oil, yield: 68%).