Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:44][C:42](=[O:43])[C@H:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:33])=[O:18])[CH2:14][CH2:15]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of trans-4-(t-butoxycarbonylaminomethyl)cyclohexyl carboxylic acid (3.86 g) dissolved in dry tetrahydrofuran (150.00 ml), triethylamine (2.25 ml) was added under ice-cooling and the mixture was stirred for 5 minutes. A solution of ethyl chlorocarbonate (1.63 g) in dry tetrahydrofuran (10.00 ml) was added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. L-phenylalanine amide hydrochloride and triethylamine (2.25 ml) were added to the mixture, and the mixture was stirred under ice-cooling for 2 hours and under room temperature for one hour, followed by concentration under a reduced pressure. Water was added to the residue, and the insolubles therein were filtered, thoroughly washed with water, and further washed with 50% aqueous ethyl alcohol and 50% ethyl alcohol-ethyl ether, followed by drying, to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine amide (I) (4.82 g) as a white powder. This structure was confirmed by NMR spectrum.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](O)=[C:19]([CH3:25])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([Br:16])=[CH:18][C:19]=1[CH3:25])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (1.004 mL) was added to an ice-cooled mixture of 4-bromo-2,6-dimethylphenol (1.00 g) and pyridine (0.482 mL) in methylene chloride (5 mL) with stirring. After being stirred for 10 minutes, the reaction mixture was poured into a mixture of 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/20) to afford 4-bromo-2,6-dimethylphenyl trifluoromethanesulfonate (1.439 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[C:40](=O)([O-])[O-:41].[K+].[K+].O>CN(C)C=O>[N:35]1([C:40]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=4[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:33][CH3:34])=[O:41])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: O=C([O-])[O-]
Reactant: c1c[nH]cn1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCC(=O)n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), imidazole (27 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (16 mg, yield 24%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[C:8]([C:16]([NH2:18])=[O:17])[CH:7]=[N:6][N:5]2[CH:19]=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCOC(C)=O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]1([C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:19]=[C:2]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([CH:20]=[CH2:21])[CH:27]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:16]([NH2:18])=[O:17])[CH3:12])[CH2:15][CH2:14]1
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1cccc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)c1
Temperature: 90 °C
Yield: 27.2 %

Procedure:
A degassed solution of (R)-6-bromo-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 4, 25 mg, 0.077 mmol), 3-vinylphenyl boronic acid (34.3 mg, 0.232 mmol) and 2M aq. potassium carbonate (0.116 mL, 0.232 mmol) in DME (1 mL) was added Pd(Ph3P)4 (5.36 mg, 4.64 mmol) and the resulting reaction mixture was heated to 90° C. for 2 hrs. The reaction mixture was diluted with 10 mL of EtOAc which was washed with 5 mL of water and 5 mL of brine. The organic phase was concentrated to yield a crude product which was purified on a preparative silica gel TLC plate with hexanes/EtOAc (2/1) as the eluent to yield a product. After trituration in MeOH, the resulting solid obtained was dried to afford the title compound (7.25 mg, 26%). HPLC (condition G): retention time=3.833 min. LC/MS (M+H)+=m/z 347.2. 1H NMR (400 MHz, MeOD) δ ppm 8.12 (1 H, s), 7.93-7.95 (1 H, m), 7.72 (1 H, s), 7.55-7.60 (1 H, m), 7.34-7.37 (2 H, m), 7.22 (1 H, d, J=1.8 Hz), 6.81 (1 H, dd, J=17.8, 11.0 Hz), 5.86 (1 H, dd, J=17.7, 1.0 Hz), 5.27 (1 H, dd, J=11.0, 0.9 Hz), 4.09-4.17 (1 H, m), 1.46 (3 H, d, J=6.4 Hz), 1.11-1.21 (1 H, m), 0.53-0.64 (2 H, m), 0.37-0.47 (2 H, m).
Reaction SMILES: ClC1C=CN=NN=1.Cl[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]=[C:11]([N:18]([CH3:20])[CH3:19])[N:10]=1.C(O)=[O:22]>>[CH3:19][N:18]([CH3:20])[C:11]1[N:12]=[C:13]([O:15][CH2:16][CH3:17])[NH:14][C:9](=[O:22])[N:10]=1
Reactant: O=CO
Reactant: CCOc1nc(Cl)nc(N(C)C)n1
Agent: Clc1ccnnn1
Product: CCOc1nc(N(C)C)nc(=O)[nH]1

Procedure:
The chlorotriazine from (b) (1.2 g.) was heated in formic acid (15 ml.) on a steam bath for 45 minutes, when gas evolution had ceased. The excess of formic acid was removed under reduced pressure and the residue was dissolved in the minimum amount of water, which was brought to pH 6-7 by adding solid sodium bicarbonate. The solution was extracted with chloroform and the extracts dried and evaporated. The residue crystallised from ethanol to give the product (1.1 g.) having a melting point of 215°-216° C. (The melting point sample resolidified and re-melted at 235° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl-].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:13][NH3+:14])([O-:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.4 ml (0.244 mol) of methanesulfonyl chloride are metered over 30 minutes with ice-cooling to a solution of 30.1 g (0.122 mol) of 3-nitro-4-methoxycarbonylbenzylammonium chloride and 34 ml (0.244 mol) of triethylamine in 300 ml of dichloromethane, and stirring of the mixture is continued for one hour. For work-up, the reaction mixture is treated with ice water, the phases are separated, and the aqueous phase is reextracted twice more with dichloromethane. After drying (Na2SO4), filtration and concentration, 31.3 g (89%) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate remain as a syrupy oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14](=[O:27])[NH:15][C:16]1[C:25]2[CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:27])[NH:15][C:16]1[C:25]2[CH2:24][CH:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Methanesulfonyl chloride (176 mg, 1.54 mmol) was added dropwise to a solution of the product from Example 20C (381 mg, 1.29 mmol) and diisopropylethylamine (332 mg, 2.57 mmol) in 15 mL CH2Cl2 at ambient temperature. The mixture was stirred 30 minutes, diluted with methylene chloride and poured into water. The separated organic phase was washed with 1N aq HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography (4% CH3OH/CH2Cl2) yielded 281 mg (58%) of the title compound as a white amorphous solid. 1H NMR (DMSO-d6) δ 8.92 (s, 1H), 7.45-7.30 (m, 5H), 7.22 (d, J=7.1 Hz, 1H), 7.15 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.93 (m, 1H), 5.13 (s, 2H), 3.51 (m, 1H), 3.02 (m, 1H), 2.96 (s, 3H), 2.85 (m, 2H), 2.50 (m, 1H+ DMSO), 2.01 (m, 1H), 1.61 (m, 1H); MS (ESI+) m/z 375 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35]2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=[C:31]([NH2:38])[C:30]=2[N:29]=[CH:28]1>>[NH2:38][C:31]1[C:30]2[N:29]=[CH:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12](/[N:11]=[N:10]/[C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:35]=2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: Cc1nc(N)c2ncn(CCCCNS(=O)(=O)c3ccc(/N=N/c4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 15-29 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reached with of 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 521.2452.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]2[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Product: O=Cc1ccn(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (3.58 g) and 2,5-dimethoxy-3-tetrahydrofurancarbaldehyde (2.50 g) in acetic acid (16 mL) was stirred at 90° C. for 30 min. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 70:30) to give the title compound (2.44 g, yield 51%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:34]=O)[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][CH:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and cyclobutanecarboaldehyde (0.5 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47 g) as yellow oil.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][Si:14]([CH3:43])([CH3:42])[CH2:15][CH2:16][O:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:34]([O:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19][C:18](=[O:41])[O:17][CH2:16][CH2:15][Si:14]([CH3:42])([CH3:43])[CH3:13])[CH:26]=[CH:25][C:24]=1[N:27]([S:2]([NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])(=[O:4])=[O:3])[CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)CNc1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cooled solution of chlorosulfonyl isocyanate (2.55 g, 18 mmol) in methylene chloride (50 mL) is added dropwise a solution of t-butanol (1.33 g, 18 mmol) in methylene chloride (5 mL). The mixture is allowed to wart to RT, stirred for 15 min then re-chilled to 0° C. To this is added dropwise a solution of [3-benzyloxy-4-(methoxycarbonylmethylamino)-phenoxy]-acetic acid 2-trimethylsilanylethyl ester (5.35 g, 12 mmol) and triethylamine (2.07 g, 20.4 mmol) in methylene chloride (15 mL) and the mixture is stirred at RT for 2 h. The mixture is washed with water and the organic phase is dried over NaSO4. The solvent is removed under reduced pressure and the residue is purified by column chromatography to using EtOAc/hexane (3:7) as eluent to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:62]=[CH:63][CH:64]=1)[C:56]([NH:58][CH:59]([CH3:61])[CH3:60])=[O:57]>CN(C=O)C>[CH:59]([NH:58][C:56]([C:55]1[CH:54]=[C:53]([NH:52][C:18]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]3[C:9]4[C:16]([CH3:17])=[CH:15][NH:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:6][CH2:7]2)=[O:19])[CH:64]=[CH:63][CH:62]=1)=[O:57])([CH3:61])[CH3:60]
Reactant: CC(C)NC(=O)c1cccc(N)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(C(=O)NC(C)C)c4)CC3)c12
Temperature: 50 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.030 g, 0.11 mmol) in DMF (1 mL) were added HATU (0.042 g, 0.11 mmol), triethylamine (0.028 mL, 0.22 mmol) and 3-amino-N-isopropyl-benzamide (0.029 mg, 0.17 mmol). The reaction was stirred at 50° C. for 48 hours and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.023 g, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(ethoxycarbonylmethyl)piperidine (0.0222 mol) and 2-chloro-5-nitropyridine (0.0222 mol) in DMSO (40 ml) was stirred in the presence of Na2CO3 during 2 hours. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The resulting precipitate was filtered and washed with water. The reaction product was purified by recrystallisation from a mixture of ethyl acetate and hexane, yielding (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester (intermediate 1, mp. 99-101° C.).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2cccs2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.1 %

Procedure:
The product from Example 10B (60 mg, 0.25 mmol), (3,5-difluorophenyl)acetic acid (51 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 76 mg, 0.49 mmol), EDC (95 mg, 0.49 mmol), and DMAP (3.0 mg, 0.025 mmol) were combined in pyridine (3 mL). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with NaHCO3, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A] to afford 19 mg (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.42 (ddd, J=7.8, 1.5, 0.6 Hz, 1H), 8.18 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 8.05 (ddd, J=8.0, 7.3, 1.5 Hz, 1H), 7.99 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.81 (dd, J=5.1, 1.1 Hz, 1H), 7.66 (dd, J=3.6, 1.1 Hz, 1H), 7.29 (dd, J=5.1, 3.6 Hz, 1H), 7.06-7.22 (m, 3H), 3.78 (s, 2H); MS (APCI) M/Z 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](N(C(C)C)CC)([CH3:13])[CH3:12].[CH2:20](Br)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1>[CH2:13]([N:10]([CH2:22][CH:21]=[CH2:20])[C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[CH:11]=[CH2:12]
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)[C@H](C)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
A mixture of 2.0 g (10.0 mmol) (R)-1-(4-bromo-phenyl)-ethylamine and 30 ml toluene (dry) was cooled to 0° C. Thereafter, 5.2 ml (30.0 mmol) of di-iso-propylethylamine was added drop-wise, followed by the addition of 7.4 ml (85 mmol) allyl bromide. The resulting mixture was warmed to room temperature and then heated to 95° C. for 2.5 hours. The mixture was filtered. The precipitate was then washed with toluene and the filtrate and washings were combined and then concentrated in vacuo to give a reddish-brown oil. Chromatography on silica gel using 15% ethyl acetate/hexanes gave 2.76 g (99%) oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Yield: 107.2 %

Procedure:
A solution of 226 mg (0.740 mmol) 5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 15 mL MeOH was treated with 110 mg 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) and 1 atm H2 at room temperature for 18 h. The mixture was filtered through Celite, and the filter cake was washed with MeOH. Concentration afforded 220 mg (107%) of the title compound as a colorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C15H23N3O2, 278.2 (M+H), found 278.0.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20]C)=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br-].[Br-].[Br-].B.O>ClCCl>[OH:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]4)[C@H:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:10][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
Ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (946 mg, 1.43 mmol) was dissolved in dichloromethane (18 ml). To this solution, a 1M solution of borane tribromide in dichloromethane (4.3 ml, 4.3 mmol) was added dropwise at −78° C. The reaction mixture was warmed slowly and stirred for 3 hours at 0° C. Water was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoro-pentyl)undecanoate (663 mg, Yield 72%).