Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.Cl.[OH-].[NH4+]>C(Cl)(Cl)Cl>[C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:12]([CH:13]=[CH:14][C:15]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C:16]=3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24])[C:11]1([CH3:40])[CH3:41])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CCC2=C3C=C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
—Hydrogen chloride gas was passed into a solution of (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregna-5,7-dien-3-ol benzoate (compound 8; Example 1, step vi; 25.0 g) and acetic anhydride (40 ml) in chloroform (250 ml) for 30 min. The mixture was heated at reflux temperature for 50 min.; addition of hydrogen chloride gas was continued for the first 20 min. After cooling to 0° C., an aqueous solution of ammonium hydroxide (5%) was added, and the mixture was stirred for 1.5 h. The product was extracted into dichloromethane; the combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give (3β,5α,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregna-6,8(14)-dien-3-ol benzoate (24.6 g). The product was used as such in the next step.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of Example 1 (371 mg, 1 mmol) in THF (4 mL), methanol (3 mL), and 1.7M LiOH (3 mL, 5.1 mmol) was stirred at reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with water, and acidified with dilute HCl. The resulting precipitate was collected by filtration, washed with cold water, and dried to provide 324 mg of the desired product (91% yield). ESI-MS m/z 358 (MH+); 1H NMR (300 MHz, DMSO-d6) 1.37-2.05 (m, 10H), 2.78 (m, 1H), 4.06 (s, 1H), 5.17 (s, 1H), 6.39 (m, 1H), 6.89 (d, J=10.61 Hz, 1H), 7.50 (m, 4H), 7.60 (m, 1H), 7.88 (d, J=8.78 Hz, 1H), 8.24 (s, 1H), 12.59, (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][N:32]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:37][C:34]4[CH:33]=[N:32][C:31]([Cl:30])=[CH:36][CH:35]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(Cl)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (150 mg, 0.46 mmol), prepared as described in Example 244, in DMF (3 mL) was added K2CO3 (80 mg, 0.58 mmol) and 2-chloro-5-(chloromethyl)pyridine (90 mg, 0.556 mmol). The reaction mixture was stirred at 70° C. for 15 min. After this time, the solution was cooled to RT and diluted with water (20 mL). The resulting solid was collected by filtration and the crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-2-((6-chloropyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (110 mg, 52%), as a yellow solid. HPLC: 2.61 min; MS, M+H=449; 1H NMR (CDCl3) δ 8.62 (2H, d, J=5.0 Hz), 8.43 (1H, d, J=5.0 Hz), 8.19 (1H, s), 7.33 (1H, d, J=5.0 Hz), 7.29-7.31 (3H, m), 7.20 (2H, d, J=5.0 Hz), 7.08 (2H, d, J=10.0 Hz), 5.17 (2H, s).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:41]=[CH:40][C:14]([CH:15]([OH:39])[CH2:16][N:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]([CH3:31])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:13][C:12]=1[N+:42]([O-])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CCCCCC>C1C=CC=CC=1.[Fe]>[NH2:42][C:12]1[CH:13]=[C:14]([CH:40]=[CH:41][C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:15]([OH:39])[CH2:16][N:17]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:18]([CH3:31])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1ccc(CCC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1OC
Agent: [Fe]
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc(CCC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1OC

Procedure:
In 50 ml. of methanol there was dissolved 5 g. of 4-benzyloxy-3-nitro-α-[N-benzyl-N-{3-(3,4-dimethoxyphenyl)-1-methylpropyl}aminomethyl]benzyl alcohol and after adding to the solution 2.5 g. of iron powder and 5 ml. of 2N hydrochloric acid, the mixture was refluxed for 50 minutes. After cooling the reaction mixture, the insoluble materials were filtered off, and 5 ml. of a 2N potassium hydride methanol solution and 20 ml. of ethyl acetate were added to the filtrate. The insoluble materials were filtered off and the filtrate was concentrated under a reduced pressure. The residue was extracted with benzene, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to provide a yellowish brown viscous product. The product thus obtained was dissolved in benzene and after adding n-hexane until the solution became slightly muddy, the solution was allowed to stand whereby 2.7 g. of yellowish brown crystals of 3-amino-4-benzyloxy-α-[N-benzyl-N-{3-(3,4-dimethoxyphenyl)-1-methylpropyl}aminomethyl] benzyl alcohol [A]were obtained. The product was recrystallized from a mixture of benzene and n-hexane and was characterized by a melting point of 115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=O)[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[CH2:8][C:7]=2[CH:24]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[CH2:8][C:7]=2[CH:24]=1
Reactant: CCOC(=O)CC1C(=O)c2ccc(OC)cc2Cc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-methoxy-11-oxo-5H-dibenzo[a,d]cycloheptene-10-acetate (0.3 g., 0.93 mmol) and 10% Pd/C (0.3 g) in glacial acetic acid (25 mL) was hydrogenated at 50 psi for 18 hours. The mixture was filtered using celite® and washed with acetic acid. The filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 0.25 g of the title compound: 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 2.60 (m, 2H), 2.90 (m, 1H), 3.30 (m, 1H), 3.80 (s, 3H), 3.85 (d, 1H), 4.18 (q, 2H), 4.30 (d, 1H), 6.70 (m, 2H), 7.0 (d, 1H), 7.22 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]([CH3:56])[CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:53]6[CH2:54][CH2:55][CH:50]([N:49]([CH3:56])[CH3:48])[CH2:51][CH2:52]6)=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CN(C)C1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCC(N(C)C)CC4)nc3)cn2)cc1
Yield: 85.5 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-48 and 4-dimethylaminopiperidine (59 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of [5′-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-dimethyl-amine as a yellow solid (197 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-73) as a yellow powder (32 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:35]2[CH2:37][CH2:36]2)=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:35]2[CH2:37][CH2:36]2)=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C1CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C1CC1

Procedure:
114 mg (0.22 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 73 mg (78% of theory)
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][C:25](=O)[CH2:24][CH2:23]2>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][CH:25]2[CH2:24][CH2:23][C:22]3[C:27](=[C:28]([F:30])[CH:29]=[C:20]([F:19])[CH:21]=3)[CH2:26]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.9, 14.1, 14.2, 19.5, 19.6, 28.2, 28.6, 28.7, 28.9, 29.6, 29.9, 36.5, 36.6, 51.9, 52.3, 60.1, 60.6, 62.9, 100.7, 100.9, 101.2, 104.2, 110.5, 110.6, 110.8, 118.2, 118.5, 132.4, 137.9, 138.0, 139.6, 139.9, 159.8, 162.1, 162.2, 172.2, 172.4; MS 419.2 m/z (M+1).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of (R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (Intermediate 5: 22.1 mg, 0.060 mmol) in THF (0.6 mL) and methanol (0.1 mL), aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added at room temperature. After stirring for 3 hours, additional aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added. The reaction mixture is allowed to stir for 30 minutes and quenched with 0.5 mL of aqueous 1M HCl and 0.5 mL of brine. The mixture is extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure to give (R)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic acid (16.4 mg). HPLC retention time=1.04 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13-2.31 (m, 3 H) 2.59-2.65 (m, 1 H) 2.81-2.90 (m, 2 H) 3.12-3.27 (m, 2 H) 7.26 (d, 2 H, J=8 Hz) 7.34 (t, 1 H, J=7.4 Hz) 7.45 (t, 2 H, J=7.7 Hz) 7.57 (d, 2 H, J=8.1 Hz) 7.63-7.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-chloro-4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
12 mg of lithium hydroxide hydrate was added to 41 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.8 mL of tetrahydrofuran and 0.4 mL of water, and the mixture was stirred for 5.5 days at room temperature. The mixture was adjusted to pH=3 with 1N hydrochloric acid in an ice bath. 30 mL of water was added thereto, and after the mixture was stirred for 1 hour at room temperature and then purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent:water, a 40% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), the obtained solids were further washed with tetrahydrofuran, thereby yielding 26 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:41][C:42]1[C:43]([CH:49]=O)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>CO>[CH3:41][C:42]1[C:43]([CH2:49][N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=3)=[O:32])=[CH:18][CH:19]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc(C)cc3C)Cc3nccn3C)cc2)cc1
Yield: 88.1 %

Procedure:
The compound (155 mg) obtained in Example 15-5 was dissolved in anhydrous methanol (3.0 ml) and added with sodium cyanoborohydride (33.7 mg), acetic acid (0.50 ml), and the compound (58.0 mg) obtained in Example 15-6, and the whole was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. Then, the solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (174 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from a mixture of toluene and petroleum ether (b.p. 60° - 80° C.) to give 1-dipropylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, m.p. 80° - 81° C. Elemental analysis satisfactory.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl[CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]2[O:12][C:14]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])=[CH:5][C:4]=2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(Br)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c2oc(C(=O)N(C)C)cc2c1

Procedure:
3-Bromo-2-hydroxy-5-methoxybenzaldehyde (1.5 g, 6.49 mmol), 2-chloro-N,N-dimethylacetamide (0.73 mL, 7.14 mmol) and potassium carbonate (1.8 g, 13.0 mmol) were heated to reflux in dimethylformamide (15 mL) for 2 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with water and brine. The organic phase was dried over MgSO4, filtered and then concentrated by rotary evaporation. The crude product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%). Yield: 1.5 g (77%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[N:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14](Br)[N:13]=2)[CH2:7]1)(=[O:4])=[O:3].[CH2:26]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[F:45])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][S:2]([O:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([C:12]2[CH:17]=[N:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([C:39]3[CH:40]=[CH:41][C:36]([C:34](=[O:35])[NH:33][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:37]([F:45])[CH:38]=3)[N:13]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)C(=O)Nc1ncc(C2CCCC(OS(C)(=O)=O)C2)nc1Br
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](OS(C)(=O)=O)C2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Temperature: 80 °C
Yield: 101 %

Procedure:
To cis racemate (+/−)-3-(6-bromo-5-pivalamidopyrazin-2-yl)cyclohexyl methanesulfonate (54 mg, 0.124 mmol) in 2.0 mL MW vial was added (4-(benzylcarbamoyl)-3-fluorophenyl)boronic acid (50.9 mg, 0.186 mmol), PdCl2(dppf) (9.10 mg, 0.012 mmol), DME (1166 μL) and 2M Na2CO3 solution (389 μL). The reaction mixture was heated at microwave synthesizer (12 min, 80° C.). The reaction mixture was diluted with EtOAc and washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH) to provide 73 mg of (+/−)-(1S,3R)-3-(6-(4-(benzylcarbamoyl)-3-fluorophenyl)-5-pivalamidopyrazin-2-yl)cyclohexyl methanesulfonate which was taken to the next reaction without further purification. LCMS (m/z): 583.4 (MH+), 0.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: CN(C)CCN
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)NCCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.