Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:37]SC)[C:6]([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C@@H:13]([CH:33]([CH3:35])[CH3:34])[C:14]([NH:16][C@H:17]([C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[O:11])=[O:7])(=[O:3])[CH3:2].O[O:41][S:42]([O-:44])=O.[K+].[CH3:46]COC(C)=O>CO.O>[C:1]([NH:4][C@@H:5]([CH2:37][S:42]([CH3:46])(=[O:44])=[O:41])[C:6]([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C@@H:13]([CH:33]([CH3:35])[CH3:34])[C:14]([NH:16][C@H:17]([C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CSC[C@H](NC(C)=O)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)O)C(=O)CCCc1ccccc1)C(C)C
Reactant: CCOC(C)=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)N[C@@H](CS(C)(=O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)O)C(=O)CCCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
The title compound from Example 201 (20 mg, 0.035 mmol) in 1 mL MeOH at OoC was treated with OXONE® (22 mg, 0.035 mmol) in 1 mL water. The mixture was allowed to warm to room temperature over 0.5 h and then poured into 30 mL EtOAc. Water was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to give 6 mg of the title compound as colorless solid: 1H NMR (400 MHz, CD3OD) 8.14 (d, 1H, J=7.81 Hz), 7.75 (d, 1H, J=7.24 Hz), 7.25-7.05 (m, 5H), 4.94 (t, 1H, J=6.59 Hz), 4.62 (t, 1H, J=6.20 Hz), 4.35-4.20 (m, 1H), 4.15-4.05 (m, 1H), 3.78-3.70 (m, 1H), 3.48-3.38 (m, 1H), 3.29 (s, 3H), 2.88-2.80 (m, 1H), 2.75-2.45 (m, 5H), 2.15-2.03 (m, 1H), 1.97 (s, 3H), 1.90-1.80(m, 2H), 1.37 (d, 3H, J=7.26 Hz), 0.93 (d, 3H, J=6.77 Hz), 0.92 (d, 3H, J=6.74 Hz); MS (−APCI) m/z 595 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[S:6][C:7]=1[CH2:8][O:9]C1CCCCO1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[O:18][N:17]=2)[S:6][C:7]=1[CH2:8][OH:9])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CO
Yield: 93 %

Procedure:
To a solution of 3-{4-ethyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-thienyl}-5-(4-phenoxyphenyl)-1,2,4-oxadiazole (0.25 g, 0.54 mmol) that was obtained in Example 22 (22e) in ethanol (5 ml) was added pyridinium p-toluenesulfonate (0.014 g, 0.54 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 4 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to afford the title compound (0.19 g) in a yield of 92% as a crystalline white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Cl.CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cncn2)cc1
Yield: 44.5 %

Procedure:
A mixture of 13.8 parts of 1H-1,2,4-triazole, 18.7 parts of 1-bromo-4-methoxybenzene, 5 parts of potassium carbonate, 0.5 parts of copper (I)chloride and 90 parts of N,N-dimethylformamide is stirred and refluxed for 2 days. The reaction mixture is cooled and poured onto water. The product is extracted twice with benzene. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7.8 parts (44.5%) of 1-(4-methoxyphenyl)-1H-1,2,4-triazole; mp. 99.4° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([Cl:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1.[C:38]([CH2:40][C:41](OCC)=[O:42])#[N:39]>CN1C(=O)CCC1>[Cl:37][C:21]1[CH:22]=[C:23]([F:36])[C:24]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[CH:25][C:20]=1[C:12]1[C:13](=[O:19])[N:14]([CH2:17][CH3:18])[C:15]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([NH:6][C:41](=[O:42])[CH2:40][C:38]#[N:39])[CH:16]=2
Reactant: CCOC(=O)CC#N
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Agent: CS(=O)(=O)O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)CC#N)cc21
Temperature: 125 °C
Yield: 10.7 %

Procedure:
A suspension of Example 21 (0.180 g, 0.398 mmol) in ethyl cyanoacetate (3 ml, 28.1 mmol) was heated at 125° C. overnight. The mixture was treated with NMP (0.3 mL), heated at 125° C. for 24 h, then cooled to RT and purified via silica gel chromatography (EtOAc/Hex). The material was re-purified via silica gel chromatography (THF/Hex), dissolved in 4:1 MeCN/H2O, frozen and lyophilized, treated with MTBE and the resulting solid collected via filtration and dried to afford N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (22 mg, 11% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 519.1 [M+H]+.
Reaction SMILES: Cl.[C:2](=[O:14])([O:12][CH3:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1.[CH3:15][N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1>CN(C)C(=O)C>[C:2](=[O:14])([O:12][CH3:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:21]([C:20]2[N:16]([CH3:15])[N:17]=[C:18]([CH3:24])[CH:19]=2)=[O:22])[CH:5]=1
Reactant: COC(=O)Oc1ccc(F)c(N)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)Oc1ccc(F)c(NC(=O)c2cc(C)nn2C)c1
Yield: 87.2 %

Procedure:
Using a solution of 3-amino-4-fluorophenyl methyl carbonate hydrochloride (740 mg, 3.34 mmol) and 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (556 mg, 3.51 mmol) in N,N-dimethylacetamide (10 mL), and by a reaction in the same manner as in Example 148, the title compound (895 mg, 87%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:3]1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)C[C@H]1C1CCCC(F)(F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: FC1(F)CCCC([C@@H]2C[C@H](c3ccccc3)CCN2)C1
Yield: 98.4 %

Procedure:
A suspension of 11 (500 mg, 1.2 mmol) and Pd(OH)2 (0.2 g) in 10 ml of EtOH was hydrogenated under 1 atmosphere of hydrogen at room temperature overnight. Filtration and concentration afforded (2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine as a colorless oil (330 mg, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])([O-])=O.[C:16](OC(=O)C)(=O)[CH3:17].C(O)(=O)C>[Ni]>[CH2:14]([N:13]1[C:12]2[CH:11]=[CH:10][C:6]([C:7](=[O:8])[NH2:9])=[CH:5][C:4]=2[N:1]=[C:16]1[CH3:17])[CH3:15]
Reactant: CCNc1ccc(C(N)=O)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CCn1c(C)nc2cc(C(N)=O)ccc21
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 125 g (0.6 mole) of compound III, 214 g (2.1 moles) of acetic anhydride, 1.2 ml of Raney nickel and 36 g (0.6 mole) of acetic acid was hydrogenated at 80° C and a pressure of 100 to 30 kg/sq.cm for 5 h. After cooling, the catalyst was filtered, and the filtrate was concentrated by normal pressure until 135 ml of distillate were collected. Then 150 ml of 6N sulphuric acid were added to the residue. The reaction was very exothermic. The solution was refluxed with active carbon for 15 min and filtered. The filtrate was mixed with 1.2 kg of ice and exactly neutralized with 2N sodium hydroxide. The precipitate was washed with water and dried at 100° C. Melting point: 251° C. Yield: 88% (108 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([N:8]([C:31](=[O:32])[C:30]1[CH:34]=[C:35]([CH3:37])[CH:36]=[C:28]([CH3:27])[CH:29]=1)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CCOC(=O)C(C)(C)NNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
2-(N′-benzyloxycarbonyl-hydrazino)-2-methyl-propionic acid ethyl ester (28 g, 0.1 mol) was dissolved in 50 mL CH2Cl2 and cooled on ice. A solution of 20.7 g K2CO3 in 30 mL of water was added. A solution of 3,5-dimethylbenzoyl chloride (17 g, 0.1 mol) in 50 mL of CH2Cl2 was added drop-wise over a period of 1 hour, maintaining the temperature at 0-5° C. The mixture was stirred for 1 hour on an ice bath, and then at room temperature overnight. TLC indicated the reaction was complete. The aqueous layer was removed in a separatory funnel and the organic phase was washed with water and then brine, and then dried over Na2SO4. The solvent was removed on a rotary evaporator. The residue was slurried in hexane, filtered, and then air-dried. 2-[N′-Benzyloxycarbonyl-N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester was obtained as a white solid (35 g), giving a single spot by TLC. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 (s, 1H), 7.3 (m, 3H), 7.15 (m, 2H), 7.1. (s, 2H), 7.0 (s, 1H), 5.2 (d, 1H), 5.0 (d, 1H), 4.2 (m, 2H), 2.25 (s, 6H), 1.78 (s, 3H), 1.64 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([NH:15][C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[C:8]([Cl:21])[CH:7]=1>C(O)(C)C>[CH:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([NH:15][C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[C:8]([Cl:21])[CH:7]=1.[Cl:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: O=C(O)CCl
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)O
Product: O=C([O-])CCl
Temperature: 2.5 °C

Procedure:
To a solution of 2.0 g of monochloroacetic acid in 10 ml of isopropyl alcohol 3.0 g of the tizanidine base (99.15% HPLC) are added. After brief heating to boil a solution results, from which a crystalline precipitated product starts to separate. After cooling to 0 to 5° C. and aspiration 3.31 g of tizanidine monochloroacetate are obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=O.[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:27]([C:40]([F:43])([F:42])[F:41])[CH:26]=3)[N:21]=[C:20]([C:44]#[N:45])[C:19]=2[N:18]=[N:17]1.CCN(C(C)C)C(C)C>CO>[C:44]([C:20]1[C:19]2[N:18]=[N:17][N:16]([CH3:15])[C:24]=2[CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([CH2:3][C@H:2]([OH:1])[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:39]3)=[C:27]([C:40]([F:42])([F:43])[F:41])[CH:26]=2)[N:21]=1)#[N:45]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: COC(=O)[C@@H]1CO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@@H](O)CN1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1

Procedure:
(S)-Methyl oxirane-2-carboxylate (1.837 mmol, 0.188 g), 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate (0.918 mmol, 0.5 g) and Hunig's base (1.837 mmol, 0.304 ml, 0.237 g) were heated in Methanol (5 ml) to 100° C. for 10 minutes in the microwave. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with DCM—90/10 DCM/MeOH to afford (S)-methyl 3-(4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoro-methyl)phenoxy)ethyl)piperidin-1-yl)-2-hydroxypropanoate. (0.34 g)
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C=CC=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][C:7]([NH:6][CH:4]1[CH2:5][C:2](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3]1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of tert-butyl 3-oxocyclobutylcarbamate (1.0 g, 5.4 mmol) in toluene (10 mL) was added ethyl 2-(triphenylphosphoranylidene)acetate (2.1 g, 5.9 mmol). The reaction mixture was heated at 100° C. for 2 hrs, and then concentrated. The residue was purified by silica gel column chromatography (10% EtOAc/petroleum ether) to afford ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutylidene)acetate (1.2 g, 89%). ESI-MS (EI+, m/z): 256 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2-(bromoacetamido)benzoic acid from Example 41 (10 g, 0.03 mol), aniline (8 g, 7.8 mL, 250 mol %) and DMF (60 mL) was heated at 100°-110° C. for 4 h. The reaction mixture was poured into ice-water (200 mL) and the resulting solid product was solubilized by adding 5% KOH (40 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the aqueous layer was acidified with 5% HBr to pH=3 and extracted with EtOAc (3×200 mL). The EtOAc washings were dried (Na2SO4), filtered and concentrated to afford, after drying under vacuum, 7.8 g (75%) of the title compound as a white solid, mp 210°-212° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.96 (s, 1H, COOH), 8.75 (d, 1H, J=8), 7.87 (d, 1H, J=2.8), 7.68 (d, 1H, J=2.4), 7.65 (d, 1H, J=2.8), 7.10 (t, 2H, J=7.6), 6.61 (m, 4H), 3.84 (s, 2H); 13C NMR (DMSO-d6) δ 171.08, 167.81, 148.05, 139.36, 133.81, 130.25, 128.97, 126.20, 121.25, 117.77, 117.14, 112.45, 48.90; MS (EI, m/z) 304 (M+).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.O.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:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]cc(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in dioxane (5 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (395 mg, 1.54 mmol), K2CO3 (106 g, 0.77 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 5 h at 90° C., and then poured into water (100 mL), extracted with DCM (4×50 mL), dried over anhydrous sodium sulfate and then concentrated under vacuum to give a residue. The residue was purified via silica gel chromatography (25% ethyl acetate in petroleum ether) to afford methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a yellow solid (80 mg, 45%).
Reaction SMILES: [O:1]=[C:2]([CH:12]=[CH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[BH4-].[Na+].Cl>CO>[OH:1][CH:2]([CH:12]=[CH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=CC(=O)CCCCCCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CC(O)CCCCCCC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 8-oxo-9-decenoic acid (910 mg, 4.94 mmol, 1.00 eq.) in MeOH (20.0 mL), was added CeCl3.7H2O (2.76 g, 7.41 mmol, 1.50 eq.). The mixture was stirred for 30 minutes with ice-cooling, and then thereto was slowly added sodium borohydride (224 mg, 5.93 mmol, 1.20 eq.). The mixture was stirred for 1 hour, and then the reaction solution was poured into 1 M aqueous hydrochloric acid solution. The organic phase was extracted with chloroform. Then, the resulting organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=97:3) to obtain 8-hydroxy-9-decenoic acid as shown below (870 mg, 4.55 mmol, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: Oc1ccc(F)cc1Br
Reactant: CS(=O)(=O)OC1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CCOC2)c(Br)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (50.0 g, 261 mmol) in 300 ml of DMF was added Cs2CO3 (213 g, 654 mmol) and heated the reaction mixture for 3 h at 80° C., after that tetrahydrofuran-3-yl methanesulfonate (Int-68) (43.5 g, 261 mmol) was added at room temperature, stirred the reaction mixture for 16 h at 80° C. filtered the base, filtrate was dissolved with EtOAc (1.2 L), washed with water and 1N NaOH solution (800 ml), water and brine solution, dried over sodium sulfate and concentrated to dryness to afford crude compound. This was purified over 60-120 mesh silica using 10-12% ethyl acetate and hexane as an eluent to get the pure product (50 g, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 1H), 7.00-6.93 (m, 1H), 6.82-6.77 (m, 1H), 4.91-4.87 (m, 1H), 4.07-3.96 (m, 3H), 3.94-3.89 (m, 1H), 2.20-2.13 (m, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20](C4C=CC=CC=4)[CH2:19]3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-:39].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([O:39][C:11]4[CH:30]=[CH:29][CH:14]=[CH:13][CH:12]=4)[CH2:19]3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCC(c4ccccc4)C3)sc2c1-c1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2nc(N3CCC(Oc4ccccc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
To a solution of (2S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-phenylpyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetate (29.3 mg, 0.653 mmol) in CH3OH (1 mL) was added NaOH (1N, 1 mL, 1 mmol), the resulting mixture was heated at 50 C for 10 hr. The mixture was acidified to pH 3 and evaporated to a small volume, and the residue was partitioned between CH2Cl2 and brine. The organic layer was separated, dried, filtered and evaporated to dryness. The residue was purified on TLC (50% EtOAc/Hex) to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-phenoxypyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C30H32ClN2O3S: 534.2, 536.2 (M+H+); found: 535.2, 537.2 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.63 (dd, J=2.0, 7.2 Hz, 1H), 7.49-7.52 (m, 3H), 7.30-7.34 (m, 5H), 7.24 (m, 1H), 5.13 (s, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.52-3.63 (m, 4H), 2.48 (s, 3H), 2.46 (m, 1H), 2.20 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17]([C:41]3[NH:45][C:44](=[O:46])[O:43][N:42]=3)[N:16]=2)=[CH:13][C:12]([Cl:47])=[CH:11][N:10]=1)C1C=CC=CC=1.[SiH](CC)(CC)CC>C(Cl)Cl.Cl[Pd]Cl>[Cl:47][C:12]1[CH:13]=[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17]([C:41]3[NH:45][C:44](=[O:46])[O:43][N:42]=3)[N:16]=2)[C:9](=[O:8])[NH:10][CH:11]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(-c4noc(=O)[nH]4)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(-c4noc(=O)[nH]4)nc(-c4cc(Cl)c[nH]c4=O)c32)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (23 mg, 0.03 mmol) in anhydrous CH2Cl2 at 0° C., Et3SiH (0.029 mL, 0.18 mmol) and PdCl2 (2 mg, 0.01 mmol) were added. The reaction was stirred at 0° C. for 0.5 hour and then concentrated. The residue was purified on a C-18 column eluting with 40% water/60% acetonitrile to afford 5-chloro-3-{2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl}pyridin-2(1H)-one. 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.04 (br s, 1H), 7.76 (d, J=2.8 Hz, 1H), 4.01 (m, 1H), 3.83-3.93 (m, 3H), 3.62 (m, 1H), 3.54 (m, 1H), 3.38 (m, 1H), 3.12 (m, 1H), 2.96 (m, 1H), 2.28 (m, 1H), 1.97 (m, 1H), 1.49-1.82 (m, 6H), 1.19-1.25 (m, 2H), 0.91-1.00 (m, 2H), 0.78 (d, J=6.4 Hz, 3H), 0.57-0.74 (m, 3H). MS ES calc'd. for C28H32ClN7O4 [M+H]+ 566. found 566.