Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CO
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methanol (1.6 g, 4.2 mmol) in toluene (30 ml) was added thionyl chloride (0.61 ml, 8.4 mmol), and the mixture was heated under reflux for 30 min. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.2 g, 6.3 mmol) was added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The extract and the organic layer were combined and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and then saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and toluene (20 ml)-ethyl acetate (10 ml) was added to the residue. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, yield 82%) as pale-yellow crystals.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:9]=[C:10]([C:14]#[N:15])[O:11][C:12]=1[CH3:13])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]#[N:15])[O:11][C:12]=1[CH3:13]
Reactant: Cc1oc(C#N)cc1C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1oc(C#N)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrile from (ii) (3.75 g) in tetrahydrofuran (100 ml) was cooled to 0° C. under an argon atmosphere, and was treated with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (22 ml). The mixture was allowed to warm to room temperature and stirred for 16 hours. The volatiles were removed and the residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with more ethyl acetate. The combined ethyl acetate extracts were washed with 1M aqueous hydrochloric acid and brine, and dried. The solvent was evaporated and the crude orange oil was purified by flash chromatography (silica, gradient elution with 0% to 40% ethyl acetate in cyclohexane) to afford compound 147 as a pale yellow oil (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:27]CC4C=CC(OC)=CC=4)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=3)=[CH:14][C:13]=2[F:37])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](=[O:27])[NH:20][CH:19]=3)=[CH:14][C:13]=2[F:37])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(Cl)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(Cl)c3)c(F)c2)c[nH]c1=O
Yield: 31.5 %

Procedure:
A solution of N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (60 mg, 0.108 mmol) in HCl(MeOH, 27.0 μl, 0.108 mmol) was stirred at 20° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The crude product was purified by preparative HPLC to give pure product N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (14.72 mg, 0.034 mmol, 31.3% yield): 1H NMR: (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.45 (s, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.38-7.32 (m, 3H), 7.28-7.25 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.14 (m, 2H), 3.79 (s, 2H), 1.47 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 435.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([O:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 92.1 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-t-butylphenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (360 mg), which is the product of Example 116, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (315 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:43]#[CH:44])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[CH:44])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCOCC2)N1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC2CCOCC2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in Example 2, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-Iodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.3 g, 1.97 mmol) was reacted with trimethylsilyl acetylene (0.4 g, 3.94 mmol), CuI (0.75 g, 3.94 mmol), triethylamine (0.4 mL, 3.94 mmol) and dichlorobis(triphenylphosphine) palladium(0) (0.28 g, 0.39 mmol), then treated with aqueous NaOH solution in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.62 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CCCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, propanesulfonyl chloride.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][N:16](CC)[CH2:15]2)[CH2:11]1)[C:4]1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11]1)[CH3:4]
Reactant: CCN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC2(CCNC2)C1
Yield: 196.6 %

Procedure:
A solution of 9.5 g (0.030 mole) 2-benzyl-7-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 100 ml methanol was hydrogenated with 1.0 g 20% palladium on carbon catalyst at 4.5×105Pa for 22 hours. After filtration, the solution was concentrated to a syrup and crystallized from acetonitrile to afford 6.7 g of 2-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride, mp 168°-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[CH3:15][O:14][C:12]([C:7]1[C:8]2[C:3](=[C:2]([NH:1][C:24]([NH:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=3)=[O:25])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1)=[O:13]
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1nccc2c(N)cccc12
Product: COC(=O)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12

Procedure:
Prepared from methyl 5-aminoisoquinoline-1-carboxylate (Description 106) and [4-(trifluoromethyl)benzyl]isocyanate (description 58) according to the procedure of description 61. m/z (ES+) 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1ccc2nonc2c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(C)=NOCc2ccc3nonc3c2)cc1O
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3-hydroxy-4-methoxyacetophenone (0.070 g, 0.421 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.126 g, 0.625 mmol) and pyridine (0.16 ml, 1.98 mmol) in ethanol (6 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water. The resultant suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a slightly sticky solid which was further triturated with petroleum spirit (40-60°), to give 1-(3-hydroxy-4-methoxyphenyl)ethanone-O -[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-33) as a light yellow solid (0.119 g, 90%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[C:26](=[N:34]O)([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:34]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:33]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=NO)c1ccccc1
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 45.9 %

Procedure:
Ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (74 mg, 0.2 mmol) and benzamidoxime (30 mg, 0.22 mmol) were suspended in dry EtOH (1 ml) and ethanolic sodium ethoxide (21% by wt., 0.111 ml, 0.3 mmol) was added. The mixture was gently warmed until solids were dissolved and then heated in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase dried (Na2SO4) and evaporated. MDAP afforded the pure title compound (40.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30](O)=[O:31].[CH3:33][NH:34][CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([N:34]([CH3:35])[CH3:33])=[O:31]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(Cl)c3)CC2)nc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N(C)C)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (50 mg, 109 mmol) was dissolved in DMF (1 ml) and dimethylamine (0.163 g, 0.326 mmol), DIEA (0.057 ml, 0.326 mmol), and HATU (62 mg, 0.163 mmol) added. The mixture was stirred at RT overnight. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 487 (M+H)+. GPR119 Human EC50: 2.3 nM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][F:11])=[N:6][CH:7]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1.COCCOC>CCOCC>[F:11][CH2:10][CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(NCCF)nc1
Solvent: CCOCC
Solvent: COCCOC
Product: N#CN=C(Nc1ccc(NCCF)nc1)Oc1ccccc1
Reaction time: 18 h
Yield: 31 %

Procedure:
A stirred mixture of the product from Step 2 (0.0112 mol), diphenylcyanocarbonimidate (2.67 g, 0.0112 mol) and ethylene glycol dimethyl ether (25 ml) was kept under nitrogen for 18 hours at 24° C. The mixture was diluted with Et2O (25 ml) and the solid was collected by filtration to give 1.04 g, mp 157°-158° C. of the titled product. The filtrate was purified by silica gel chromatography with 2.5% MeOH--CHcl3 to give 0.39 g of additional product: MS m/z (relative intensity) 299 (M+, 100), 278 (23.5), 266 (24.4), 206 (37.7), 184 (42.6), 172 (68.3), 94 (95.4).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[NH:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].[OH-].[Na+:35]>CO>[Na+:35].[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[CH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1C)C(=O)[O-]
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of {4-[2-(pyrid-3-yl)ethenyl]-2-(2-methylphenyl)benzoyl}methionine methyl ester, prepared as in Example 274, (3.285 g, 7.13 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (0.979 N, 7.35 mL). After 15 hours, the solvent was evaporated in vacuo to give the title compound (3.35 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, 1H), 8.46 (dd, 1H), 8.05 (dt, 1H), 7.70-7.53 (m, 3H), 7.48-7.37 (m, 4H), 7.27-7.18 (m, 3H), 6.97 (m, 1H), 3.50 (m, 1H), 2.21, 2.03 (2 s's, 3H), 2.00-1.92 (m, 2H), 1.93 (s, 3H), 1.70 (m, 1H), 1.58 (m, 1H). MS (APCI) m/e 445 (M−H)− as the acid form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[OH:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][OH:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: OC[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1CO

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-hydroxymethyl-pyrrolidine (0.077 g, 0.76 mmol) gives the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC[C@@H](C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC[C@@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 88.8 %

Procedure:
(R)-6-Methyl-hept-5-en-2-ol (1) (2.26 g, 17.6 mmol) and DIEA (5.52 mL, 31.7 mmol) were dissolved in anhydrous DCM (24 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.64 mL, 21.1 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (60 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.225 g, 86%). H1 NMR: see supporting information. TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). 1H NNMR in CDCl3 (500 MHz): 5.08 ppm 1 Hm, 4.80 ppm 1 Hm, 2.99 ppm 3 Hs, 2.08 ppm 2 Hm, 1.75 ppm 1 Hm, 1.69 ppm 3 Hs, 1.624 1 Hm, 1.61 3 Hs, 1.43 ppm 3 Hd.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:10](=[O:20])(=[O:19])[CH2:9]1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:27]([O-:29])=[O:28])=[CH:4][C:3]=1[C@@:8]1([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[S:10](=[O:20])(=[O:19])[CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
(R)-8-(2-Fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (172 mg, 554 μmol, Eq: 1.00) was dissolved in conc. sulfuric acid (2.72 g, 1.48 ml, 27.7 mmol, Eq: 50), then at 0° C. fuming nitric acid (52.4 mg, 37.1 μl, 831 μmol, Eq: 1.5) was added dropwise. The light brown solution was stirred at 0° C. for 2 hours. The reaction mixture was poured on ice and basified with 3 N NaOH followed by extraction with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the crude and pure (R)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (210 mg, 591 μmol, 107% yield) as an off-white foam. MS (ISP): m/z=356.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:20])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C([O:23][C:24]([C:26]12[CH2:43][CH:42]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:44])[C:34](=[O:45])[N:33]1[CH:29]([CH2:30][CH:31](O)[CH2:32]1)[C:28](=[O:47])[NH:27]2)=[O:25])C>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:31]3[CH2:30][CH:29]4[N:33]([C:34](=[O:45])[N:35]([CH3:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:26]([C:24]([OH:25])=[O:23])([NH:27][C:28]4=[O:47])[CH2:43]5)[CH2:32]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(O)nc(-c3ccccc3)nc2c1C
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccccc3)nc2c1C
Yield: 17 %

Procedure:
Quinazolinol derivative (83) (449 mg, 1.7 mmol) was coupled to compound 51 (400 mg, 1.1 mmol) followed by hydrolysis of the ethyl ester as described in example 52, which gave the title compound (112 mg, 17%).
Reaction SMILES: [Si]([C:8]1[C:13]([Cl:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([C@:21]([O:26][Si](C)(C)C)([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH2:16]2)[N:11]=[C:10]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)[C:9]=1[F:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:14][C:13]1[C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([C@:21]([OH:26])([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH2:16]2)=[N:11][C:10]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)=[C:9]([F:40])[CH:8]=1
Reactant: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)c([Si](C)(C)C(C)(C)C)c2Cl)CCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)cc2Cl)CCN1
Reaction time: 48 h
Yield: 84.5 %

Procedure:
3-(4-(tert-butyldimethylsilyl)-5-chloro-3-fluoro-6-((S)-3-((R)-3-methyl-2-(trimethylsilyloxy)butan-2-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (125 g, 206.5 mmol) was dissolved in THF (450 mL) at ambient temperature. Tetrabutylammonium fluoride (433.6 mL of 1 M THF solution, 433.6 mmol) was added dropwise via cannula to the yellow solution. The internal temperature increased from 21.3° C. to 27.7° C. The reaction was stirred for 48 hours. The mixture was then diluted with ethyl acetate (1.5 L) and washed with a 1:1 mixture of saturated aqueous sodium bicarbonate and water (3×600 ml). The combined aqueous phases were back-extracted with ethyl acetate (2×600 ml). The combined organic phases were then washed with brine (600 ml), dried over MgSO4, filtered and partially concentrated in vacuo until the title product began to precipitate. A few drops of methanol were added and the mixture stirred at ambient temperature overnight. The product was then was filtered, rinsed with a minimum of ethyl acetate and petroleum ether to give an off-white solid which was dried under vacuum overnight (40° C. and 1.5 mbar). This afforded the title compound as a white solid (73.1 g, 84%); mp (DSC) onset 215.3° C., peak 218.1° C.; 1H NMR (400.0 MHz, DMSO) 0.91 (d, 3H), 0.94 (d, 3H), 1.10 (s, 3H), 1.83 (b quint, 2H), 2.72 (t, 1H), 2.80-2.94 (m, 3H), 3.14-3.17 (m, 1H), 3.62 (d, 1H), 3.88 (d, 1H), 4.14 (s, 1H), 7.37 (dd, 1H), 8.16 (d, 1H), 8.65 (dd, 1H), 8.86 (dd, 1H), 14.12 (bs, 1H); 19F NMR (decoupled) −127.9; MS ES(+) 419.1 (M+1); ee>98% (Minigram SFC, ODH 250×10 mm, 20% MeOH (0.1% TEA), 5 mg/ml.