Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:39][CH3:40])[CH2:4][C:5]1([OH:38])[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:2].[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:39]([CH:3]([CH2:1][CH3:2])[CH2:4][C:5]1([OH:38])[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:23])[NH:48][O:47][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][O:41]4)=[CH:20][CH:19]=3)[CH:27]=[C:28]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:29]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:40]
Reactant: CCC(CC)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(=O)NOC4CCCCO4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.1 %

Procedure:
The compound prepared in Example 9(1) (20 mg) was dissolved in DMF (200 μL), added with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (4.2 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (19 mg) and 1-hydroxybenzotriazole monohydrate (HOBt) (15 mg) and stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and added with water and the aqueous layer was extracted with MTBE. The organic layer was combined, washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated ammonium chloride aqueous solution and then concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the titled compound (19.6 mg) having the following physical properties.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To a solution of PPh3 (2.2 g, 8.2 mmol) in dry DCM (60 mL) was added I2 (2.1 g, 8.2 mmol). After I2 was dissolved completely, TEA (1.7 g, 16.4 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (2.0 g, 4.1 mmol) was added. The mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0˜40% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate (1.3 g, 66%) as a white solid. ESI-MS (EI+, m/z): 470 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1)[CH2:5][CH:6]1[CH2:9][O:8][CH2:7]1.O.[OH-].[Li+]>CO.O>[Cl:20][C:12]1[CH:11]=[C:10]([CH:4]([CH2:5][CH:6]2[CH2:9][O:8][CH2:7]2)[C:3]([OH:21])=[O:2])[CH:15]=[CH:14][C:13]=1[S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: COC(=O)C(CC1COC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2COC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid methyl ester (1.0 g, 3.00 mmol) was dissolved in methanol (50 ml) and treated with a solution of lithium hydroxide monohydrate (0.50 g, 11.92 mmol) in water (1 ml) at 25° C. It was stirred at 25° C. for 1.5 h. The reaction was then concentrated in vacuo to remove the methanol. The remaining aqueous layer was then diluted with water and acidified to pH=3 with an aqueous 1N hydrochloric acid solution. This was then extracted with methylene chloride (3×50 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid (0.87 g, 91%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1H, CH of CH2), 2.25-2.41 (m, 1H, CH of CH2), 2.75-2.89 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.68 (t, J=7.8 Hz, 1H, ArCHCO), 4.13 (t, J=6.3 Hz, 1H, OCH of OCH2), 4.27 (t, J=6.3 Hz, 1H, OCH of OCH2), 4.44 (dd, J=7.9, 5.9 Hz, 1H, OCH of OCH2), 4.57 (dd, J=7.9, 5.9 Hz, 1H, OCH of OCH2), 7.54 (dd, Jo=8.1 Hz, Jm=1.7 Hz, 1H, Ar), 7.68 (d, Jm=1.7 Hz, 1H, Ar), 8.00 (d, Jo=8.1 Hz, 1H, Ar), 12.77 (brs, 1H, CO2H).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]Br)=[CH:5][CH:4]=1.[CH2:12]=[C:13]1[C:18](=[O:19])[CH:17]2[CH2:20][CH2:21][N:14]1[CH2:15][CH2:16]2>C(OCC)C.[Cu]Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][CH2:12][CH:13]2[C:18](=[O:19])[CH:17]3[CH2:20][CH2:21][N:14]2[CH2:15][CH2:16]3)=[CH:5][CH:4]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: C=C1C(=O)C2CCN1CC2
Agent: Cl[Cu]
Agent: [Mg]
Solvent: CCOCC
Product: Cl
Product: O=C1C2CCN(CC2)C1CCCc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To 3.30 g (0.136 mole) magnesium turnings in 50 ml anhydrous diethyl ether under nitrogen, add 28.6 g (0.13 mole) p-chlorophenethyl bromide slowly. Allow the reaction mixture to reflux gently with mechanical stirring for 11/2 hours. Chill the reaction mixture on an ice/MeOH bath and add 1.29 g (0.013 mole) copper (I) chloride. Suspend 10.3 g (0.067 mole) 2-methylene-3-quinuclidinone in 30 ml diethyl ether and add dropwise to the chilled reaction mixture. Heat to reflux for an additional 2 hours. Follow progress of the reaction by thin-layer chromatography on silica gel (methanol:NH4OH, 9:1). When complete, quench the cooled reaction mixture with 25 ml saturated ammonium chloride solution. Filter the 2-phase reaction mixture and separate the layers. Wash the aqueous phase with 1×50 ml diethyl ether. Combine diethyl ether layers and dry over potassium carbonate. Remove solvents in vacuo to obtain the free base of the title compound. Dissolve the residue in 25 ml diethyl ether and acidify with HCl gas. Collect the title compound via filtration.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.C([NH:44][C:45]([NH:47]C(OC(C)(C)C)=O)=S)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.[Hg]Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:45]([NH2:47])=[NH:44])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NC(=N)N)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 34-1 (72.5 mg, 0.18 mmol) and triethylamine (0.15 mL, 1.07 mmol) in 1 mL of DCM, was added mercury chloride (60 mg, 0.22 mmol) and di-Boc-thiourea (60 mg, 0.22 mmol). The mixture was stirred at room temperature for 4 h. It was then diluted with DCM (40 mL), filtered through a pad of celite, water (40 mL) was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (2×40 mL), the combined extracts were dried over magnesium sulfate, filtered and the solvent was removed under vacuum to give a yellow oil. The oil was dissolved in DCM (5 mL) and TFA (2 mL, 25.96 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated and dissolved in DCM for purification on preparative HPLC to give 36-1: LC-MS 453.1 (MH), tR=5.05 (Method 2). EC50: 1320 nM.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][N+:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:23])[CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:19]([OH:23])=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc2c[n+](CCCC(c3ccc(F)cc3)c3ccc(F)cc3)ccc12
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc2c1CCN(CCCC(c1ccc(F)cc1)c1ccc(F)cc1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a solution of 2-[4,4-bis-(4-fluorophenyl)-butyl]-5-hydroxyisoquinolinium bromide (4.99 g, 10.61 mmol) in 165 mL of methanol at 0° C. was added sodium borohydride (1.54 g, 40.71 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes. The mixture was concentrated on a rotavap. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (150 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic layers was dried with magnesium sulphate, filtqred, and concentrated to give 1.9 g of crude product as a brown oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate in hexanes to give 2.54 g of product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cnccn2)s1
Product: O=C/C=C/c1ccc(-c2cnccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-pyrazinyl-2-thiophenecarboxaldehyde (prepared as described in Reference Example 87) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5]([S:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([NH:12][C:13](=[O:17])[CH2:14][CH2:15][NH2:16])=[O:11])=[O:6].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:22]1([CH2:2][CH2:3][NH:4][C:5]([S:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([NH:12][C:13](=[O:17])[CH2:14][CH2:15][NH2:16])=[O:11])=[O:6])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br-:1]
Reactant: NCCC(=O)NC(=O)c1ccccc1SC(=O)NCCBr
Reactant: c1ccncc1
Product: NCCC(=O)NC(=O)c1ccccc1SC(=O)NCC[n+]1ccccc1
Product: [Br-]
Yield: 82 %

Procedure:
A solution of N -[2-(2-bromoethylcarbamylthio)benzoyl]-β-alaninamide (0.37 g, 1.0 mmol) in pyridine (5 ml) was stirred for 8 h under nitrogen. The pyridine was removed in vacuo, and the crude product was purified by column chromatography on silica using chloroform-methanol(7:3 v/v) as eluent. Yield: 82%. 1H NMR (DMSO-d6): 2.38(t, 2H, CH2), 3.40(q, 2H, CH2), 3.72(q,2H, CH2), 4.72(t, 2H, CH2), 6.92(brs, 1H, NH2), 7.36-7.58(m, 5H, Ar—H, NH2), 8.26(t, 2H, Py-H), 8.36(t, 1H, NH), 8.66(t, 1H, Py-H), 9.12(d, 2H, Py-H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:11][C:5]=2[N:4]=1.[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:10]4[CH:9]=[CH:8][C:6]5[NH:7][C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][C:5]=5[CH:11]=4)=[O:20])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 32.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbamate (278 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.811 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 115 mg (32.8%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([CH3:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4].O.[OH-].[Li+].C(OCC)(=O)C.Cl>CO.O>[CH3:19][C:7]1[C:6]([N+:20]([O-:22])=[O:21])=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([C:15]([F:17])([F:16])[F:18])=[N:12]2
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1c([N+](=O)[O-])c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Yield: 96.9 %

Procedure:
5-Methyl-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (3.78 g) is dissolved in 200 mL of methanol/water (3:1 mixture) and treated with lithium hydroxide hydrate (1.06 g) at room temperature. After reaction completion, the mixture is poured into ethyl acetate and 2N hydrochloric acid, the organic phase is washed 3× with water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue is triturated with a small amount of hexane. Filtration gives 3.50 g of the title compound of the formula
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:50]=[CH:49][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.065 g, 55%). LCMS: 559.35 (M+1)+; HPLC % 99.26 (@ 254 nm) (Rt; 3.983; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.36 (d, 3H, J=8.4 Hz), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.84 (d, 2H, J=11.2 Hz), 3.57 (m, 3H), 3.48 (m, 3H), 3.24 (m, 2H), 3.40 (m, 1H), 2.63 (s, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
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].[CH3:16][O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[C:29]3[CH:30]=[CH:31][C:32](O)=[CH:33][C:28]=3[O:27][N:26]=2)[CH2:20]1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([N:21]3[CH2:20][C@H:19]([CH2:18][O:17][CH3:16])[O:23][C:22]3=[O:24])=[N:26][O:27][C:28]=2[CH:33]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC[C@H]1CN(c2noc3cc(O)ccc23)C(=O)O1
Solvent: c1ccncc1
Product: COC[C@H]1CN(c2noc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C(=O)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
8.4 ml (0.050 mol) of trifluoromethanesulphonic anhydride are added at 0° C. over 10 minutes to a solution of 11 g (0.042 mol) of (R)-5-(methoxymethyl)-3-(6-hydroxy-1,2-benzisoxazol-3-yl)oxazolidine-2-one in 110 ml of pyridine. The solution is stirred for 18 hours and then poured into ice-cold 2N aqueous hydrochloric acid solution. The product is extracted with ethyl acetate and then the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 16.5 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:27][O:28][C:29](=[O:77])[NH:30][CH:31]([C:35]([N:37]1[CH:43]([C:44]2[NH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][CH:59]=[C:60]([C:65]6[NH:66][C:67]([CH:70]7[CH2:74][CH:73]([C:75]#[N:76])[CH2:72][NH:71]7)=[N:68][CH:69]=6)[CH:61]=5)[CH:56]=4)=[CH:51][CH:50]=3)=[CH:47][N:48]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[CH:32]([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([C:7]([N:71]1[CH2:72][CH:73]([C:75]#[N:76])[CH2:74][CH:70]1[C:67]1[NH:66][C:65]([C:60]2[CH:59]=[CH:58][C:57]3[C:62](=[CH:63][CH:64]=[C:55]([C:52]4[CH:51]=[CH:50][C:49]([C:46]5[NH:45][C:44]([CH:43]6[CH2:42][C:39]7([CH2:41][CH2:40]7)[CH2:38][N:37]6[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:77])[CH:32]([CH3:34])[CH3:33])=[N:48][CH:47]=5)=[CH:54][CH:53]=4)[CH:56]=3)[CH:61]=2)=[CH:69][N:68]=1)=[O:9])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (77 mg, 48%). MS (ESI) m/z 855 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Li+].Cl[CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl>COCCOC.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:32][CH:31]=[CH:30][CH2:29]2)=[O:16])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClC/C=C\CCl
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: COCCOC
Product: CCOC(=O)C1(C(=O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)CC=CC1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (2.0 g), lithium hydride(0.11 g) in 1,2-dimethoxyethane and hexamethylphosphoramide was stirred at 40° C. for 1 hour. cis-1,4-Dichloro-2-butene was then added, and the mixture stirred at 65° C. for 48 hours. The mixture was extracted with ether, washed with brine, dried (magnesium sulphate), evaporated and purified by column chromatography eluting with ethyl acetate/hexane (1:5) to give ethyl 1-[2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionyl]cyclopent-3-enylcarboxylate (Compound 9, 0.62 g), NMR: 1.20(3H, t), 1.52(6H, s), 1.91(3H, s), 3.0-3.25(4H, m), 4.14 (2H, q), 5.17(2H, s), 5.56(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](C)[CH:5]=1)#[N:2].Cl.N[CH2:16][CH2:17][SH:18].[CH2:19](N(CC)CC)C>CCO>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:1]2[S:18][CH2:17][CH2:16][N:2]=2)=[CH:12][CH:11]=1)([O:10][CH3:19])=[O:9]
Reactant: CCN(CC)CC
Reactant: NCCS
Reactant: Cc1cc(CC#N)ccc1C(=O)[O-]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(CC2=NCCS2)cc1

Procedure:
To a solution of 1.75 g (10 mmol) of the above 4-(cyanomethyl) methyl benzoate (6) in 10 mL of EtOH was added 1.14 g (10 mmol) of cysteamine hydrochloride and 1.4 mL (10 mmol) of triethylamine. The reaction mixture was refluxed for 24 h. and evaporated to dryness. The residue was dissolved in CH2Cl2 (50 mL), washed with water and dried over Na2SO4. Removal of the solvent gave crude 7, which was crystallized from EtOH. Yield 2.1 g (89%); mp 67°-68° C.; NMR (CDCl3), δ8.0 (m, 2H, aromatic), 7.4 (m, 2H, aromatic), 4.2 (t, 2H, CH2), 3.9 (s, 3H CH3), 3.85 (s, 2H, CH2); IR (Nujol), 720 (ester), 1620 (C=N) cm-1 ; MS (EI) calculated for (C12H13NO2S), 235.00; found, 235 (M+).