Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]=[C:15]=[O:16].O>CS(C)=O>[CH3:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CN=C=O
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1csc(NC(=O)NC)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (27.4 g.) in dimethylsulfoxide (135 ml.) was dropwise added methylisocyanate (13.05 g.) with stirring at room temperature, and the mixture was stirred for 3 hours at 40° C. After the reaction, the reaction mixture was poured into water (500 ml.), and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and then dried to give colorless crystals of ethyl 2-(3-methylureido)thiazol-4-ylacetate (25.7 g.), mp 158° to 159° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[NH:3]1.O[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=2[O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=4[O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24]3)=[O:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)CCCOc1ccccc1N1CCN(CCCO)CC1
Reactant: O=C1CCc2ccc(C(=O)O)cc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccccc1N1CCN(CCCOC(=O)c2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid 22 (0.21 g, 0.001 mol), ethyl 4-(2-(4-(3-hydroxypropyl)piperazin-1-yl)phenoxy)butanoate 27 (0.38 g, 0.001 mol), dicyclohexylcarbodiimide (0.21 g, 0.001 mol), 4-(dimethylamino)pyridine (0.12 g, 0.001 mol) in 20 mL THF was stirred at room temperature for 12 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated; the residue was diluted with DCM (25 mL). The filtrate was washed with saturated aqueous NaHCO3 solution (25 mL×2) and water (25 mL×2), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-100% gradient of hexane and ethyl acetate to give the pure 3-(4-(2-(4-ethoxy-4-oxobutoxy)phenyl)piperazin-1-yl)propyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate 28. Colorless oil, 0.075 g (13%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.2 Hz, 3H); 1.99 (quintet, J=7.2 Hz, 2H); 2.13 (quintet, J=7.2 Hz, 2H); 2.50-2.65 (m, 8H); 2.99 (t, J=7.6 Hz, 4H); 3.08 (broad s, 4H); 4.01 (t, J=6.4 Hz, 2H); 4.12 (q, J=7.2 Hz, 2H); 4.38 (t, J=6.4 Hz, 2H); 6.81-6.89 (m, 4H); 7.20 (d, J=8.0 Hz, 1H); 7.50 (d, J=1.6 Hz, 1H); 7.64 (dd, J=1.6, 8.0 Hz, 1H, 9.00 (broad s, 1H). MS (ESI): m/z=524.50 (M+H+).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)=[CH:10]\[CH2:11][CH2:12][CH3:13])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:20][C:16]1[CH:15]=[C:14]([C:9](=[O:8])[C@H:10]([OH:42])[CH2:11][CH2:12][CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CCC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCC[C@@H](O)C(=O)c1cccc(Cl)c1
Yield: 86.8 %

Procedure:
Compound 10k was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)pent-1-enyloxy)dimethylsilane (9k, 4.1 g, 0.013 mol), AD-mix-β (18.5 g), and CH3SO2NH2 (1.3 g, 0.014 mol) in tert-butyl alcohol-water (50 mL:50 mL). The reaction was quenched with sodium sulfite (13.2 g). After purification, 2.4 g (77%) of the desired product was isolated: [α]20D +33.3° (c 1.1, CHCl3); 1H NMR (CDCl3) δ 7.91-7.87 (m, 1H), 7.80-7.75 (m, 1H), 7.63-7.17 (m, 1H), 7.45 (t, 1H, J=7.6 Hz), 5.08-5.00 (m, 1H), 3.58 (d, 1H, J=6.5 Hz), 1.89-1.75 (m, 1H), 1.61-1.35 (m, 3H), 0.93 (t, 3H, J=7.2 Hz); 13C NMR (CDCl3) δ 201.1, 135.4, 133.8, 130.2, 128.6, 126.5, 73.2, 37.8, 18.2, 13.8. C11H13ClO2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:12][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]([C:8]1[CH:13]=[N:12][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])(=[O:4])=[O:3]
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (56 μl, 0.72 mmol) was added slowly to the mixture of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid {5-[hydroxy-(2-methoxy-phenyl)-methyl]-pyridin-2-yl}-amide (50 mg, 0.12 mmol) and DIEA (24 μl, 0.14 mmol) in dichloromethane (2 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h. Solvents were evaporated and the residue was used for the next step without any additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: OC(CBr)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.91 g), 3-bromo-1,1,1-trifluoropropan-2-ol (1.2 mL), cesium carbonate (3.8 g) and N,N-dimethylacetamide (20 mL) was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 65%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[B:16]([OH:19])[O:17][CH2:18][C:14]=3[CH:13]=2)=[CH:7][C:6]=1[O:22][CH3:23])C.[OH-].[Na+].Cl>CO.O>[OH:19][B:16]1[C:15]2[CH:20]=[CH:21][C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[C:6]([O:22][CH3:23])[CH:7]=3)=[CH:13][C:14]=2[CH2:18][O:17]1
Reactant: CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C(=O)O
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of compound (D35) (0.1 g, 0.31 mmol) in methanol (2 mL) was added 2N NaOH (1 mL). The resulting mixture was stirred at rt O/N. The solvent was removed under reduced pressure to give crude product, which was dissolved in H2O (1 mL) and acidified using 1N HCl. The solid obtained which was filtered and washed with ether (10 mL) to afford the title compound (D36) (78 mg, 86%) as a white solid. Mp 109.6-110.1° C. 1H NMR 400 MHz (DMSO-d6) δ: 9.20 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J=9.4 Hz, 1H), 6.80 (s, 1H), 6.60 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H); MS (ES) m/z: 301 (M+1)+; HPLC purity: 100% (220 nm), 99.79% (254 nm).
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1C2[C:39](=[CH:40][CH:41]=CC=2)[CH2:38][CH2:37]1>C(#N)C>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[C:4]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:7][CH2:6]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCc3ccccc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (62 mg, 0.13 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.16 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added indoline (17 mg, 0.14 mmol) dissolved in acetonitrile (0.7 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([Br:9])([CH3:8])[CH3:7].[O:11]=[C:12]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19][C:20](O)=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[O:11]=[C:12]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19][C:20]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([Br:9])([CH3:8])[CH3:7])=[O:21]
Reactant: O=C(O)CCN1C(=O)C=CC1=O
Reactant: CC(C)(Br)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(Br)C(=O)OCCOC(=O)CCN1C(=O)C=CC1=O
Reaction time: 24 h
Yield: 84 %

Procedure:
2-Hydroxyethyl-2-bromo-2-methylpropionate (initiator 9) (0.187 g, 0.887 mmol) and 3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (0.300 g, 1.77 mmol) were dissolved in dichloromethane (10 ml) under nitrogen in a 25 ml round-bottomed flask. Then N,N′-Dicyclohexylcarbodiimide (DCC) (0.366 g, 1.77 mmol) was added to the solution. After one day at room temperature, very low conversion was observed and 0.5 ml (9.50×10−3 mmol) of a solution of 4-dimethylaminopyridine (DMAP) in dichloromethane (Conc.DMAP=19 mmol/l) was added. Total conversion was then achieved in 12 hours and the solvent was removed under reduced pressure. The solid residue was extracted with 3×50 ml of petroleum ether and the petroleum ether was removed by evaporation under vacuum in order to isolate a colourless oil (0.270 g, 0.745 mmol, 84%). The pale pink residue was extracted with 3×50 ml of diethylether, but TLC (CH2Cl2/AcOEt 9:1) revealed that only traces of the ester were present. An analytical pure sample was obtained by flash chromatography (cc, SiO2, Pet. Ether/Et2O 3:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH:20]([CH:24]([CH3:26])[CH3:25])[C:21](O)=[O:22])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.C[Si](C)(C)[O:45][NH2:46]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH:20]([CH:24]([CH3:25])[CH3:26])[C:21]([NH:46][OH:45])=[O:22])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)C(C(=O)O)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NO)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (66 mg; 0.18 mmol) was dissolved in THF (2 ml). At 0° C., diisopropylethylamine (DIEA; 124 μl; 0.71 mmol) and ethyl chloroformate (51 μl; 0.53 mmol) were successively added. The mixture was allowed to reach RT from 0° C. over the course of 2 h and then O-trimethylsilylhydroxylamine (80.43 μl; 1.07 mmol) was added. Stirring at RT for a further 3 h was followed by partitioning between dilute HCl (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 5 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Trituration of the residue with EtOAc (2 ml) resulted in 2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (22 mg; 0.06 mmol). MS: 384.25 (M+H); Rt: 1.94 min (method: gradient acetonitrile+0.08% formic acid: H2O+0.1% formic acid from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min); flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>C(OCC)(=O)C.CCCCCC>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([C:2]5[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=5)([OH:35])[C:29]=4[C:36]=3[CH3:37])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: CN(C)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(N(C)C)cc3)C(C)(C)O4)CC2)cc1
Yield: 73 %

Procedure:
Using 4-bromo-N,N-dimethylaniline and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 73%. mp. 144–146° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To admixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.38 g, 77%) of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]3[N:27]=2)=[CH:6][CH:7]=1
Reactant: Cc1cccc[n+]1N
Reactant: COC(=O)C#Cc1ccc(F)cc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2c(C)cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (3.47 g, 19.5 mmol) and 1-amino-2-methylpyridinium 2,4,6-trimethylbenzenesulfonate (6.0 g, 19.5 mmol) in dry acetonitrile (75 mL) was added, dropwise over 10 min a solution of 1,8-diazabicycloundec-7-ene (5.82 mL, 39 mmol) in dry acetonitrile (25 mL). The mixture was allowed to stir at room temperature for about 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water (500 mL) and ethyl acetate (250 mL) and the organic phase separated. The aqueous was extracted with ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulfate, and the solvent removed under vacuum. The residue was purified by chromatography on silica gel using 10:1 hexanes:ethyl acetate as eluent to give the title compound as a white solid, 4.65 g (86%). 1H NMR (CDCl3) δ 8.15 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.41 (t, 1H, J=8.9 Hz), 7.19 (t, 2H, J=17.6 Hz), 6.87 (d, 1H, J=7.0 Hz), 3.89 (s, 3H), 2.85 (s, 3H). MS (+ve ion electrospray) 285 (100), (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:46][CH2:47][CH3:48])[C:44]=5[CH3:45])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:46][CH2:47][CH3:48])[C:44]=5[CH3:45])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncn(CCC)c4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncn(CCC)c4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1-propylimidazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (220 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (119 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Dimethylsulfide (0.1 ml) was added to the mixture and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure: and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=10:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1-propylimidazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (132 mg) (Compound 441) as yellow amorphous.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N:24][C:23]=2[CH:35]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N+:24]([O-:6])[C:23]=2[CH:35]=1)[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
Hydrogen peroxide (70%, 0.7 mL, ca. 13.9 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (2.0 mL, 13.9 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 18 (385 mg, 1.4 mmol) and trifluoroacetic acid (0.53 mL, 6.9 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (20 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was chromatographed, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 19 (125 mg, 31%) as a red solid, mp (MeOH/EtOAc) 150-152° C.; 1H NMR 8.23 (d, J=9.6 Hz, 1 H, H-8), 7.48 (d, J=2.6 Hz, 1 H, H-5), 7.46 (brs, 1 H, NH), 7.03 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.25 (q, J=7.0 Hz, 2 H, CH2O), 3.64 (br dd, J=6.0, 5.9 Hz, 2 H, CH2N), 2.61 (t, J=6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, (CH3)2], 1.49 (t, J=7.0 Hz, 3 H, CH3); 13C NMR δ 165.5, 150.2, 140.3, 125.6, 123.5, 120.6, 95.4, 65.4, 57.5, 45.2 (2), 35.9, 14.3; MS (FAB+) m/z 294 (MH+, 100%), 278 (30), 276 (20); HRMS (FAB+) calcd for C13H19N5O3 (MH+) m/z 294.1566, found 294.1568. Anal. Calcd for C13H19N5O3: C, 53.2; H, 6.5; N, 23.9. Found: C, 53.1; H, 6.3; N, 23.6%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[O:6]=[C:7]1[C:11]2([CH2:14][CH2:13][CH2:12]2)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:9](=[S:28])[N:8]1[C:29]1[CH:30]=[C:31]([C:37]([F:40])([F:39])[F:38])[C:32]([C:35]#[N:36])=[N:33][CH:34]=1.C(N(CC)CC)C.CO>C1COCC1>[O:6]=[C:7]1[C:11]2([CH2:14][CH2:13][CH2:12]2)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:9](=[S:28])[N:8]1[C:29]1[CH:30]=[C:31]([C:37]([F:39])([F:38])[F:40])[C:32]([C:35]#[N:36])=[N:33][CH:34]=1
Reactant: CCC(=O)Cl
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Propionyl chloride (17 μL, 0.2 mmol) was added to a mixture of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (50 mg, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol) in THF (2 mL) and the resulting milky mixture was stirred at room temperature overnight. Methanol was added to quench the reaction and the mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 50 to 100% EtOAc/hexanes to afford 21 mg of 5-(8-oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (d, 1H), 8.69 (s, 1H), 7.25 (d, 2H), 7.13 (d, 2H), 4.62 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.29 (m, 1H), 3.15 (m, 1H), 2.55-2.52 (m, 2H), 2.42 (m, 2H), 2.39-2.25 (m, 2H), 1.92-1.88 (m, 3H), 1.50-1.45 (m, 3H), 0.93 (t, 3H). LCMS [M+1]+ 558.1.