Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([N:35]2[CH2:39][CH2:38][O:37][C:36]2=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([N:35]5[CH2:39][CH2:38][O:37][C:36]5=[O:40])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1OCCN1c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N5CCOC5=O)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(6-bromo-pyridin-2-yl)-oxazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2cccnc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of 8-aminoquinoline (2.88 g, 20 mmol) in dichloromethane (100 mL) was treated sequentially with triethylamine (3.1 mL, 2.23 g, 22 mmol) and trichloroacetyl chloride (2.5 mL, 4.0 g, 22 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 hours, and the solvent removed under reduced pressure. The residue was taken into ethyl acetate, washed sequentially with water and saturated aqueous ammonium chloride. The isolated organic layers were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 5.79 g of the title compound (99% yield) which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.18 (br s, 1H, NH), 9.00 (dd, 1H, J=4.4 and 1.7 Hz), 8.53 (m, 2H), 7.89 (d, 1H, 7.1 Hz), 7.73 (m, 2H). MS (ESI) m/e 289 (M+H)+.
Reaction SMILES: C1(S(O[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)(=O)=O)C=CC=CC=1.[CH3:19][NH:20][CH:21]=[O:22].CCCCCC>C(OCC)(=O)C>[CH3:18][C:13]1[CH:12]=[C:11]([N:20]([CH3:19])[CH:21]=[O:22])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)cc(OS(=O)(=O)c2ccccc2)c1
Reactant: CNC=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Yield: 93.1 %

Procedure:
Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with N-methylformamide (45 mg, 0.75 mmol) with the reaction time of 20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 76 mg (93%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24][CH2:25][CH2:26]Cl>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:26][CH2:25][S:24][CH3:23])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CSCCCl
Reactant: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCCOc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 7-hydroxy-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml), was added potassium carbonate (2 g, 0.014 mol). After 5 min, 2-chloroethyl methyl sulfide (0.34 g, 0.0028 mol) was added and the solution was heated to 100° C. for 24 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was cooled, concentrated under vacuum and purified by flash column chromatography (elution: 70% heptane, 30% EtOAc) to give the title compound (0.3 g, 24% yield) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[CH:6]=NC(C(C)C)C(C)C)([CH3:3])[CH3:2].Cl.C1C[O:27]CC1>>[CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[CH:6]=[O:27])([CH3:3])[CH3:2]
Reactant: COc1cc(C=NC(C(C)C)C(C)C)c(C(C)C)cc1OC
Reactant: C1CCOC1
Agent: Cl
Product: COc1cc(C=O)c(C(C)C)cc1OC
Yield: 43 %

Procedure:
(2-Isopropyl-4,5-dimethoxy-benzylidene)-(1-isopropyl-2-methyl-propyl)-amine was dissolved in 30 ml of THF. HCl (4.1 mL, 4 M) was added and the mixture was warmed to reflux. After 3 hours the mixture was cooled concentrated in vacuo. 100 mL of H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and then with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification via flash chromatography (85:15 hexane/ethyl acetate) gave 2-isopropyl-4,5-dimethoxy-benzaldehyde (0.331 g, 43%) as a clear oil
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])=[CH:6][C:3]=1[CH2:4]Br.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[CH:18]([N:21]([CH2:4][C:3]1[CH:6]=[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[C:8]([F:10])=[CH:9][C:2]=1[Cl:1])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)N(C(C)=O)c1cc(CBr)c(Cl)cc1F
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N(C(C)=O)c1cc(CN(C(C)C)C(C)C)c(Cl)cc1F
Yield: 95.7 %

Procedure:
A mixture of 0.82 g (0.0025 mole) of 2-chloro-4-fluoro-5-diacetylaminobenzyl bromide, 0.28 g (0.0028 mole) of diisopropylamine, 0.39 g (0.0028 mole) of potassium carbonate, and 25 ml of acetonitrile was heated at reflux overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water. After being dried, the solvent was evaporated under reduced pressure, yielding 0.82 g of N,N-diisopropyl-2-chloro-4-fluoro-5-diacetylaminobenzylamine.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].Cl>C(Cl)Cl.O1CCOCC1>[CH2:7]1[C:8]2([CH2:13][CH2:12][NH:11][CH2:10]2)[CH2:9][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6]1
Reactant: CCC(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(=O)N1CCC2(CCNC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-propanoyl-3,7-diazaspiro[4.4]nonane-7-carboxylate (153 mg, 0.54 mmol) in DCM (0.5 mL) was added a solution of hydrogen chloride (1.4 mL of 4 M, 5.4 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude product was dried on the high vacuum for 1 h to yield 1-(3,7-diazaspiro[4.4]nonan-3-yl)propan-1-one as an off white gum. LC/MS m/z 183.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Cl)cn1
Yield: 81.4 %

Procedure:
1.44 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.56 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.73 g of [(4-chloro-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (19), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH:9]=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[C:9]1[C:15]2[NH:11][C:12]([C:9]([C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=3)=[C:12]3[N:11]=[C:15]([C:9]([C:3]4[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=4)=[C:12]4[NH:11][C:15](=[C:9]([C:3]5[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=5)[C:12]5[CH:13]=[CH:14][C:15]=1[N:11]=5)[CH:14]=[CH:13]4)[CH:14]=[CH:13]3)=[CH:13][CH:14]=2
Reactant: c1cc[nH]c1
Reactant: Cc1nc(C=O)n(C)c1C
Solvent: CCC(=O)O
Product: Cc1nc(-c2c3nc(c(-c4nc(C)c(C)n4C)c4ccc([nH]4)c(-c4nc(C)c(C)n4C)c4nc(c(-c5nc(C)c(C)n5C)c5ccc2[nH]5)C=C4)C=C3)n(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4,5-Trimethylimidazole-2-carboxaldehyde (37, 750 mg, 5.42 mmol), prepared according to literature procedure (Alcalde, E. et al., Tetrahedron 52:15171-15188 (1996)), was dissolved in propionic acid (120 mL) in a 250 mL three neck round-bottom flask equipped with a thermometer and a condenser. The solution was heated to reflux then pyrrole (0.38 mL, 5.42 mmol) was added. The reaction mixture was heated at reflux for an additional 5 h, then cooled to room temperature while exposed to air overnight. The propionic acid was removed by vacuum distillation yielding a dark solid residue which was adsorbed onto silica gel. Purification by column chromatography (gradient elution 5-10% MeOH/CH2Cl2) provided porphyrin 38 as a mixture of atropisomers (108 mg, 10.7%). 1H NMR (300 MHz, CDCl3)*−2.90, −2.85, −2.78 (3 s, 2H, atropisomer NH), 2.50 (s, 12 H), 2.57 (s, 12 H), 3.15-3.42 (multiple s, 12 H, atropisomer N—CH3), 8.91 (multiple s, 8 H, atropisomer).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH:17]=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O-])(O)=[O:34].[Na+].BrBr.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([C:17]([O:34][CH3:33])=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C[C@@H]1[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Yield: 107.1 %

Procedure:
To a stirred and ice-cooled mixture of crude (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-formyl-5-methyl-2-phenylpyrrolidine (3.66 g, 5.90 mmol) and NaHCO3 (19.8 g, 0.24mol) in MeOH--H2O (9:1 by volume; 30 ml) was added a 2.0 M solution of Br2 in MeOH--H2O (9:1; 30 ml, 60 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours, during which the color changed from deep red to orange. Sat. Na2S2O3 (hypo) aq. solution was added dropwise to the mixture with ice-cooling, until the orange color due to the excess Br2 was discharged. The mixture was filtered through a pad of Celite, and the filter cake was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo. The syrupy residue was diluted with AcOEt--PhMe (2:1, 120 ml), washed with sat. Na2S2O3 aq. solution (×2), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution, dried (MgSO4), and concentrated in vacuo to give a white solid (2.96 g). This was recrystallized from AcOEt-n-hexane to give title compound (2.44 g, 88% in 2 steps from (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine) as white powders. mp 147-148 C.; IRmax (nujol): 3310(s), 1728(s), 1701(s, shoulder), 1690(vs), 1537(s), 1535(s), 1280(m), 1165(m), 750(m), 700(s) cm-1 ; 1H-NMR δ: 7.52-7.15(m, 9H), 7.05(br.s, 1H), 5.28(br.d, J=8.1 Hz, 1H), 5.05(br.s, 2H), 4.60(ddd, J=11.7, 8.8, 8.1 Hz, 1H), 4.35-4.17(m, 1H), 4.02(br.d, J=8.8 Hz, 1H), 3.71(s, 3H), 2.58(dd, J=11.7, 9.9 Hz, 1H), 1.62(br.d, J=5.5 Hz, 3H), 1.39(s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH:8]([C:12]([O:14]C)=O)[C:7]2=O.[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18].C(O)(=O)C>C(OCC)(=O)C>[F:1][C:2]1[C:11]2[S:10][CH:9]=[C:8]3[C:12](=[O:14])[N:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=4)[N:18]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CSc2c(F)cccc2C1=O
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1

Procedure:
Methyl 8-fluoro-4-oxothiochromane-3-carboxylate (1.19 g, 4.95 mmol) and 4-hydrazinobenzoic acid (755 mg, 4.95 mmol) were mixed with glacial acetic acid (10 ml). The mixture was heated to reflux for 4 h. Excess acetic acid was removed under vacuum to give an orange oil. Ethyl acetate (10 ml) was added and the mixture sonicated. Precipitation of an orange solid was observed. The solids were collected by filtration and washed with ethyl acetate. The filter cake was taken up in dimethyl suphoxide (10 ml) and air-oxidised at room temperature for one week. Water (20 ml) was added to the reaction mixture, the solids were collected by filtration, slurried in ethyl acetate, filtered and dried under vacuum. The title compound was isolated as an orange powder (175 mg, 0.51 mmol, 10%). LCMS: m/z 341.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH2:3][N:2]([OH:1])[C:17](=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: ONCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)N(O)Cc1ccc2c(c1)Cc1ccccc1-2

Procedure:
Using the method in Example 4, N-hydroxy-9H-fluorene-2-methanamine is reacted with isobutyryl chloride to give N-(9H-fluoren-2-ylmethyl)-N-hydroxy-2-methyl-propanamide as white crystalline solid. Yield 3.5 g (62%); mp 163°-166° C.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[C:21]([C:22]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:10][N:9]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[C:16]([S:15][CH2:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:13]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Reactant: CCCN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Yield: 33 %

Procedure:
n-Propyl isocyanate (20 mg, 0.23 mmol) was added to a solution of 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (The free base of Compound No. 3-1, 28 mg, 0.077 mmol) in N,N-dimethylformamide (0.60 mL) at room temperature, and the mixture was stirred for 4 hours at 80° C. Ethyl acetate (10 mL) was added to the reaction mixture, the whole was washed with water (15 mL) and brine (15 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 12 mg of the target compound as a colorless solid(Yield 33%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:19])[CH3:18]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC1CCN(CC#CCN2CCCC2)C1=O

Procedure:
A solution of 0.4 of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 1.0 ml of acetic anhydride in 20 ml of dichloromethane was stirred overnight. The solvent was removed in vacuo. The residue was basified with potassium bicarbonate solution and extracted with dichloromethane. The dichloromethane solution was washed with water, dried, concentrated in vacuo and the residue was purified by chromatography (alumina), giving the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[S:11][CH:12]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine (0.13 g, 0.50 mmol), triethylamine (0.10 mL, 0.75 mmol), and CH2Cl2 (1.7 mL) was cooled in an ice bath, and isobutyl chloroformate (0.10 mL, 0.75 mmol) was added. The reaction was stirred at 0° C. for 20 min, diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate. LC/MS: m/z 364.1 (M+H)+ at 3.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Product: CC(C)NC(=O)Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=379.4 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: O=C1COc2ccccc2N1
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Reaction time: 20 h
Yield: 77.9 %

Procedure:
A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (4.01 g, 15.0 mmol), and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) and stirred at 55° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 10:1) to give the title compound (3.92 g, 78%). 1H NMR (CDCl3) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [I-].[CH:2]([C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:16]([N:18]1[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19]1)=[O:17])[CH2:9]2)=[O:3].N1(CCN)C[CH2:28][O:27][CH2:26]C1.C(N(CC)CC)C>ClCCl>[N:20]1([CH2:21][CH2:22][NH:18][C:16]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:4]=3[CH:2]=[O:3])[CH2:9]2)=[O:17])[CH2:23][CH2:28][O:27][CH2:26][CH2:19]1
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)n1cc[n+](C)c1)C2
Reactant: NCCN1CCOCC1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1C=O)CCN(C(=O)NCCN1CCOCC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
A mixture of 3-(5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (321 mg, 0.75 mmol), 2-(morpholin-4-yl)-ethylamine (99.5 μL, 99.5 mg, 0.75 mmol) and triethylamine (106 μL, 76 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature for 24 h. After dilution with dichloromethane (1.0 mL), the solution was washed with brine (2×5 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography over silica, eluting with a 9:1 mixture of chloroform and methanol. In this manner the title compound (154 mg, 0.44 mmol, 58.7%) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[C:49]([CH3:50])=[N:48][N:47]=[N:46]3)=[C:41]([C:51]([F:54])([F:53])[F:52])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[C:49]([CH3:50])=[N:48][N:47]=[N:46]2)=[C:41]([C:51]([F:54])([F:52])[F:53])[CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
A solution of triphenylphosphine (450 mg, 1.72 mmol) in methylene chloride (20 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (306 mg, 1.72 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of the (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid (326 mg, 0.86 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (257 mg, 2.57 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid thiazol-2-ylamide (52 mg, 13%) as an amorphous white solid: EI-HRMS m/e calcd for C21H21F3N6OS (M+) 462.1450, found 462.1451.