Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13].[OH-].[Na+].S(=O)(=O)(O)O>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]([OH:13])[CH3:14]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(/C=C/C(C)O)C(C)(C)CCC1

Procedure:
β-Ionol was synthesized from β-ionone as described above for synthesis for aα-ionol with the following modification: 20% sodium hydroxide solution was used to hydrolyze the reaction complex in place of the sulfuric acid solution and the separated organic layer was neutralized by washing with water. α-Ionol thus prepared had the following constants: boiling point, 78° C./0.2 mm; nD25 1.4975; yield 5.9 g. Infrared spectrum and GC retention time was identical to that of a commercially available sample.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24].Cl>ClCCl>[C:1]([Si:5]([O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]=[C:23]=[O:24])[CH2:11][CH2:12]1)([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine (1.0 g, 4.36 mmol) (from Example 3a supra) and triethylamine (3.04 mL, 21.8 mmol) (Burdick & Jackson) in dichloromethane (30 mL) at 0° C. was added phosgene (˜20% in toluene, 6.4 mL, 13.1 mmol) (Fluka) in one portion. The reaction mixture was stirred at 0° C. for 40 minutes, followed by addition of 0.5N aqueous hydrochloric acid (50 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (1:9) to give tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane. (Yield 0.90 g, 81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:12]1[CH2:13][CH2:14][N:9]([CH:7]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: O=CCc1cccs1
Reactant: C1COCCN1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C(=CN1CCOCC1)c1cccs1

Procedure:
A mixture of 1.5 g of 2-thienylacetaldehyde, 1.4 mL of morpholine, and 0.012 g of p-toluenesulfonic acid hydrate in 7.5 mL of toluene is heated at reflux under a Dean-Stark Trap with azeotropic removal of water for 3 hours. The solution is cooled, neutralized by the addition of solid sodium methoxide, and concentrated in vacuo. The residue is taken up in toluene, filtered, and concentrated in vacuo to afford the desired enamine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].CCN(CC)CC.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22].Cl>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[S:21]([O:12][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:20]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1OS(=O)(=O)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 2-bromo-6-methyl-4-nitrophenol (110.0 g, 0.474 mol) in DCM (950 mL) at −70° C. was added Et3N (62.3 g, 0.616 mol) and Tf2O (147.1 g, 0.521 mol). The resulting solution was stirred at −70° C. for 20 min. TLC showed the reaction was complete. Aqueous HCl (0.5 M, 1 L) was added to quench the reaction. The DCM layers were separated, dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by silica gel column (Petroleum Ether→Petroleum Ether:EtOAc (20:1)) to afford desired 2-Bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (146.7 g, 85%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.41 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:43][C:44]([F:56])([F:55])[C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:54])[CH2:52][CH3:53])=[CH:47][CH:46]=1>CN(C)C=O>[F:43][C:44]([F:55])([F:56])[C:45]1[CH:46]=[CH:47][C:48]([C@H:51]([NH:54][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:52][CH3:53])=[CH:49][CH:50]=1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (150 mg, 0.593 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (80 mg, 0.593 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.593 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-trifluoromethyl-phenyl)-propylamine (120 mg, 0.593 mmol) was added and the mixture was stirred at 25° C. overnight. The mixture was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 163 mg (65%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 4): Rt=1.29 min; m/z=464.22 (M+H+). 1H-NMR: δ (ppm)=8.18 (1H, d), 7.69 (2H, d), 7.55 (2H, d), 7.26 (1H, s), 4.96 (1H, d), 4.83-4.92 (2H, m), 4.20-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.69, (2H, bs), 2.06 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.59 (1H, m), 1.19 (3H, d), 0.90 (3H, t).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[N:13]1([CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>C(O)C>[N:13]1([CH:18]([CH3:22])[CH2:19][CH2:20][N:21]2[C:2](=[O:4])[C:1]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5]2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(CCN)n1ccnc1
Solvent: CCO
Product: CC(CCn1cnc2ccccc2c1=O)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.25 g of isatoic anhydride, 2.78 g of 3-(1H-imidazol-1-yl)butanamine and 40 ml of ethanol was stirred at room temperature for 20 hours and concentrated. The residue and 10 ml of triethyl orthoformate were heated at 95°-115° C. for 3 hours and concentrated to obtain the desired product as an oil.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH2:7]1.Br.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1
Reactant: COc1cccc(C2CCCN(CCCC(=O)c3ccc(F)cc3)C2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCN1CCCC(c2cccc(O)c2)C1)c1ccc(F)cc1
Yield: 39.5 %

Procedure:
A mixture of 1.4 g (4 mmole) of 1-(4-oxo-4-[4-fluorophenyl]butyl)-3-(3-methoxyphenyl)piperidine, 10 ml of 48% aqueous hydrobromic acid and 5 ml of glacial acetic acid was heated under reflux for ca. 20 hours. The reaction mixture was then poured onto a mixture of ice and water. The resulting mixture was basified with potassium carbonate and then it was extracted with ethyl acetate. The extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on 150 ml of silica gel, eluting with chloroform/methanol (95:5). The product was then recrystallized from chloroform to give 540 mg (30% yield) of the title compound as a chloroform solvate, m.p. 77°-78° C.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:18]
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC1=NCc2c[nH]c3cccc1c23

Procedure:
Similarly, treatment of equimolar amounts of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, described in Example 5, and hydrazine hydrate in methanol gives 5-hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, mp 263° - 265°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:23])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CO
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(C)(=O)=O)c1

Procedure:
The mixture of 4-chloro-3-methylsulfonyl-5-nitrobenzoic acid (10.0 g) and conc. sulfuric acid (5.0 ml) in methanol (100.0 ml) was heated under reflux for 10 hours and the mixture was evaporated in vacuo. To the residue was added water and the mixture was adjusted to pH 8 with potassium carbonate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 4-chloro-3-methylsulfonyl-5-nitrobenzoate (10.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: COC[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[C:17][Si](C)(C)C)=[O:10].[OH-].[Na+].[C:24]1([Li])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(OCC)C.C1CCCCC1.C(OCC)C.O.O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][S:12][C:11]=1[CH:9]([OH:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:17]
Reactant: [Li]c1ccccc1
Reactant: COC(=O)c1sccc1C#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C#Cc1ccsc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
131 mg of lithium aluminum hydride was added to a mixture of 821 mg of 2-methoxycarbonyl-3-(trimethylsilylethynyl)thiophene and 10 ml of tetrahydrofuran, followed by heating under reflux for 1.5 hours. After cooling as it was, 131 μl of water, 131 μl of an aqueous 1N sodium hydroxide solution and 393 μl of water were successively added thereto, followed by filtering through Celite. After removing the solvent, 5.25 g of manganese dioxide was added to a solution of 10 ml of dichloromethane containing the residue, followed by stirring at room temperature overnight. The mixture was filtered through Celite, and the solvent was removed. 3.5 ml of a cyclohexane-diethyl ether solution containing 1.8 mol of phenyl lithium was added dropwise to a mixture of the residue and 5 ml of diethyl ether at −78° C., followed by stirring at the same temperature for 20 minutes. Aqueous ammonium chloride was added to the reaction solution and the temperature of the system was raised to room temperature. Ethyl acetate was added thereto, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10% ethyl acetate/hexane, to give 85.7 mg of the target compound.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:23]2[C:24]([CH3:40])=[C:25]([NH:29]C(=O)OCC4C=CC=CC=4)[CH:26]=[CH:27][CH:28]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:12]=3)(=[O:3])[NH2:2]>C1COCC1.CO.[Pd]>[NH2:29][C:25]1[C:24]([CH3:40])=[C:23]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.2735 g, 0.511 mmol) and 10% Pd/C (0.109 g, 0.102 mmol) in THF (12.8 mL) and MeOH (19.2 mL) was hydrogenated. After 1.5 hr, the reaction was flushed with nitrogen and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, dissolved in CH2Cl2, dried over MgSO4, and concentrated in vacuo to give the desired product (0.196 g, 0.450 mmol, 88% yield) as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17].[CH2:18](Br)[CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)ccc2s1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCCC(C)C)ccc2s1

Procedure:
A mixture of 9 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, 15 parts of isoamyl bromide and 14 parts of anhydrous potassium carbonate in 130 parts of acetone was stirred and heated under reflux for 18 hours. Insoluble material was then filtered off and washed with acetone and the total acetone solution was evaporated to leave a yellow solid, which was crystallized from ethanol to give 4.1 parts of ethyl 6-(3-methylbutoxy)-1-thiachromone-2-carboxylate, melting point 83°-84°C. This entire product was heated under reflux for 2 hours with a solution of 1.5 parts of sodium bicarbonate in 35 parts of water and 25 parts of methanol. The methanol was then boiled off and the solution was diluted with 70 parts of water. The aqueous solution was thoroughly washed with ether, filtered then acidified with concentrated hydrochloric acid. A precipitate was obtained which was filtered off, washed with water and dried, then extracted with boiling benzene. The product was then filtered off and dried to leave 3.95 parts of 6-(3-methylbutoxy)-1-thiachromone-2-carboxylic acid, melting point 208°-209°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1>C(Cl)Cl>[CH:49]1([NH:54][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) was bubbled with nitrogen for 5 min, then it was added HBTU (30 mg, 0.079 mmol) and cyclopentylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (21 mg, 47%). LC-MS m/z 589 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=O)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[NH2:11][C:12]12[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N)CC1
Yield: 102 %

Procedure:
To a mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (2 g, 4.68 mmol) in ethanol (75 mL) was added 1N HCl (5.15 mL, 5.15 mmol) followed by Pd/C (0.498 g, 0.468 mmol) and the mixture stirred under 1 atm of hydrogen for 18 h. The mixture was then filtered through a pad of CELITE® and the pad washed with dichloromethane. The filtrate was then concentrated to afford the title compound (1.4 g, 91% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ: 10.5 (1 H, brs), 4.3 (2 H, q, J=7.02 Hz), 4.0 (2 H, d, J=3.66 Hz), 2.4 (1 H, brs), 2.0-2.1 (4 H, m), 1.8-1.9 (2 H, m), 1.7-1.8 (2 H, m), 1.3 (3 H, t, J=7.02 Hz). LCMS (M+H)=294.32.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C(O[CH2:16][CH:17]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])(=O)C>C1COCC1>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:17]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[CH2:16]
Reactant: CC(=O)OCC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 97 %

Procedure:
DBU (1.5 eq) in THF was added to a solution of 2-(2,4-dichlorophenyl)-2-(phenylsulfonyl)ethyl acetate (3) (1 eq) in THF at rt. After stirring for 40 min., the reaction was quenched with sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the {[1-(2,4-dichlorophenyl)vinyl]sulfonyl}benzene (4) (97% yield).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[C:23]([CH:28]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[N:30]=2)[C:24](OC)=O)[CH2:16][CH2:15]1)=[O:13]>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:30]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[CH:28]=[C:23]([C:24]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:22]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: CC(=N)NO
Reactant: COCn1ccsc1=Nc1cc(C(=O)OC)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1ccsc1=Nc1cc(-c2nc(C)no2)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 9.4 mg of N-hydroxyacetamidine, molecular sieves 4A and 1 ml of tetrahydrofuran was added sodium hydride followed by stirring at 65° C. for 1 hour. To the reaction solution was added a solution of 22.6 mg of methyl 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)6-((3-(methoxymethyl)-thiazol-2(3H)-ylidene)amino)isonicotinate in 1 ml of tetrahydrofuran, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#CCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
3-(4-Hydroxyphenyl)propionitrile (1.47 g, 0.01 mol) was dissolved in DMF (24 ml), and to this solution were successively added benzyl bromide (1.31 ml, 0.011 mol, 1.1 eq) and anhydrous potassium carbonate (4.15 g, 0.030 mol, 3.0 eq). The mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and water (100 ml) was added. The mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(4-benzyloxyphenyl)propionitrile (2.39 g, 100%) as a colorless solid.