Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:42])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:29]([Cl:41])[CH:28]=1)=[O:4].[C:43](Cl)(=[O:46])[CH:44]=[CH2:45].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:41][C:29]1[CH:28]=[C:27]([NH:26][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:43](=[O:46])[CH:44]=[CH2:45])[CH3:42])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: C[C@H](N)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 33 %

Procedure:
500 mg of (2S)-2-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 12 ml of THF and 4 ml of water, and reacted with 0.08 ml of acryloylchloride at room temperature for 1.5 hours after adding 213 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (180 mg, 33%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[Si:14]([O:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]cccc1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Reaction time: 8 h
Yield: 53.6 %

Procedure:
3-Hydroxypyridin-2(1H)-one (15 g, 135 mmol) and imidazole (23 g, 338 mmol) were suspended in dimethylformamide (200 mL) under inert atmosphere. A solution of tert-butyldimethylsilyl chloride (20.5 g, 136 mmol) in dimethylformamide (200 mL) is added dropwise at room temperature over 30 minutes. The reaction was then allowed to stir overnight. The resulting solution was then poured into water (300 mL) and the mixture extracted with tert-butyl methyl ether (3×500 mL). The combined organic layer was washed with water (300 mL), brine (300 mL) then dried over Na2SO4. The solvent is removed under reduced pressure and the crude product crystallized from heptanes to afford 16.3 g (53% yield) of the desired product. 1H NMR (250 MHz, CDCl3) δ ppm 12.98 (1H, m); 6.91 (1H, dd, J=1. Hz, J=6.8 Hz); 6.81 (1H, dd, J=1.8 Hz, J=7.2 Hz); 6.02-6.007 (1H, m); 0.90 (9H, s), and 0.17 (6H, s).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([I:1])=[CH:3][N:4]=2)[N:9]=1
Reactant: O=c1ccc2ncc(I)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2ncc(I)cc2n1
Yield: 90.5 %

Procedure:
7-iodo-1,5-naphthyridin-2(1H)-one (D-16) (740 mg, 2.72 mmol, 1.0 eq) was dissolved in POCl3 (10 mL), and then heated at reflux for 1 h. The reaction was complete based on TLC analysis. The reaction mixture was concentrated in vacuo, poured into ice-water (30 mL), and neutralized with saturated sodium carbonate solution (about 30 mL) to adjust pH value to 8-9. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (5-10% ethyl acetate/petroether) to afford the desired product, 2-chloro-7-iodo-1,5-naphthyridine (D-17) (715 mg, 90.5%) as a solid. 1H NMR (400 MHz, CDCl3-d6) δ: 9.13 (d, J=2.0 Hz, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H); ESI-MS m/z: 290.93 [M+H]+.
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:11]([NH:15][C:16](=[O:33])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)[CH:12]([OH:14])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:4]([CH:11]([NH:15][C:16](=[O:33])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)[C:12](=[O:14])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)O)ccc1-n1cnc(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
To a methylene chloride (2.0 mL) solution of (E)-N-(1-benzyl-2-hydroxy propyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (29.0 mg), Dess-Martin reagent (60.7 mg) was added. After agitating the reaction solution at room temperature for 4 hours and 30 minutes, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:ethyl acetate→ethyl acetate ethanol=10:1), and 15.4 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: C(O[N:9]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]OCC1C=CC=CC=1)[CH2:10][C:11](=C=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C(=C=O)CN(CCCCNOCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCCCCN
Yield: 99.8 %

Procedure:
2.49 g (5.14 mmol) of t-butyl 4,9-bisbenzyloxy-carbonyl-4,9-diazanonanoate was dissolved in 20 ml of methanol and 0.3 g of palladium black was added thereto. The obtained mixture was reduced at room temperature under atmospheric pressure in a hydrogen gas stream for three hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to thereby give 1.11 g of the aimed compound in the form of an oily product (yield: 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:26][C@H:25]3[C:33]([OH:35])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:36][N:37]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O>[OH:36][NH:37][C:33]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][N:27]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:26]1)=[O:35]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a solution of 152 mg (0.24 mmol) of cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxylic acid and 97.3 mg (0.72 mmol) of 1-hydroxybenzotriazole in 3 mL of N,N-dimethylformamide at 0° C. was added 138 mg (0.72 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 1.5 h. To the 0° C. reaction mixture was added 0.12 mL of 50% hydroxylamine solution. The resulting reaction mixture was stirred at room temperature for 18 h. The volatile materials were removed under reduced pressure below 40° C. The residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution (5×30 mL) and a saturated sodium chloride solution (2×30 mL), dried over sodium sulfate and filtered. After removal of the ethyl acetate, the residue was triturated with a 7:3 hexane:ethyl acetate mixture to give 114.1 mg of cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxamide as a yellow solid in 89% yield. MS: 535.2 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[NH:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:9]1.CNCCNC.Br[C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>[Cu]I>[CH3:39][O:38][C:36]([C:35]1[CH:40]=[CH:41][C:32]([N:12]2[CH2:11][C:10]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[O:9][C:8]2=[O:7])=[CH:33][CH:34]=1)=[O:37]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc(N2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC2=O)cc1

Procedure:
A mixture of cesium carbonate (4.27 g, 13.11 mmol), copper (I) iodide (0.832 g, 4.37 mmol), tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (1.12 g, 4.37 mmol), N,N′-dimethylethane-1,2-diamine (0.385 g, 437 mmol) and methyl 4-bromobenzoate (1.128 g, 5.24 mmol) was heated under nitrogen for 18 hours. The crude mixture was filtered through celite. Upon removal of the volatiles, the crude was purified by flash chromatography (EtOAc/hexanes 20 to 100%) to afford the title intermediate as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][C@H:32]([OH:34])[CH3:33])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@@H](O)CN
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: CCCCn1c(=O)c(C(=O)NC[C@@H](C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 63 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and (2R)-1-amino-2-propanol (0.05 mL) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(2R)-2-hydroxypropyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (20 mg, 63% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.48 (br s, 1 H), 8.56 (s, 1 H), 7.27 (s, 1 H), 7.19-7.15 (m, 2 H), 7.06-7.02 (m, 2 H), 4.14 (s, 2 H), 4.10-4.06 (m, 3 H), 3.61 (m, 1 H), 3.66 (m, 1 H), 1.52 (m, 2 H), 1.34 (m, 2 H), 1.27 (d, J=6.4 Hz, 3 H), 0.91 (m, 3 H); MS m/z 428 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9].[CH3:27]OC(OC)OC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([O:22][CH3:27])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(=O)CCC2
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)=CCC2
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of Example 458A (240 mg, 0.64 mmol), trimethylorthoformate (0.7 mL, 6.4 mmol) and pyridinium p-toluenesulfonate (80 mg, 0.32 mmol) in methanol (7 mL) was refluxed overnight, cooled to room temperature, and partitioned between diethyl ether and brine. The organic phase was dried (MgSO4), filtered, concentrated, and passed through a silica gel plug eluting with 30% acetone/hexanes to provide the desired product (210 mg, 83% yield). MS (ESI) m/e 390 (M−H)−, 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.73-7.62 (m, 2H), 7.44 (m, 1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.02 (d, 1H), 5.19 (t, 1H), 3.54 (s, 3H), 3.50 (s, 3H), 2.64 (t, 2H), 2.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[Cl:27])[CH:6]=1.[S:29]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:37])[CH:35]=O)=[CH:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[C:18]=2[Cl:27])[CH2:35][CH:34]([C:31]2[CH:32]=[CH:33][S:29][CH:30]=2)[CH3:37])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCc2cccc(C(F)(F)F)c2Cl)c1
Reactant: CC(C=O)c1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a solution of {3-[3-(2-chloro-3-trifluoromethyl-benzylamino)-propoxy]-phenyl}-acetic acid methyl ester (70 mg, 0.17 mmol) in dry dichloromethane (20 ml) was added acetic acid (2 drops) followed by 2-thiophen-3-yl-propionaldehyde (26 mg, 0.19 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol). After the resulting mixture was stirred at room temperature overnight, water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacco. The crude mixture was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give 50 mg (32% yield) of the title compound as an oil MS m/e 541.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.Cl.[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1ccc(Br)cc1CC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To 5-bromo-2-methoxyphenylacetic acid (0.900 g, 3.7 mmol) in MeOH (20 mL) was added hydrogen chloride (4N in 1,4-dioxane; 4 mL), and the reaction was stirred at 80° C. for 6 hours. The mixture was then concentrated to dryness to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].CCCCCC>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:26][N:25]2[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1cc(C)cc(C)c1
Product: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared as described in U.S. Ser. No. 09/308,954, now U.S. Pat. No. 6,011,159, filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol) was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g, 175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with 500 mL of diethyl ether and 600 mL of water. Organic layer was separated and aqueous layer extracted with 500 mL of ethyl acetate. Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL), dried over MgSO4 and concentrated which gave a brown-red oil. Hexane (600 mL) was added to crude reaction product and the mixture boiled in a steam bath for a few minutes. This was followed by cooling still the heterogeneous mixture to room temperature and allowing to stand at room temperature for 12-14 hours. The reaction mixture was filtered, undissolved solid washed with additional hexane and filtrate which contained approximately 80% pure desired product concentrated in vacuo to give brown-yellow solid. Purification of this product on silica gel column and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams of light brown-tan solid. Recrystallization from hexane gave light tan needles. mp=72-73° C.; MS (APCI) m/z 319 (base).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C(O)C1CC=C(c2ccc(Cl)cc2)CC1
Yield: 92.8 %

Procedure:
Dissolve the product (1.75 g) from STEP 1 in THF (100 mL), treat with 40% H2SO4 (25 mL) and heat the reaction mixture at reflux for 5.5 h. Remove most of the solvent in vacuo, dilute the reaction mixture with water and extract with Et2O. Separate the organic layer and concentrate to give 4-(4-chlorophenyl)-cyclohex-3-enecarboxylic acid (1.36 g).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-oxo-3-phenylpropionate (28.6 g, 145 mmol) in 1,2-dimethoxyethane (1.50 ml) was added sodium hydride (60% in oil, 5.65 g, 141 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 2 hrs. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (45.4 g, 75%) as a yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[S:28]([NH2:31])(=[O:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(S(N)(=O)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Into a 25 mL round bottomed flask were added (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (188 mg, 0.513 mmol), sulfamide (103 mg, 1.07 mmol) and 1,4-dioxane (3 mL). The reaction mixture was refluxed under nitrogen for 3.5 h then cooled to room temperature and adsorbed onto silica gel. Purification by silica gel flash chromatography with a 0-100% EtOAc/Hexanes gradient to afford product as tan solid (165 mg, 72%). LC/MS (Method B) 3.90 min, [M+1]+ 446.
Reaction SMILES: C(OC([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:18][O:17][C:15]([CH2:14][CH:9]1[CH:8]([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10]1)=[O:16]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC#CCC1C(=O)C=CC1CC(=O)OC

Procedure:
A 800 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone is dissolved in 50 ml of benzene, and 30 mg of p-toluenesulfonic acid is added to the solution. The mixture is refluxed for 30 minutes. The resulting reaction mixture is neutralized with sodium bicarbonate, and the solvent removed. The residue is purified by a silica gel column and distilled in a vacuum, giving 4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (3), R2 =CH3) in a yield of 93%, b.p. 102°-103° C./3 mm Hg.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[CH:33]=[CH2:34].O>CN(C=O)C>[CH2:34]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH:33]=[CH2:32]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Temperature: 50 °C
Yield: 90.5 %

Procedure:
A suspension of (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.028 mmol) and K2CO3 (0.019 g, 0.140 mmol) in DMF (1.0 mL) was treated with allyl bromide (0.024 mL, 0.280 mmol) and heated at 50° C. for 16 h. The reaction mixture was poured into 25 mL water and extracted with EtOAc (2×25 mL). The extracts were washed with 25 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) gave 0.010 g (91%) of (3R)-4-allyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.006 g, 0.015 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (1.0 mL) heated at 70° C. for 1 h to afford 0.004 g (80%) of Compound 126, a yellow solid. Rf 0.6 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 11.82 (broad s, 1H), 7.12 (d, 1H, J=8.9), 7.11 (s, 1H), 6.93 (d, 1H, J=8.9), 5.92–5.81 (m, 1H), 5.27–5.17 (m, 2H), 4.48 (d, 1H, J=10.9), 3.99 (dd, ABX, 1H, J=16.4, 5.8), 3.84 (dd, ABX, 1H, J=16.4, 5.8), 3.77 (dd, ABX, 1H, J=10.9, 2.8), 2.96–2.93 (m, 1H), 1.94–1.84 (m, 1H), 0.98 (d, 3H, J=6.7), 0.96 (d, 3H, J=6.7).