Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:41]I>C1COCC1.CCCCCC>[I:41][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1
Reactant: OCCCCCCOC1C#CCCCCC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: ICCCCCCOC1C#CCCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred solution of 6-(cyclooct-2-yn-1-yloxy)hexan-1-ol (126 mg, 0.566 mmol, 1 eq) in dry THF (1.5 ml) under Ar atmosphere, Imidazole (1.1 eq, 0.622 mmol, 42 mg) and Ph3P (1.3 eq, 0.736 mmol, 193 mg) were added. The solution was cooled to 0° C. and Iodine (0.680 mmol, 1.2 eq, 173 mg) was added in three portions. Solution was warmed to RT and stirred for 4 h. The reaction was monitored by TLC (hexane 100% as eluent), quenched by addition of a saturated solution of Na2SO3 (3 ml) and the phases were separated. The aqueous phase was extracted with Et2O and combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The obtained raw product was purified using a column of silica gel (40 g) and Hexane as eluent to obtain 3-[(6-iodohexyl)oxy]cyclooct-1-yne.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]([CH2:15][CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F-].[K+].Br[CH2:32][CH2:33]Br.O>CN(C)C=O>[CH2:32]1[CH2:33][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[N:14]([CH2:15][CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11](=[N:19][C:20]4[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=4[CH3:28])[CH:10]=3)=[CH:3][C:2]=2[O:1]1
Reactant: CCn1c(-c2ccc(O)c(O)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Reactant: BrCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc3c(c2)OCCO3)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dihydroxyphenyl)--ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (1.0 g) in dimethylformamide (30 ml) were added spray-dried potassium fluoride (0.77 g) and 1,2-dibromoethane (0.25 ml). The mixture was stirred at 110° C. for 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and eluted with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure to give 3,4-dihydro-6-(3,4-ethylenedioxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.3 g).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>CO>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:1])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccccc1F
Solvent: CO
Product: COC(=O)Cc1ccccc1F
Yield: 22016.1 %

Procedure:
p-Toluenesulfonic acid (20 mg) was added to a solution of 2-fluorophenyl acetic acid (3.8 g, 24.65 mmol) in methanol (29 ml). After heating the reaction mixture for 1 h on the steam bath, the solvent was removed in vacuo. Filtration through a pad of silica gel (ethyl acetate/hexanes 10/90) gave methyl 2-fluorophenylacetate (4.3 g) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[O-:10][N+:11]1[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][C:15]=2[N:14]=[C:13]([CH2:24][CH2:25][CH:26]=O)[N:12]=1)[CH2:21][CH2:20][CH2:19]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:26][CH2:25][CH2:24][C:13]1[N:12]=[N+:11]([O-:10])[C:16]2[CH:17]=[C:18]3[C:22]([CH2:21][CH2:20][CH2:19]3)=[CH:23][C:15]=2[N:14]=1
Reactant: COCCNCCOC
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCCN(CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3)CCOC
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Bis-(2-methoxyethyl)amine (3.0 g, 22.5 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 ml) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 80 (1.1 g, 50%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.19 (s, 1H, H-9), 7.83 (s, 1H, H-5), 3.61-3.68 (m, 4H, 2×CH2O), 3.31-3.38 (m, 4H, 2×CH2N), 3.26 (s, 6H, 2×OCH3), 3.20-3.14 (m, 4H, 2×CH2), 3.07-3.12 (m, 4H, H-6, H-8), 2.15-2.10 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 154.7, 149.0, 146.7, 131.8, 122.2, 113.6, 58.0 (2), 57.4 (2), 52.4, 52.3, 32.5, 32.2, 25.3, 23.0 (2), 19.1; HRMS (FAB+) calcd for C19H29N4O3 (MH+) m/z 361.2240, found 361.2243.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1CCN(Cc2ccccc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCN(Cc2ccccc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a 5 mL microwave vial equipped with a stir bar was added sodium carbonate (79 mg, 0.75 mmol). The vial was dried in an oven for 16 hours, then cooled to room temperature under nitrogen. 1-(2-Bromo-benzyl)-piperidin-4-one (100 mg, 0.37 mmol), 4-fluorophenyl boronic acid (52.2 mg, 0.37 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were added, followed by dioxane (5 mL) water (1 mL). The resulting mixture was degassed thoroughly with nitrogen and then heated in a microwave to 100° C. for 10 minutes. The reaction was filtered and the filtrate was concentrated. The crude residue was purified via flash chromatography (heptanes/EtOAc gradient) to afford the desired product as a yellow solid (58 mg, 40% yield). MS (ESI) ink (M+H+): 283.3.
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1>C(#N)C>[N:9]1([CH:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: CCCCOC(C)Cl
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CCCCOC(C)n1cncn1

Procedure:
Crude n-butyl 1-chloroethyl ether (Straus and Weber, Ann, 1932, 498, 124) was treated with 1,2,4-triazole (2.4 g) in acetonitrile (50 ml) to give at once a precipitate. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was treated with water and extracted with diethyl ether. The ethereal layer was washed with water and dried over magnesium sulphate, and the solvent was removed to give the title product as a colourless oil, which was shown by GLC to be 95% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C.Cl>CCOCC>[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CC(F)=C(F)F)Oc1ccc([N+](=O)[O-])cc1
Yield: 92.1 %

Procedure:
A solution of 4-nitrophenol (1.10 g, 0.0079 mole) and 3,4,4-trifluoro-3-butenoyl chloride (1.85 g, 0.0116 mole) in dry ether (15 mL) is treated dropwise with triethylamine (1.01 g, 0.01 mole) at -78° C. with stirring. The mixture is stirred at -78° C. for 10 min and allowed to reach room temperature. The reaction mixture is diluted with ether (20 mL), stirred with 15 mL of 2N HCl. The organic layer is successively washed with water, 5% sodium bicarbonate, brine, and dried. The dark brown residue obtained after evaporation of the solvent was purified by passing through a short column of silica gel to give 1.9 g of the product as a brown solid, a 91% yield. m.p. 58°-62° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC.[B:19](OCC)([O:23]CC)[O:20]CC>C1COCC1>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:19]([OH:23])[OH:20])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOB(OCC)OCC
Reactant: CC(C)CCOc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 1-bromo-2-(isopentyloxy)benzene (9.68 g, 40 mmol) in THF (160 mL) under N2 atmosphere at −78° C. was added dropwise n-butyl lithium (1.6 M in hexanes, 26.3 mL, 42 mmol, Aldrich) over 30 min period. The reaction mixture was stirred for an additional 1 hour at −78° C., followed by the drop wise addition of triethyl borate (5.86 mL, 51 mmol). The cooling bath was removed, and the reaction was allowed to warm up to the room temperature then stirred for an additional 18 h at room temperature. The reaction mixture was acidified with 2 N HCl (20 mL) and water (50 mL). The resulting slurry was extracted with 5 of 80 mL portions of Et2O. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6.30 g (77%) of 2-(isopentyloxy)-phenylboronic acid. 1H NMR (400 MHz, CDCl3): 7.83 (d, 1H), 7.43 (dd, 1H), 7.03 (t, 1H), 6.93 (t, 1H), 6.05 (s, 1H), 4.10 (t, 2H), 1.85-1.75 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1)=[O:20]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (607 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: C1COCCN1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCOCC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z=516.96 (M+H+); retention time=0.76 minutes.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16](=[NH:15])[S:17][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(C)nn(C)c1CCl
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(C)c1CSC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
A solution under nitrogen was prepared from 10.7 g of the compound produced in Example 1 and 3.95 g of thiourea in 200 ml of ethanol. After refluxing the solution four hours, it was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure. Then, the residue was triturated with hexane to give 16 g of solid (wet weight), m.p. 175°-180° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:31]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1cc([C@@H](CC2CCOCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cc([C@@H](CC2CCOCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (75 mg, 0.23 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (2 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (54 μL, 0.46 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate) to afford N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (70 mg, 66%) as a white foam: [α]30589=−6.9° (c=0.16, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6 H, 2×CH3), 1.07-1.43 (m, 3H, 3×CH of 2×CH2), 1.49-1.70 (m, 3H, 3×CH of 2×CH2), 1.98-2.12 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.14-3.25 (m, 2H, OCH2), 3.17 (s, 3H, SO2CH3), 3.73-3.83 (m, 2H, OCH2), 3.84 (s, 2H, NCH2), 3.90-3.99 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.43 (d, J=2.3 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.48 (d, J=2.3 Hz, 1H, Ar),), 7.83 (d, J=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[C:4](=[O:13])[CH:3]=1.[CH3:14]I>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:12][CH3:14])([CH3:10])[CH3:11])[C:4](=[O:13])[CH:3]=1
Reactant: CI
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Product: COC(C)(C)Cn1ccc(Br)cc1=O

Procedure:
The title compound was prepared from 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one and methyl iodide following a procedure analogous to that described in Intermediate XXIX. Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:8][CH:9]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH:12]=[CH:39][C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cccc(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide (17.5 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° C. and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.) It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:18][C@H:19]([OH:33])[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:10]([OH:12])=[O:11].[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:18][C@H:19]([O:33][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][O:44]1)[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:10]([OH:12])=[O:11]
Reactant: C1=COCCC1
Reactant: N[C@@H](CCCCN(C[C@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 51.9 %

Procedure:
Trifluoroacetic acid (164 mg, 1.44 mmol) was added to a solution of 17a (360 mg, 0.72 mmol) in CHCl3 (7 mL). The solution was concentrated in vacuo. The resultant oil was dissolved in CH2Cl2 (20 mL), and 3,4-dihydro-2H-pyran (69 mg, 75 μL, 0.83 mmol) was added at room temperature. The reaction progress was monitored by TLC, and six additional portions of 3,4-dihydro-2H-pyran (69 mg each) were added over the next 31 hours. The reaction mixture was stirred for an additional 16 hours and concentrated in vacuo. The oil was dissolved in water (4 mL) and methanol (8 mL), then adjusted to pH 7 with saturated NaHCO3 solution. The solution was concentrated, and the crude oil was purified by chromatography on a C-18 column (30% acetone/water, followed by 55% acetone/water) to give 18a (219 mg, 52%) as a colorless oil: 1H NMR δ 1.20-1.98 (m, 14H), 3.06-3.56 (m, 8H), 3.68-4.02 (m, 2H), 4.33-4.62 (m, 1H), 5.06 (s, 2H), 5.11 (s, 2H), 7.24-7.36 (m, 10H); 13C NMR δ 20.7, 21.1, 21.7, 23.6, 26.3, 26.5, 32.0, 32.5, 34.2, 38.1, 38.5, 52.0, 56.2, 64.2, 65.2, 67.3, 68.3, 74.9, 100.1, 101.6, 128.79, 128.96, 129.02, 129.10, 129.20, 129.47, 129.56, 129.62, 138.3, 138.5, 158.0, 158.7, 174.8; HRMS m/z calcd for C31H43N3NaO8 608.2948, found 608.2954.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([OH:26])=O)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:24]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 58.2 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (35 mg, 0.096 mmol), 1-methylpiperazine (12 μL, 0.11 mmol), EDCI (20 mg, 0.11 mmol), HOBT (14 mg, 0.11 mmol) were stirred in DMF (5 mL) for 18 hours at room temperature. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to yield 25 mg of a brown solid (70%). 1H NMR (300 MHz, CDCl3): δ 7.34-7.37 (m, 2H), 7.19-7.24 (m, 4H), 4.79 (s, 2H), 4.24 (s, 2H), 3.84 (br s, 2H), 3.44 (br s, 2H), 2.79 (s, 3H), 2.55 (br s, 2H), 2.36 (s, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:24]
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.—RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Eluent: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 4-nitro aniline (1.01 g, 7.23 mmol) in anhydrous CH2Cl2 (20 mL) was added NMM (0.95 mL, 8.68 mmol). To the reaction mixture was added dropwise butyryl chloride (1.00 mL, 8.68 mmol) at 0° C. After stirring for 0.5 h, the reaction was extracted with CH2Cl2 (20 mL), washed with H2O (30 mL), dried over Na2SO4, and evaporated in vacuo to give N-(4-Nitrophenyl)butyramide (1.50 g, 100%) as a white solid.