Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=3[CH3:22])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2o1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc([N+](=O)[O-])cc3C)ccc2o1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
2-Methylbenzo[d]oxazol-5-ol (0.86 g, 5.77 mmol), 1-fluoro-2-methyl-4-nitrobenzene (0.98 g, 6.34 mmol) and K2CO3 (1.59 g, 11.53 mmol) were combined in DMF and heated to 50° C. for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographed (20% to 40% ethyl acetate in hexanes) to provide the product (0.671 g, 41%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:5][C:6](=O)[CH3:7].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:7][C:6]1[S:15][C:3]([O:2][CH3:1])=[C:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)[C@H](CC(C)C)NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1sc(C)nc1CC(C)C

Procedure:
A one-liter three necked flash equipped with a stirrer, condenser, and heating mantle is charged with 10 g (0.052 mole) of N-acetylleucine methyl ester and 14.5 g (0.062 mole) of phosphorus pentasulfide in 250 ml of chloroform, and the reaction mixture is refluxed for 24 hours while care is taken to exclude moisture. The reaction mixture is then cooled and made basic with 200 ml of 10% potassium hydroxide.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].CO>O>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)c1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Br
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (2.2 g, 14.6 mmol), NaOH (1.5 g) and MeOH (20 mL) was heated to 50° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15A (2.8 g, 94.4% yield).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:12])[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=1.[C:13]1([CH2:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C.[Cu+2].[I-].[I-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:4]1[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=[C:2]([C:22]#[C:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)n1cc(I)nc1C
Reactant: C#CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [I-]
Solvent: CCN(CC)CC
Product: CCOC(=O)n1cc(C#CCCc2ccccc2)nc1C
Temperature: 25 °C
Yield: 70.2 %

Procedure:
In a dry reaction tube containing in suspension iodide copper (20 mg, 0.1 mmol) and triethylamine (5.81 mL 41.40 mmol), were added ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (580 mg, 2.07 mmol) and the Pd(PPh3)2Cl2 (66 mg, 0.1 mmol). A yellow suspension is obtained and after a few minutes stirred at room temperature was added the commercially available 4-phenyl-1-butyn (269 mg, 2.07 mmol) in triethylamine (0.5 mL). Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine, dried (MgSO4) and concentrated. Purification by flash chromatography (prepacked 25 g silicagel column, DCM/MeOH: 99/1 as eluent to afford 410 mg of ethyl 2-methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-1-carboxylate (Yield: 70%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)[CH2:17][CH2:18]1)=[O:31]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)N1CCN(CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)CC1
Yield: 42 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and o-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 42%.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:23])[CH:3]=1.C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:23])[CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(O)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 120 °C
Yield: 90 %

Procedure:
A mixture of ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (325 mg, 1.005 mmol), acetic acid (3 ml) and concentrated hydrochloric acid (1.5 ml) was heated under reflux for 2 hours in an oil bath at 120° C. After then adding water (30 ml) and cooling with ice, the crystals formed were filtered out and then washed with water, 5% aqueous ethanol solution, and diethyl ether to obtain 267 mg (90%) of the title compound as a pale-yellow powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([CH3:21])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[CH3:20][C:16]1[CH:15]=[C:14]([N:13]2[C:9]([C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=3)=[CH:10][C:11]([CH3:21])=[N:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cc(C)nn2-c2cccc(C)c2)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-n2nc(C)cc2-c2cc[nH]c(=O)c2)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a solution of 2-methoxy-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 22; 0.56 g, 0.002 mol) in 5 mL of acetic acid was added 5 mL of hydrobromic acid. The reaction mixture was heated at reflux for 3 hours and then cooled to room temperature. Water was added and the solution was basified with ammonium hydroxide. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 0.45 g (85%) of product as a white solid: mp: 182-183° C.; Anal. Calc'd. for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.37; H, 5.66; N, 15.97.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.[OH-].[Na+].O>C(O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:26]1[CH2:25][CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Yield: 90 %

Procedure:
A mixture of 12.5 g of 2-(2-bromoethyl)naphthalene, 14 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 4.34 g of sodium hydroxide, 135 ml of water and 95 ml of 95% ethanol is heated for 5 hours under reflux, and the reaction mixture is then left to cool overnight to room temperature. The mixture is cooled to below 25° C., and then is filtered, the product thus isolated is washed with water and then dried in vacuo at 50° C. 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine base is thus obtained in a yield of 90% calculated on the starting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1([C:13](O)=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C.N>ClCCl>[C:13]([C:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:12][CH2:11]1)(=[O:14])[NH2:26]
Reactant: CN(C)C=O
Reactant: O=C(NC1(C(=O)O)CC1)c1cccc([N+](=O)[O-])c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 369.6 %

Procedure:
To the suspension of 1-(3-nitrobenzamido)cyclopropanecarboxylic acid (0.38 g, 1.519 mmol) in dichloromethane (5 ml), oxalyl chloride (0.199 ml, 2.278 mmol) was added followed by DMF (0.024 ml, 0.304 mmol). Reaction mixture was stirred at room temperature for 3 hr. After complete dissolution of the compound, cold aqueous ammonia (5 ml) was added under cooling. Allowed and stirred the content at room temperature for 1 hr. concentrated the reaction mixture to remove dichloromethane and the obtained slurry was filtered to obtain titled compound (0.28 g, 74%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)(=O)=O.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.[Cl-].[Li+]>O1CCOCC1.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>[CH:20]([C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCCc2nc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(n1)CCCC2=O
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (Preparation 54B, 2.21 g, 7.49 mmol) in dioxane (12 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (2.418 mL, 8.23 mmol) and lithium chloride (0.952 g, 22.46 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (3×). To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.865 g, 0.749 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. The reaction mixture was filtered and the solid was rinsed with ethyl acetate (150 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with ether (150 mL). The resulting solid was removed by vacuum filtration and rinsed with ether (150 mL). The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12.5%-20%) to give 2-vinyl-7,8-dihydroquinolin-5(6H)-one (1.09 g, 6.29 mmol, 84% yield) as a pale yellow solid. The compound had an HPLC ret. time=0.738 min. (condition A); LC/MS M+1=273.8; 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (quin, 2H), 2.67-2.73 (m, 2H), 3.15 (t, J=6.10 Hz, 2H), 5.65 (d, J=10.82 Hz, 1H), 6.35 (d, J=17.48 Hz, 1H), 6.86 (dd, J=17.48, 10.54 Hz, 1H), 7.34 (d, J=8.05 Hz, 1H), and 8.25 (d, J=8.05 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[O:27])[NH:13][CH2:14][CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[CH:5]=[C:4]([CH3:28])[C:3]=1[S:29]([NH:32][C@@H:33]([CH2:38][NH:39][C:40]([C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH2:52][CH2:53][CH2:54][NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)=[N:47][N:48]2[CH3:51])=[CH:44][CH:43]=1)=[O:41])[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30].FC(F)(F)C(O)=O>CO.[Pd]>[NH2:16][CH2:15][CH2:14][NH:13][C:12]([CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[C:4]([CH3:28])[C:3]([S:29]([NH:32][C@@H:33]([CH2:38][NH:39][C:40]([C:42]2[CH:50]=[C:49]3[C:45]([C:46]([CH2:52][CH2:53][CH2:54][NH:55][C:56]4[CH2:61][CH2:60][CH2:59][CH2:58][N:57]=4)=[N:47][N:48]3[CH3:51])=[CH:44][CH:43]=2)=[O:41])[C:34]([O:36][CH3:37])=[O:35])(=[O:30])=[O:31])=[C:2]([CH3:1])[CH:7]=1)=[O:27]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(CCCNc3ccccn3)nn(C)c2c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)c1ccc2c(CCCNC3=NCCCC3)nn(C)c2c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCN)cc1C
Reaction time: 7.5 h
Yield: 116.2 %

Procedure:
In a Parr bottle were added 10% Pd/C (50 mg) and methanol (5 mL) under nitrogen. The product of Step A (113 mg, 116 umol) in methanol (5 mL) was added, along with 20 uL of trifluoroacetic acid. The mixture was hydrogenated at 50 psi with shaking for 7.5 hours, filtered through Celite, the Celite rinsed with methanol, and the combined filtrates concentrated. The residue was redissolved in 1:1 acetonitrile/water/0.1% TFA, frozen and lyophilized to afford the product as a white powder (98 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:20]([CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[OH:21])=[CH:4][CH:3]=1
Reactant: O=CC1CCOCC1
Reactant: Brc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C1CCOCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 1-bromo-4-iodobenzene (31.1 g, 110 mmol) in THF (300 ml) (under argon atmosphere) was added isopropylmagnesium chloride (2M in THF) (60 ml, 120 mol) during 10 min at −25° C. The solution was stirred for 1 h at −20° C. and then warmed up to 0° C. and tetrahydro-pyran-4-carbaldehyde (10.98 ml, 100 mmol) was added dropwise over 10 min at 0-7° C. The reaction mixture was quenched with 1M NH4Cl (500 ml) and extracted with EtOAc (2×). The organic phases were washed with water and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from DCM-diisopropyl ether (1:2) to give the title compound as a white solid (24.32 g, 90 mmol, 90%): HPLC: CtRet=4.43 min; 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 1H), 1.21 (m, 2H), 1.62 (m, 2H), 3.15 (m, 2H), 3.78 (m, 2H), 4.23 (m, 1H), 5.26 (d, 1H), 7.35 (dd, 4H)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N(CC)CC)C.[OH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17]1.[Cl-].[NH4+]>ClCCl>[O:21]=[C:19]1[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17][C@H:16]([CH2:15][O:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:20]1
Reactant: CCOC(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
Ethyl chloroformate (5.7 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for 18 hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 4 mg (17%) of ethyl carbonate (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([N:13]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:12])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(C=O)ccc1Cl
Temperature: 25 °C
Yield: 82.4 %

Procedure:
5.0 g (22.8 mmol) of 2-Chloro-5-formyl-benzenesulfonamide were dissolved in 50 ml of dichloromethane. 4.08 g (34.3 mmol) of dimethylformamide dimethylacetal were added and the mixture was refluxed for 2 h. After cooling to room temperature, the solution was washed twice with H2O, dried over magnesium sulfate and evaporated. 5.16 g of the crude product were obtained and used in the next step without further purification. Rt=1.14 min (Method #1). Detected mass: 275.1/277.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=O)[N:3]=1.[CH3:21][NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:20])[NH:25][C@@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH:22][CH3:21])=[O:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3-bromo-7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (11) (0.53 g, 1.53 mmol), L-leucine-N-methylamide (0.26 g, 1.80 mmol) and DIEA (0.5 mL, 2.9 mmol) in DMF (20 mL) was added TBTU (0.69 g, 2.15 mmol) in two batches over 10 minutes at 0° C. After stirring from 0° C. to room temperature for 2 hours, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 70% to 100% EtOAc/Hexanes to give the desired product 20C as an oil (48% yield). LCMS (+ESI) m/z 474.1, 475.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1>C(#N)C>[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[N:65]=[C:66]([NH2:69])[N:67]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:9]5[C:4]([CH:3]3[C:16]3[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:23])[N:68]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1
Reactant: CC(C)(c1ccc(Br)cc1)c1nc(N)n[nH]1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(c1ccc(Br)cc1)c1nc(N)n(C(=O)C2(C)CC3([N+](=O)[O-])c4ccccc4C2c2ccccc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (31 mg, 0.10 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (20 mg, 0.15 mmol), and N-ethyl-N,N-diisopropylamine (0.15 mL) in anhydrous acetonitrile (1.5 mL) was added EDCI (39 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-[1-(4-bromophenyl)-1-methylethyl]-1H-1,2,4-triazol-3-amine (28 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT for 2 h and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 53 mg (93% yield) of the title compound as a white solid which was used as such for the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][CH:24]=1)[O:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: COCOc1cc(O)cc(C)c1C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1cc(Oc2cccc(OCc3ccccc3)c2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
A mixture of 4-hydroxy-2-methoxymethoxy-6-methyl-benzaldehyde (5.3 g, 27.2 mmol), 3-benzyloxyphenylboronic acid (9.3 g, 40.8 mmol), Cu(OAc)2 (4.9 g, 27.2 mmol), Et3N (18.9 mL, 135.9 mmol) and 4 Å molecular sieves (26 g) in DCM (150 mL) was stirred at room temperature for 12 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-(3-benzyloxy-phenoxy)-2-methoxymethoxy-6-methyl-benzaldehyde (3.5 g, 34%). 1H NMR (400 MHz, CDCl3): δ 10.55 (s, 1H), 7.43-7.25 (m, 6H), 6.82 (dd, J=2.0, 8.4 Hz, 1H), 6.69-6.66 (m, 3H), 6.37 (s, 1H), 5.21 (s, 2H), 5.04 (s, 2H), 3.49 (s, 3H), 2.52 (s, 3H). MS (ESI) m/z=379 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH:8]=[O:9])[CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12][CH2:13]O>C1C=CC=CC=1.S(=O)(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH2:6][CH3:7])=[CH:8][O:9][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: CCOC(=O)C(C=O)CC
Reactant: OCCCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=COCCCl)CC
Yield: 83.6 %

Procedure:
28.8 g 2-Formyl-butyric acid ethyl ester was refluxed in 250 ml benzene with 54 g 2-chloroethanol in the presence of 250 mg sodium bisulfate, and the water of reaction formed thereby was withdrawn continuously. Conditions analogous to those in Example 1 were maintained to produce 34.5 g 3-(2-chloroethoxy)-2-ethyl-acrylic acid ethyl ester (84% yield) boiling at 104°-107° C./2 torr. nD23 =1.4719. The compound was hydrogenated as in Example 1, and 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester was obtained in a yield of 81.5%. It boiled at 120°-122° C./14 torr, nD27 =1.4352.