Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[CH3:11][C:12](O)([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]=[CH2:14].[CH2:27]=[C:28]1[O:32]C(=O)[CH2:29]1>>[CH3:11][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:13][CH2:14][CH2:27][C:28](=[O:32])[CH3:29]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)C
Solvent: c1ccc2c(c1)CCCC2
Product: CC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Yield: 84.7 %

Procedure:
The procedure was the same as in Example 2 except that the diluent solvent was 10 g of tetraline and the starting reactants were 226 g (1.0 mole) of 3,7,11-trimethyl-1-dodecen-3-ol and 101 g (1.2 moles) of diketene. 6,10,14-Trimethyl-5-pentadecen-2-one with the boiling point of 123° to 125°C/1 mmHg and the refractive index of 1.4560 at 20°C was obtained in an amount of 212 g corresponding to 84.7% yield based on 3,7,11-trimethyl-1-dodecen-3-ol.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:15][CH:16]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in methanol and powdered 3A sieves were added. Morpholine (2 eq) was added, followed by acetic acid (5 eq). After stirring for 30 minutes, sodium cyanoborohydride (2 eq) was added portionwise and the suspension was stirred under nitrogen at ambient temperature for 16 hours. The reaction mixture was filtered through celite and concentrated to dryness. Column chromatography, eluting with 5% MeOH in DCM gave 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless oil.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:48])[CH3:47])/[C:41]([Cl:43])=[O:42])[N:36]=1.C(OCC)C>O1CCCC1>[ClH:43].[ClH:1].[ClH:43].[NH2:34][C:35]1[S:39][N:38]=[C:37]([C:40](=[N:44][O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:47])[CH3:48])[C:41]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:42])[N:36]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 194.8 %

Procedure:
To a solution of 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (2 g) and N-(trimethylsilyl)acetamide (6.28 g) in tetrahydrofuran (40 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride (1.84 g) under ice-cooling. After being stirred for 1 hour, the reaction mixture was added dropwise to ethyl ether (300 ml), and the resulting precipitate was collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (syn isomer) (3.4 g).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[CH:16]1>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:6])=[CH:16]1
Reactant: CON(C)C(=O)c1c(Cc2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1c(C(=O)c2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
DDQ (0.25 g) was added to a stirred solution of the product of example 4 (0.25 g) in THF (9 ml) and water (1 ml). The solution was stirred for a further 2 h and the concentrated in vacuo. The residue was purified by flash silica chromatography eluting with ethyl acetate:isohexane (7:3) to give the title compound as a pale pink solid (0.1 g).
Reaction SMILES: P(C[C:6]1[N:11]2C=C(C(O)=O)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(O)(O)=O.[O:18]1CCC[CH2:19]1>>[NH2:14][C:10]1[N:11]=[CH:6][C:7]([CH2:19][OH:18])=[CH:8][CH:9]=1
Reactant: O=C(O)c1cn2c(CP(=O)(O)O)cccc2n1
Reactant: C1CCOC1
Product: Nc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 250 mL 3-neck flask equipped with an addition funnel, an argon (Ar) inlet and a stopper was flame dried and cooled to room temperature. Dry tetrahydrofuran (THF, 30 mL) was added to the flask, followed by 1M. lithium aluminum hydride (LAH) in Et2O (16 mL). After cooling the solution to 0° C. with a wet ice/water bath, the product from Example 8 (0.92 g, 6 mmol) suspended in THF (100 mL) was added dropwise. The reaction was allowed to warm to room temperature and stir for 3 h. The reaction was quenched with H2O, the salts filtered off and the filtrate stripped to give 0.591 g (99%) of title material.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.CS(C)=O>O>[CH3:20][S:19][C:17]1[N:16]=[C:15]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[N:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc2c(c(OS(=O)(=O)C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNCC2
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A solution containing methylsulfanyl-4-trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester (950 mg, 2.15 mmol), 4-trifluoromethylaniline (0.6 mL, 4.74 mmol) and DMSO (8 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified (FCC; MeOH/CH2Cl2) to give the title compound (422 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.ClCCCl>[C:15](=[N:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=[CH:5]2)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc2c(Cl)nccc2cc1N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc2c(Cl)nccc2cc1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (0.1 g, 0.52 mmol) in MeOH (5 mL) at 0° C. is bubbled HCl gas for 1 minute, then the solvent is removed in vacuo. The remaining white solid is diluted with 1,2 dichloroethane and benzophenone imine (0.15 mL, 0.89 mmol) is added. The resulting suspension is heated to reflux for 48 hours, then cooled to room temperature and concentrated to dryness. The crude material is diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography using 10% EtOAc/hexanes as the eluent to afford the title compound (0.159 g, 0.45 mmol) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(C)o1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of methyl 5-methyl-2-furancarboxylate (2.33 g, 16.29 mmol) and aluminum chloride (3.3 g, 24.75 mmol) in chloroform (50 ml) at room temperature was added Br2 (1.1 ml, 21.35 mmol). The resulting solution was stirred at room temperature in a 150 mL sealed tube reactor for 2 hours. Upon completion, the solution was cooled in an ice bath, H2O added and reaction partitioned between CHCl3/H2O. The organic layer was washed with NaHCO3 and then Na2S2O3. The organic layer was dried with Na2SO4, concentrated, adsorbed onto silica and purified via column chromatography (0-20% EtOAc/Hexanes) affording the title compound (2.13 g, 9.72 mmol, 60%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]([CH2:21][CH3:22])[C:6](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:7].C1COCC1.[BH4-].[Na+]>O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]([CH2:21][CH3:22])[CH2:6][OH:7]
Reactant: CC[C@@H](Cc1ccc(F)cc1F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](CO)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A flask was charged with 29.5 g (˜78.6 mmol) of (4R,5S)-[(S)-2-(2,4-difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidin-2-one and 200 mL of dry THF, and the solution was cooled to 0° C. In a separate flask, 11.9 g (314 mmol) of sodium borohydride was taken up in 70 mL of water and added dropwise over 15 minutes to the imide solution. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with conc. HCl until pH=3 (keeping the reaction mixture temperature <20° C.). THF was removed under reduced pressure, and the residue was taken up in hexanes. The hexane layer was washed with sat. aq. sodium bicarbonate. The hexane layer was removed under reduced pressure, and the residue was purified by column chromatography (9:1 Hexanes/EtOAc) which gave 7.2 g (46% yield) of the titled compound as a clear oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cccc(CBr)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-3-fluorobenzene (0.41 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
400 mg (0.70 mmol) of the compound from Example 39A were initially charged in 17 ml of acetic acid, and 8.6 ml of water were then added carefully. The mixture was stirred at RT for 12 h. The reaction mixture was concentrated on a rotary evaporator, and the residue was then purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gave the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:14][C:13]2[CH2:12][C@@H:11]3[C@H:6]([CH2:7][C@@H:8]([C:16]([N:18]([CH2:27][CH2:28][CH3:29])[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:20])=[O:17])[CH2:9][N:10]3[CH3:15])[CH2:5][C:4]=2[C:3]=1[C:30]#[N:31].[C:32](O)(=[O:34])[CH3:33]>>[C:30]([C:3]1[C:4]2[CH2:5][C@@H:6]3[C@@H:11]([CH2:12][C:13]=2[S:14][C:2]=1[NH:1][C:32](=[O:34])[CH3:33])[N:10]([CH3:15])[CH2:9][C@H:8]([C:16]([N:18]([C:19](=[O:20])[NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:27][CH2:28][CH3:29])=[O:17])[CH2:7]3)#[N:31]
Reactant: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N)c3C#N)C[C@H]2N(C)C1
Reactant: CC(=O)O
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(NC(C)=O)c3C#N)C[C@H]2N(C)C1
Temperature: 135 °C

Procedure:
To 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H, 8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (example 1-15) (100 mg) was added acetic acid (2 mL) and the mixture was heated at 135° C. and refluxed for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (26 mg). The structure was illustrated in Table 11.
Reaction SMILES: C(OC(OCC)C(=O)CC1C=CC(CC)=CC=1)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[NH:35][C:34]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)=[CH:33][N:32]3[C:27]=2[N:28]=[C:29]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)[C:30]3=[O:31])=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]3[N:32]([CH:33]=[C:34]([C:36]4[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=4)[N:35]=2)[C:30]([OH:31])=[C:29]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)[N:28]=3)=[CH:21][CH:20]=1
Reactant: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn1-2
Agent: CCOC(OCC)C(=O)Cc1ccc(CC)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(Cc2nc3c(Cc4ccccc4)nc(-c4ccc(O)cc4)cn3c2O)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 64.2 %

Procedure:
Under an argon atmosphere, 1,1-diethoxy-3-(4-ethylphenyl)propan-2-one (43) (301 mg, 1.20 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). To this was added coelenteramine (238 mg, 858 μmol) and, after cooling to 0° C., conc. hydrochloric acid (0.20 mL) was further added thereto, and then stirred overnight (17 hours) at 100° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography in an argon flow (n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=50/1→10/1). The solid obtained was further reprecipitated (n-hexane/acetone) to give et-coelenterazine (44, et-CTZ) as a yellow powder (240 mg, 551 μmol, 64.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:27][CH:26]=2)[C:21](O)=[O:22])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:37][O:38][CH2:39][C@@H:40]([NH2:42])[CH3:41].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH3:37][O:38][CH2:39][C@@H:40]([NH:42][C:21]([C@@H:20]([NH:19][C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:9])=[O:18])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:27][CH:26]=1)=[O:22])[CH3:41]
Reactant: COC[C@H](C)N
Reactant: COCCCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COCCCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)N[C@@H](C)COC)cc1

Procedure:
To (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-methoxy-propoxy)-phenyl]-propionic acid (98 mg, 0.19 mmol) in dichloromethane (2 mL) was added 2-methoxy-1-(S)-methyl ethyl amine (19 mg, 0.19 mmol), 1-hydroxybenzotriazole hydrate (36 mg, 0.27 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol) at room temperature. Upon reaction completion water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane/ethyl acetate, 80/20 as eluant) to produce 87 (77%) mg of (S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid {(S)-1-((S)-2-methoxy-1-methyl-ethylcarbamoyl)-2-[4-(3-methoxy-propoxy)-phenyl]-ethyl}-amide. LC/MS rt=3.95, 536 m/e (M+H). 1H NMR (300 MHz, dmso-d6) 7.90 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.48-7.37 (m, 4H), 7.13 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.50 (m, 1H), 4.28 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.79 (m, 1H), 3.63 (m, 1H), 3.42 (t, J=6.2 Hz, 2H), 3.30-3.21 (m, 9H), 3.17-3.05 (m, 2H), 3.90-3.82 (m, 1H), 3.75-3.65 (m, 1H), 1.98-1.85 (m, 2H), 1.45-1.10 (m, 4H), 1.00 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])O.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl>ClCCl>[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH:27][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C)O
Reactant: Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Under ice-cooling, methyl D-lactate (8.5 g) and 2,6-lutidine (11.4 g) were dissolved in dichloromethane (100 ml). After dropping anhydrous trifluoromethanesulfonic acid (25.4 g), the mixture was heated to room temperature and stirred for 30 minutes. Then it was cooled to 0° C. again and a solution (30 ml) of 2,3,4-trifluoroaniline (12.0 g) in dichloromethane was dropped thereinto. The mixture was stirred at the same temperature for 17 hours. To the resultant solution, hydrochloric acid (0.5 mol/l) was added and the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporating the solvent, the residue thus obtained was subjected to silica gel column chromatography. Thus, 17.1 g (90%) of the title compound was obtained as an oily substance. The optical purity determined by HPLC was 97% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C(C(CCCC)C([O-])=O)C.[Na+:46].CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:46]
Reactant: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
6-Chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.050 g, 0.098 mmol) in THF (1.5 mL) was heated until a homogeneous solution resulted. The reaction was filtered and sodium 2-ethylhexanoate (0.020 g, 0.12 mmol) was added. The reaction was cooled to 0° C. Hexane was added in 0.5 mL portions and the solution was stored in the freezer overnight. The resulting solids were collected by filtration and dried to provide the desired product (0.043 g, 0.081 mmol, 82% yield). MS (ESI)=509.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.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>[Cl:1][C:2]1[CH:9]=[C:8]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1c(F)cc(I)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-iodobenzonitrile (5.75 g, 20.4 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.39 g, 26.6 mmol) in THF (60 ml) was added bis(triphenylphosphine)-palladium(II) chloride (0.717 g, 1.02 mmol), sodium carbonate (5.20 g, 49.0 mmol) and water (20 ml). Reaction mixture was heated at 60° C. for 2 h, concentrated to ¼ of the volume, diluted with water (40 ml) and stirred at RT for 1 h. Thus resulting solid was filtered and suspended in EtOH (30 ml). Suspension was stirred at −10° C. for 1 h, precipitate was filtered and washed with EtOH to yield 2.90 g (46%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49-1.72 (m, 3H), 1.78-2.03 (m, 2H), 2.29-2.44 (m, 1H), 3.56-3.68 (m, 1H), 3.93-4.03 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd, 1H), 7.81 (m, 1H).