Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][OH:32])=[CH:24][N:23]=1.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][O:32][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][N:23]=1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCc1cnc(C)c(O)c1C=O

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 ml) was added slowly dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol) and 4-(N,N-dimethylamino)pyridine (few mg, catalytic amount) in methylene chloride (20 ml) at 0° C. under nitrogen. On completion, as indicated by tlc, the mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane), yielding 2-methyl-3-hydroxy-4-formyl-5-( z,z,z-octadeca-6,9,12-trienoyloxy)methyl pyridine as a colourless oil which subsequently solidified.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 656.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([O:19][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Oc1cc2ccccc2nc1-c1ccc(F)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccc(F)cc3F)c2cc1OC
Temperature: 145 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
2-(2,4-Difluoro-phenyl)-quinolin-3-ol (220 mg), 4-chloro-6,7-dimethoxyquinoline (237 mg), and 4-dimethylaminopyridine (380 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 145° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (104 mg, yield 27%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>CCOCC>[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: COC=C1CCC(c2cccc(F)c2F)CC1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
First, 27.4 g of (methoxymethyl)triphenylphosphonium chloride, 9 g of potassium t-butoxide, and 225 ml of dry ether were placed in a 500 ml flask whose content was replaced with argon. The mixture was stirred for 30 minutes under ice water cooling. Then, 50 ml of an ether solution containing 16.8 g of 4-(2,3-difluorophenyl)cyclohexanone was added dropwise to the reaction mixture. The reaction mixture was stirred under ice water cooling for 30 minutes and at room temperature for 8 hours. Thereafter, a precipitate was filtered out. A filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/4) to obtain 17.1 g of 1-(2,3-difluorophenyl)-4-methoxymethylene cyclohexane (Y: 89.7%). The compound thus obtained had a purity of 99.2% by GC.
Reaction SMILES: [N:1]([C@@H:4]([C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@H:19]([C:21]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:23][CH:22]=2)[CH3:20])[N:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:1][C@@H:4]([C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@H:19]([C:21]2[S:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:23][CH:22]=2)[CH3:20])[N:13]=1)[CH3:5]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)N=[N+]=[N-])n1)c1cnc(-c2ccc(Cl)cc2)s1
Agent: CP(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)N)n1)c1cnc(-c2ccc(Cl)cc2)s1
Yield: 15.3 %

Procedure:
To a round bottom flask containing (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.03 mmol) and stir bar was added THF (1 mL) and trimethylphosphine (0.06 mL, 0.06 mmol, 1.0 M in THF). The resulting reaction mixture allowed to stir 2 hr at RT. A second addition of trimethylphosphine (0.06 mL, 0.06 mmol) occurred and the mixture allowed to stir 1.5 hr at RT. Reaction was quenched by the addition of a saturated solution of NH4Cl and EtOAc. The phases were partitioned and aqueous phase extracted with EtOAc. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated to a yellow residue. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (2.6 mg, 4.60 μmol, 15% yield) as a TFA salt.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10].CO.C(Cl)Cl>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][NH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: NNc1ccnc(Cl)n1
Yield: 94.8 %

Procedure:
A solution of 2,4-dichloropyrimidine (2.0 g) in EtOH (25 mL) was cooled to 0-20° C. and treated with hydrazine (2.8 mL). The progress of the reaction was followed by TLC using 10% MeOH:CH2Cl2 as mobile phase and visualizing under UV light. The mixture was concentrated under reduced pressure to afford 3.1 g of crude 2-chloro-4-hydrazinyl-pyrimidine (yield=94.8%).
Reaction SMILES: [SH:1]/[C:2](/[C:7]#[N:8])=[C:3](\[SH:6])/[C:4]#[N:5].[Na].[Na].[OH2:11]>CN(C=O)C>[O:11]=[C:4]1[NH:5][N:8]=[CH:7][C:2]2[S:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[S:6][C:3]1=2
Reactant: O
Reactant: N#C/C(S)=C(/S)C#N
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CC1=C(C#N)Sc2c(cn[nH]c2=O)S1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred solution of 20 g (0.1 mole) disodiumdimercaptomaleonitrile in 250 ml of DMF was added 16.5 g (0.1 mole) of 4,5-dichloro-3-pyridiazone. The reaction mixture was stirred at room temperature (approximately 20° C.) for 0.25 hours and was thereafter poured with stirring into 1.5 liters of water. The resulting mixture was allowed to stand for four hours during which time a brown precipitate slowly formed. This precipitate was separated by filtration, washed with water, and dried in vacuo to yield 10.2 g (43% yield from the pyridiazone) of a brown solid, m.p. (decomposition) 240°-260° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][OH:8].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:12]1[C:2]2[NH:1][C:21](=[S:22])[N:4]([CH2:5][CH2:6][CH2:7][OH:8])[C:3]=2[CH:9]=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(NCCCO)cccc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCCCn1c(=S)[nH]c2c(OCc3ccccc3)cccc21
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 2-amino-3-benzyloxy-N-(3-hydroxypropyl)aniline (100 mg) in chloroform (2 ml) was added 1,1′-thiocarbonyldiimidazole (72.7 mg) at ambient temperature, and the mixture was stirred for 2 hours at the same temperature and refluxed for 5 hours. The reaction mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, v/v) to give 4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole (75 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:17]N(C=O)C.[H-].[Na+].IC>O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
7 g (24.7 mmol) of 3-bromo-2-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 40 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. 890 mg (29.6 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 1.7 ml (27 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.3 g (99%) of the expected product are collected in the form of an oil which crystallizes slowly. Melting point 77-8° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.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>[N:17]1([CH2:16][CH2:15][S:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)(=[O:14])=[O:13])[CH:21]=[CH:20][N:19]=[N:18]1
Reactant: C=CCOc1ccc(CS(=O)(=O)CCn2ccnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: O=S(=O)(CCn1ccnn1)Cc1ccc(O)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 69.7 %

Procedure:
A solution of 2.39 g (7.78 mmol) 1-[2-(4-allyloxy-phenylmethanesulfonyl)-ethyl]-1H-[1,2,3]triazole in 50 ml dichloromethane was added to a solution of 3.64 g (23.3 mmol) 1,3-dimethylbarbituric acid and 220 mg (0.19 mmol) Pd(PPh3)4 in 90 ml dichloromethane and stirred for 7 h at 40° C. The reaction mixture was washed with 3×80 ml sat. NaHCO3-solution, 2×30 ml water and the water phase extracted with 2×80 ml dichloromethane. The remaining precipitate was collected, washed with water and ethyl acetate and dried to yield. All dichloromethane fractions were combined, dried over 0.86 g of product. The aqueous phase from above was acidified by acetic acid to pH=5 and extracted with ethyl acetate. After washing with water and drying over sodium sulphate the ethyl acetate extract was evaporated to give 1.45 g of an orange powder that was purified by chromatography on silica gel (eluent:ethyl acetate) to yield an additional amount of 0.47 g product. Combined yield: 1.33 g (58%).
Reaction SMILES: BrC1C=C[C:5]([N:8]=C=S)=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[OH:20].CCN=C=NCCCN(C)C>C1COCC1>[CH3:18][C:16]1[CH:15]=[C:14]([CH3:19])[C:13]2[O:20][C:5]([NH2:8])=[N:11][C:12]=2[CH:17]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: S=C=Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 177.5 %

Procedure:
A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50° C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. A mixture of 5,7-dimethyl-1,3-benzoxazol-2-amine (76.4 g, 0.230 mol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (73.9 g, 0.292 mol), potassium acetate (71.5 g, 0.730 mol), and DMF (760 mL) was cycled three times through vacuum degassing and nitrogen purging, treated with Pd(dppf)Cl2.CH2Cl2 (19.9 g, 0.024 mol), sealed, cycled three times through vacuum degassing and N2 purging, heated to 80° C. for 5 hours, and distilled on high vacuum (0.2 mm Hg) at 40° C. to 80° C. to remove DMF. The residue was treated with CH2Cl2 (1300 mL), stirred for 10 minutes, and filtered. The filter cake was washed with CH2Cl2 (300 mL) and the filtrate was concentrated to a volume of about 800 mL. The solution was treated with SiO2 (509 g), stirred for 10 minutes, poured onto a bed of SiO2 (790 g) in a 4 L coarse glass fritted funnel. The SiO2 was washed with 16 L of 15% ethyl acetate and the solution was concentrated at 50° C. The concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50° C. for 30 minutes, cooled to room temperature over 2 hours, and filtered. The filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 68.3 g (77%) of the desired product. The final product was determined to be 98.2% potency (vs. analytical standard) by HPLC. Rt=6.5 min. HPLC conditions: Zorbax SB-C8 Rapid Resolution (4.6 mm×75 mm, 3.5 um); flow 1.5 mL/min; 5:95 to 95:5 acetonitrile:water (0.1% H3PO4) over 7 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=[O:3])[CH3:2].O.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:31]([OH:35])=[O:32])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.2 %

Procedure:
To a stirred solution of afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (20 mg, 0.045 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (25.3 mg, 0.18 mmol), 2-methyl-2-butene (0.030 mL, 0.27 mmol) and sodium chlorite (24.8 mg, 0.27 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (8.0 mg, 39% yield) as a white solid: HR-MS m/e calcd for C24H23N1O8 (M−H+) 454.1496, found 454.1502; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].Br[CH2:20][CH2:21]Br.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH:10]1([CH:16]([CH:15]2[C:14]3[CH2:21][C:20]4[C:3](=[CH:2][CH:1]=[CH:13][CH:12]=4)[C:4]=3[CH2:5][CH2:6][CH2:7]2)[CH3:17])[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C1CCCC2=C1Cc1ccccc12)C1CCCC2=C1Cc1ccccc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Tetrahydrofluorene (17.6 mmol) was dissolved in 20 ml of dry THF and cooled to 0° C. Butyllithium, (11 ml of a solution 1.6M in hexane, 17.6 mmol) was added dropwise to give a red/orange solution that was stirred for 6h. 1,2-dibromoethane (1.66 g, 8.81 mmol) was added quickly. The resulting beige suspension was stirred overnight. The mixture was hydrolyzed with NH4Cl and extracted in THF and diethyl ether. The organics were collected, dried, filtered and the solvents were removed to give a yellow solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[NH2:17][C:18]1[C:32]([Cl:33])=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[CH:20][C:19]=1[Cl:34]>COCCOC>[NH2:17][C:18]1[C:19]([Cl:34])=[CH:20][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:31][C:32]=1[Cl:33]
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C(c1ccc(Cl)cc1)c1cc(Cl)c(N)c(Cl)c1

Procedure:
A solution of 108 g (0.55 mol) of ethyl diethylphosphonoacetate in 150 ml of dry 1,2-dimethoxyethane was slowly added dropwise, while stirring and cooling with ice to a suspension of 13.2 g (0.55 mol) of sodium hydride (26.4 g of 50% oil suspension) in 50 ml of dry 1,2-dimethoxyethane, whereupon the mixture foamed vigorously. After all the solution had been added the mixture was stirred for another 30 minutes. It was then combined with a suspension of 150 g (0.5 mol) of 4-amino-3,4',5-trichloro-benzophenone in 800 ml of dry 1,2-dimethoxyethane and heated for one hour at reflux temperature, whereby a clear solution was formed. The solution was evaporated to dryness in vacuo, and the residue was distributed between chloroform and water. The organic phase was dried and evaporated to dryness in vacuo. After mixing with 150 ml of ethanol, crystallization set in. The crystals were suction-filtered off and washed with ethanol and petroleum ether.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.[CH3:21]O.[O:23]1CCC[CH2:24]1.O>Cl(O)(=O)(=O)=O.N1C=CC=CC=1.CCOCC>[CH3:21][O:15][CH:14]([O:23][CH3:24])[CH:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[C:3]3[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=3[CH:5]=[CH:6][C:7]=2[CH:12]=1)[CH3:16]
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: C1CCOC1
Reactant: CO
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: COC(OC)C(C)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
0.200 G. of 2-(5-oxo-5 -H-dibenzo[a,d]cyclohepten-2-yl)propanal is dissolved in 10 ml. of methanol and 20 ml. of tetrahydrofuran, and 1 drop of 60% aqueous perchloric acid is added. The mixture is left for 1 hour then 2 drops of pyridine are added and the mixture added to water and ether. The organic layer is washed with water, dried and evaporated and the residue chromatographed on 5 gm. of silica gel, eluting with 50:50:1 hexane:ether:triethylamine to afford 1,1-dimethoxy 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-benzaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.