Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14](I)=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].CC[Mg+].[Br-].O.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of [2-(4,5-diiodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (8.690 g; 17.204 mmol) in anhydrous THF (100 ml), under nitrogen, was cooled to −40° C., and a solution of 1M EtMgBr in THF (20.5 ml; 20.5 mmol; 1.2 eq.) was then added dropwise over 15 min. After addition, the resulting solution was stirred between −40° C. and −30° C. for 10 min. (conversion=55% according to LC-MS), and additional 1M EtMgBr in THF (13.9 ml; 13.9 mmol; 0.8 eq.) was added in order to complete the reaction. The reaction mixture was then treated with water (5 ml) at −40° C., and was allowed to warm-up to rt. Ether (200 ml) was added, and the resulting solution was washed with brine (2×200 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=20/1) to give the pure product [2-(4-iodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow oil (6.110 g; 94%). LC-MS: tR=0.74 min.; [M+H]+=380.00 g/mol.
Reaction SMILES: O1CCCC1.[F-].[CH2:7]([N+:11](CCCC)(CCCC)CCCC)CCC.C(#N)C.Br[CH2:28][C:29]1[CH:34]=[C:33]([CH:35]([S:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[C:32]([Cl:52])=[CH:31][N:30]=1>CCCCCC>[Cl:52][C:32]1[C:33]([CH:35]([S:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[CH:34][C:29]([CH2:28][C:7]#[N:11])=[N:30][CH:31]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(CBr)ncc2Cl)c1
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Under an argon atmosphere, trimethylsilylnitrile (0.226 ml, 1.63 mmol) and a tetrahydrofuran solution (1M, 1.63 ml, 1.63 mmol) of tetrabutylammonium fluoride were added sequentially to an acetonitrile (10 ml) solution of 2-bromomethyl-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (516 mg, 1.09 mmol) at room temperature. The resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure to give the title compound (390 mg, 0.93 mmol, 85%) as a brown oil.
Reaction SMILES: [NH2:1][C:2](=[N:41][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:45]([OH:48])(=[O:47])[CH3:46]>[Pd]>[C:17]1([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([NH:8][C@@H:7]([C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]3[CH2:39][CH2:38][NH:37][C:36]3=[O:40])=[CH:32][CH:33]=2)=[O:25])[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:41])=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:45]([O-:48])(=[O:47])[CH3:46]
Reactant: CC(=O)O
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CN2CCNC2=O)cc1
Agent: [Pd]
Product: CC(=O)[O-]
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CN2CCNC2=O)cc1
Yield: 32 %

Procedure:
Prepared analogously to Example 4c) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-N-[[4-[(2-oxo-1-imidazolidinyl)methyl]phenyl]methyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 32% of theory.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.[C:13]1([S:19]([NH:22][C:23]2[C:28](I)=[CH:27][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[K+].O1CCOCC1>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.C(OCC)(=O)C.O>[C:13]1([S:19]([N:22]2[C:23]3[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH:5]=[C:6]2[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1cccnc1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
A mixture of 3-trimethylsilylethynylpyridine (1.07 g), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (1.75 g), potassium acetate (1.60 g), cuprous iodide (60 mg), dichlorobis(triphenylphosphine)palladium (0.20 g) and 1,4-dioxane (4 ml) was stirred at 100° C. for 12 hours under nitrogen atmosphere. To the reaction solution were added water and ethyl acetate. The insolubles were filtered off. The filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 1.04 g of the desired product.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To ethanolamine (9.0 ml, 149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chlorformate (10.0 ml, 70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid. 1H-NMR (CDCl3,TMS) 7.47 (m,5H), 5.11 (s,2H), 3.73 (m,2H), 3.38 (m,2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCOCC1.[ClH:34]>CO.[Pd]>[ClH:34].[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH2:16])[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester (7.806 g, 20.68 mmol) in 120 mL of methanol and 4 M HCl in dioxane (41.4 mmol, 10.3 mL) is hydrogenated over 10% Pd/C (1.0 g) at 50 psi. After 8 hr, another portion of 10% Pd/C (1.0 g) is added. After 24 hr, the catalyst is removed by filtration over a pad of Celite, and the filtrate is concentrated in vacuum. The resulting solid is dissolved in a minimum amount of methanol and slowly added to ether (150 mL). The resulting slurry is aged for 30 min and then filtered. The solid is dried under suction to afford (S)-2-amino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester hydrochloride (4.950 g, 85.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COCC(N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCC(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-3-methoxypropionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=165-168° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:36])[CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:25][CH2:24]1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
tert-Butyl 2-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.020 g, 0.036 mmol) was placed in DCM (3 mL). TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give N-(4-(4-(2-aminoacetyl)piperazin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.015 g, 74% yield) as the trihydrochloride salt. MS APCI (+) m/z 459 detected.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(N(CC)CC)C>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.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43 a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (75 mg); MS-(+)-ion: MS-(+)-ion: M+1=348.4.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][C@H:17]2[NH:19][CH2:20][C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2.[S:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][Cl:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]1=2.CCN(C(C)C)C(C)C.Cl>C(OCC)C.CN1C(=O)CCC1>[S:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][N:19]2[CH2:20][CH:12]3[N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:18][CH:17]2[CH2:16][CH:15]=[CH:14][CH2:13]3)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]1=2.[ClH:29]
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: O=C(CCCl)c1csc2ccccc12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CC2CC=CCC1CN2c1ccc2ccccc2c1)c1csc2ccccc12
Temperature: 160 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.189 mmol), 1-benzo[b]thiophen-3-yl-3-chloro-propan-1-one (50 mg, 0.22 mmol) and DiPEA (0.1 mL, 0.57 mmol) were placed in a μW tube with NMP (2 ml), and heated to 160° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via reverse phase chromatography (20% CH3CN to 90% CH3CN in water) to yield a residue which was then treated with 1N HCl in diethyl ether. The solvent was then evaporated under reduced pressure to yield the title compound as its corresponding HCl salt, as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:12].O>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(C(F)(F)F)cc1
Yield: 58.4 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (408 mg). and 2-bromo-4'-trifluoromethyl-acetophenone (824 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 45 mins. Water (100 ml) was added and the precipitate was collected. This solid was crystallised from acetone to give the title pyrimidinone (571 mg,); m.p. 243°-245°; λmaxEtOH 235.5 nm (ε 20040), 282 nm (ε 1880), 333.5 nm (ε 1860), λinf 287.5 nm (ε 1790).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1.[ClH:25]>ClCCl.O1CCCC1>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:15][Cl:25])[CH:11]=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl
Reactant: CC(=O)c1ccnc(Nc2ccccc2)n1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccnc(Nc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This ketone (1.3 g, 6.1 mmol) was dissolved in dichloromethane (40 mL), then TEA (5.1 mL, 36.6 mmol) and tert-butyl-dimethyl-trifluoro methansulphonate (4.2 mL, 18.3 mmol) were added. The orange solution was stirred overnight, then diluted with more dichloromethane (150 mL), washed twice with a 5% sodium hydrogencarbonate solution (50 mL), with water, with brine, then dried over sodium sulphate and concentrated to give the bis-silylated derivative (2.67 g). To half of the material (1.32 g, 2.94 mmol) dissolved in tetrahydrofuran (THF, 25 mL) and cooled to 0° C., a solution of NBS (0.549 g, 3.09 mmol) in THF (10 mL) was added dropwise in 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour, then 2 N HCl was added and the reaction mixture was stirred for 24 hours at r.t. The crude was purified by flash chromatography (eluant: hexane/ethyl acetate 5:1) to yield 0.325 g of title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCC.CCOCC>[CH2:20]([N:27]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])([OH:32])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (536 mg, 0.00251 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.4 mL) under nitrogen at −78° C. The mixture was stirred at −78 Celsius for 15 min, then at 0 Celsius for 1 hour, and then cooled down to −78 Celsius again. A solution of 1-benzylpyrrolidin-3-one (400.0 mg, 0.002283 mol) in ether (3 mL) was added to the above solution. The reaction solution was stirred at ±78 Celsius for 2 hours, then quenched with saturated NH4Cl aqueous solution, and then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4. The residue was purified by flash chromatography on silica gel column with 30% AcOEt in hexanes to give the desired compound (350 mg, 39% yield). MS (ESI): 389.1 (M+
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])([O:3][CH2:4][CH3:5])=[O:2].CO.C(CCCCCCC1C(=O)CC(=O)C=1OC)(OC)=O>C(O)(C)C>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1[O:17][CH3:18])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1=C(OC)C(=O)CC1=O
Agent: COC(=O)CCCCCCC1=C(OC)C(=O)CC1=O
Solvent: CO
Solvent: CC(C)O
Product: CCOC(=O)CCCCCCC1=C(OC)C(O)CC1=O
Yield: 98.6 %

Procedure:
The procedure similar to that of Step 2 of Example 1 was repeated except that 2.82 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-oxo-2-cyclopenten-1-one and 35 ml of methanol were used instead of 24 g of 2-(6'-carbomethoxyhexyl)-3-methoxy-4-oxo-2-cyclopenten-1-one and isopropanol respectively to provide 2.8 g of 2-(6'-carboethoxyhexyl)-3-methoxy-4-hydroxy-2-cyclopenten-1-one as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO.O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(F)cc1N
Yield: 80.6 %

Procedure:
A stirred solution of 2-amino-4-fluorobenzoic acid (4.86 g, 31.3 mM) in anhydrous methanol (100 mL) was saturated with anhydrous hydrogen chloride and then refluxed for 4 days. During the reflux period, the reaction mixture was periodically resaturated with hydrogen chloride. After the reflux period, the reaction mixture was cooled and concentrated to leave a whtie solid. This material was dissolved in water and the resulting solution neutralized with aqueous sodium bicarbonate and extracted with diethyl ether. The combined extracts were dried (MgSO4), filtered and concentrated to leave (4.08 g, 80.6%) of the title compound as an off white solid, mp 66°-67° C.; MS(CI): 170 (M+H).
Reaction SMILES: Cl.C[O:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.B(Br)(Br)Br.C[OH:28]>C(Cl)Cl>[CH:4]([OH:3])=[O:28].[OH:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c1CC(c1ccccc1)C1=C2CNC1
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=CO
Product: Oc1cccc2c1CC(c1ccccc1)C1=C2CNC1
Temperature: 25 °C

Procedure:
A suspension of 44.1 mg. (0.159 mmol) of 6-methoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e]isoindole hydrochloride, from Step 6, in 2 mL of methylene chloride is cooled to -78° C. and 0.64 mL of a 1M solution of boron tribromide in methylene chloride is added. The reaction is warmed to ambient temperature for 1 h and recooled to -78° C. before 1 mL of methanol is added. After warming to ambient temperature for 1 h, the solvents are removed in vacuo. Additional methanol (5 mL) is added and removed in vacuo. The product is chromatographed on silica gel, eluting with 18:1:1 ethyl acetate:formic acid: water to give 6-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e]isoindole formic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=C([CH:18]=[CH:19][CH:20]=1)C#N)=[N:9][NH:8][C:7]2=[O:21].[OH-:22].[K+].[CH2:24]([OH:26])[CH3:25]>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:25]([CH:18]=[CH:19][CH:20]=1)[C:24]([OH:22])=[O:26])=[N:9][NH:8][C:7]2=[O:21]
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Temperature: 100 °C
Yield: 95 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzonitrile (117) (3.75 g, 12.68 mmol) and potassium hydroxide (7.11 g, 126.81 mmol) were added to ethanol (30 mL) and water (70 mL) and heated at 100° C. for 5 hours. The ethanol was evaporated off and the aqueous was extracted with ethyl acetate (1×75 mL). The aqueous was then acidified to pH1 with conc HCl to afford a solid, this was filtered, washed with water and dried to afford the desired material as a beige solid (3.81 g, 95% yield); 1H NMR (400.132 MHz, DMSO) δ 4.67 (2H, s), 7.42-7.41 (2H, m), 7.72 (1H, s), 7.79-7.76 (1H, m), 7.81 (1H, t), 7.97 (1H, dd), 8.34 (1H, dd), 12.88 (1H, s); m/z (LC-MS, ESI+), RT=0.92 (M+H 315).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:19][O:24][C:21](=[O:23])[CH3:22])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 61.6 %

Procedure:
To 41.2 g (0.1 mol, 1.0 eq.) of 4-decyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 8.5 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 19.8 g of 4-decyloxy-2-acetoxymethyl-3-methylpyridine as a black brown oily matter (total yield of two processes 61.7%).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)[C@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.