Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][O:25][C:26]1([C:30]2[S:31][C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:34]=2)[CH2:29][CH2:28][CH2:27]1>CN(C)C=O.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[C:3]([C:32]2[S:31][C:30]([C:26]3([O:25][CH2:24][O:23][CH3:22])[CH2:27][CH2:28][CH2:29]3)=[N:34][CH:33]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCOC)CCC2)s1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-4-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 1D) (7.12 g, 16.46 mmol), bis(triphenylphosphine)palladium dichloride (0.809 g, 1.15 mmol), and 2-(1-(methoxymethoxy)cyclobutyl)-5-(tributylstannyl)thiazole (Example 1C) (10.45 g, 21.39 mmol) in N,N-dimethylformamide (54.9 ml) was heated to 70° C. for 1 hour. The reaction was cooled to room temperature and quenched by the addition of an aqueous potassium fluoride solution (19 g in 100 mL water) and ethyl acetate (200 mL). The mixture was stirred vigorously overnight and was then filtered through diatomaceous earth, eluting with ethyl acetate. The layers were separated, and the organic layer was washed with aqueous saturated bicarbonate solution and water. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 35% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 504 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([O:15]C)=[O:14])=[C:7]([NH:17][C:18]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[O:19])[CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[C:7]([NH:17][C:18]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[O:19])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1ccc(NC(C)=O)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C=CC(=O)O)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Reaction time: 15 h
Yield: 12.6 %

Procedure:
0.65 g (1.4 mmol) of methyl 3-{4-acetylamino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate was dissolved in 8 ml of tetrahydrofuran, and 8 ml of H2O and 0.17 g (7.2 mmol) of lithium hydroxide were added. After 15 hours at room temperature, the mixture was made acid with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, concentrated and stirred up with diethyl ether. The resulting precipitate was filtered off with suction and yielded 77 mg (13%) of the desired product.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:14][C:13]1[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1ccc(C)cc1

Procedure:
Pentanoyl chloride (39.8 g) in dichloromethane (50 ml) was added slowly to a solution of p-cresol (32.4 g) and triethylamine (36.4 g) in dichloromethane (250 ml) with ice cooling. After 1 hour the reaction mixture was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-methylphenyl pentanoate.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting yellow solution was stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-phenylmethoxycinnamaldehyde (25.3 g, 82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution was stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12N hydrochloric acid (ca. 20 ml). The reaction mixture was diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts were combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo leaving the title compound as a yellow oil (34.8 g, 100%): pmr (CDCl3)δ2.75 (2H, d), 3.45 (2H, s), 3.72 (3H, s), 4.71 (H, m), 5.50 (2H, s), 7.37 (5H, s).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:25]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:26])[CH2:12]2)[O:8][N:7]=1.[ClH:34]>O>[Cl:34][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:25]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:26])[CH2:12]2)[O:8][N:7]=1
Reactant: Cl
Reactant: CCc1ccc(C2CC(c3nc(N)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 332 mg (4.81 mmol) of sodium nitrite in 1.25 ml of water was added dropwise at 0° C. to a solution of 1.60 g (2.40 mmol) of the amine from Example 24A in 60% purity in 25 ml of concentrated hydrogen chloride solution. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for 45 min. The reaction mixture was diluted with 1 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 220 mg (22% of theory)
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]([NH2:12])=[S:11]>>[C:3]([C:2]1[S:11][CH:10]=[N:12][CH:8]=1)([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NC=S
Reactant: CCOC(=O)C(Cl)C=O
Product: CCOC(=O)c1cncs1
Yield: 33 %

Procedure:
According to the procedure of Mashraqui and Keehn (J. Am. Chem. Soc. 1982, 104, 4461), ethyl α-chloro-α-formylacetate was condensed with thioformamide and vacuum distilled to provide 5.65 g (33%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH4+:11].[Mn]([O-])(=O)(=O)=O.[K+]>>[Cl:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1cc(Cl)c([N+](=O)[O-])cn1
Temperature: -33 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To 4-chloro-3-nitropyridine (10.0 g, 63.1 mmol) in 500 ml of liquid ammonium was added potassium permanganate (19.9 g, 126.1 mmol). The reaction was stirred at this temperature (−33° C.) for 5 hours then slowly warmed to room temperature. After evaporation of ammonia, water (1 L) was added. The solid formed was collected by filtration and washed with water (2 L). The solid was extracted with 1:1=DCM:EtOAc (5×500 ml). The solvent was removed and the resulting solid was recrystallized from EtOAc (400 ml) to give the title compound as a yellow solid (4.4 g, 33%). 1H NMR (400 MHz) 8.88 (s, 1H), 7.65 (b, 2H), 6.62 (s, 1H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>O1CCCC1.O>[CH2:13]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([I:3])=[N:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Ic1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.49 g of 95% pure sodium hydride (59.0 mmol) were added in portions to a solution of 12.0 g (49.2 mmol) of 3-iodoindazole in 100 ml of anhydrous tetrahydrofuran under argon. After the mixture had been stirred at room temperature for 45 minutes, 7.02 ml (59.0 mmol) of benzyl bromide were added dropwise. The mixture was stirred overnight at room temperature, and diethyl ether and water were then added. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. The excess benzyl bromide was separated off by bulb tube distillation. The distillation residue gave a product in the form of an oil which gradually crystallized.
Reaction SMILES: [C:1]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([F:13])[F:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([O-:21])([OH:20])=[O:19].[Na+:22].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[F:13][C:11]([F:12])([S:18]([O-:21])(=[O:20])=[O:19])[CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([F:16])([F:15])[F:17].[Na+:22]
Reactant: O=C(OC(=C(F)F)C(F)(F)F)c1ccccc1
Reactant: O=S([O-])O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Reaction time: 65 h
Yield: 43 %

Procedure:
10.0 g of 1,1,3,3,3-pentafluoropropen-2-yl benzoate which had been synthesized by a conventional technique, was dispersed in 72 g of water, after which 12.0 g of sodium hydrogen sulfite and 1.24 g of benzoyl peroxide were added. Reaction occurred at 85° C. for 65 hours. The reaction solution was allowed to cool, after which toluene was added, followed by separatory operation to separate a water layer. A saturated sodium chloride aqueous solution was added to the water layer whereupon white crystals settled out. The crystals were collected by filtration, washed with a small volume of saturated sodium chloride aqueous solution and then dried in vacuum, obtaining the target compound, sodium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate. White crystals, 5.85 g (yield 43%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cccc(O)c2N1
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 2-aminobenzene-1,3-diol (2.00 g, 16.0 mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous DMF (30 mL) was added 2-chloroacetyl chloride (1.81 g, 16.0 mmol). After 16 h, K2CO3 (2.65 g, 19.2 mmol) was added and the reaction mixture was stirred for another 16 h. The mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with water, brine, the combined organic extracts dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography. (1.7 g, yield 65%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:37](N)[CH2:38][NH2:39]>>[NH:22]1[CH2:37][CH2:38][N:39]=[C:21]1[C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=3)[NH:7][C:2](=[O:1])[C:3]2=[CH:20][CH:19]=1
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(C3=NCCN3)ccc12
Temperature: 120 °C
Yield: 81.8 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile (Example 2) (0.03 g, 98.9 μmol), phosphorus pentasulfide (8 mg, 36.0 μmol) and ethane-1,2-diamine (0.5 mL, 7.48 mmol) in a sealed vial was heated at 120° C. for 2 h. At this time, the green/yellow reaction mixture was allowed to cool to room temperature and was then poured onto ice water. The resulting solid was collected by filtration, washed with water and dried in vacuo to afford 6-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (28 mg, 81%) as light yellow solid. 1H NMR (methanol-d4) δ ppm 7.86-7.91 (m, 3H), 7.77-7.84 (m, 3H), 7.44 (d, J=0.8 Hz, 1H), 3.81 (s, 4H). LC-MS calcd. for C17H14F3N4O [(M+H)+] 347, obsd. 347.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)CCCCC>[Pd]>[CH2:11]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC=O
Reactant: COc1nc(C)nc(N)n1
Agent: [Pd]
Solvent: CCCCCCO
Product: CCCCCCNc1nc(C)nc(OC)n1
Yield: 67 %

Procedure:
A 38-mL stainless steel autoclave was charged with 1.40 g (10.0 mmol.) of 2-amino-4-methyl-6-methoxy-1,3,5-triazine, 204 mg of 5-% Pd-carried active carbon, 2.00 g (20.0 mmol.) of 1-hexanal and 15 mL of 1-hexanol. After the inside of the system was fully purged with a nitrogen gas, the reaction was conducted at a reaction temperature of 200° C. for twenty hours and under a hydrogen gas (initial pressure of 50 kg/cm2). After the completion of the reaction, unreacted starting materials were determined. As a result, the conversion ratio of the starting materials was 88.0%. As a result that the reaction product were analyzed, 2-n-hexylamino-4-methyl-6-methoxy-1,3,5-triazine was obtained at a yield of 67.0%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:2][C:3]3[C:4]([CH3:9])=[N:5][O:6][C:7]=3[CH3:8])=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1noc(C)c1CCl
Product: Cc1nc(-n2ccc(OCc3c(C)noc3C)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 10 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)-3,5-dimethylisoxazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 10% yield: 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=8.1 Hz, 1H), 7.41-7.26 (m, 5H), 6.16-6.06 (m, 3H), 4.76 (s, 2H), 4.59 (d, J=5.5 Hz, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H); MS (ES+) m/z 451.1 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[H-].[Na+]>[CH2:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])=[CH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)CCc1c[nH]c2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCc1cn(Cc2ccccc2)c2ccc(I)cc12
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of [2-(5-iodo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 7) (35.0 g, 111.4 mmol) in DMF (250 mL), sodium hydride is added (2.81 g, 117 mmol) at RT in portions during 15 minutes. The mixture is then stirred for another 15 minutes, and then cooled to 4° C. A solution of benzyl chloride (14.1 g, 111.4 mmol) in DMF (50 mL) is added during 20 minutes, and the temperature is maintained during 4 to 8° C. The mixture is left stirring over night, and then most of the solvent is removed on the rotavapor. To the residue is added water (500 mL), and the product is extracted with TBME (2×250 mL). The organic layer is washed with brine (2×250 mL), and after removal of the solvent, 28.5 g of a brown oil is obtained. This is dissolved in ethyl acetate (500 mL) and the product is extracted with 4 N Hcl (550 mL). The product is liberated by adding 30% NaOH to the aqueous layer (300 mL), and re-extracted into ethyl acetate (500 mL). The organic layer is washed with brine (2×250 mL), and the solvent removed to leave 20.2 g of a brown oil which is crystallized from di-isopropyl ether and pentane to give the title product (17.3 g, 38%). Concentrating the aqueous layer of the first gives a precipitate (18.8 g) which is recrystallized from ethyl acetate (250 to give 12.3 g of the N-benzyl ammonium chloride of the target.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:21]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:21])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccccc1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Yield: 60 %

Procedure:
Following the procedure of Preparation I, Part b, but substituting 2.0 gm. (0.0069 mole) of the dimethyl ester of 4-cyano-4-phenylpimelic acid (prepared in Part a, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 45 ml. of the tetrahydrofuran, 1.57 gm. (0.014 mole) of the potassium tert-butoxide, and 10 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm., and the 175 ml., respectively, there is obtained a residue which upon recrystallization from technical hexane gives 1.07 gm. (60% yield) of the desired 2-carbomethoxy-4-cyano-4-phenylcyclohexanone having a melting point at 79.5° to 81.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 2.799999952316284 °C
Reaction time: 0.25 h

Procedure:
Tropine (500 g, 3.54 mol) and triethylamine (590 mL, 430 g, 4.25 mol) were mixed in dichloromethane (10 L) and cooled to <−5° C. under a stream of nitrogen. A solution of methane sulphonyl chloride (329 mL, 487 g, 4.25 mol) in dichloromethane (2 L) was added over 4.33 h between −10.4 and −4.9° C. The mixture was stirred for 15 min, the cooling bath removed, and potassium carbonate solution (2.5 L, GB98596-043)) and deionised water (1.25 L) were added. The additions took 4 min and caused an exotherm raising the temperature to 2.8° C. The mixture was warmed to 15 to 20° C., filtered and the phases allowed to separate. The aqueous phase was extracted further with dichloromethane (2.5 L). The combined organic phases were heated to distil off dichloromethane at atmospheric pressure; 10 L were collected over 1.75 h reaching a base temp. of 42.8° C. and vapour temperature of 42° C. Hexane (7.5 L) was added and after allowing the mixture to cool (overnight) the mixture was filtered and the filtrate returned to a clean flask. The solution was reheated to distil at atmospheric pressure; 7.5 L were collected up to base and vapour temperatures of 60.5 and 62° C. respectively. The mixture was cooled to 0 to 5° C., stirred for 1 h, the product filtered off and washed with hexane (1.5 L). The product was dried under vacuum in a dessicator. Crystallisation from ethyl acetate/hexane or dichloromethane/hexane gave crystalline title compound which was then used in Step 3.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.Cl.C([O-])([O-])=[O:18].[K+].[K+]>>[OH:18][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(CO)c2ccccc12

Procedure:
4-Bromomethylnaphthoic acid (16 g, 160 mmol) in an aqueous solution of K2CO3 (10%, 100 mL) was stirred at 70° C. for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCl. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.Cl[C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.O.[H-].[Na+]>CN(C=O)C>[CH3:30][C@@:28]1([CH2:31][N:13]2[CH2:12][CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[O:29][C:19]2=[N:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][N:20]2[CH2:27]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)Oc1ccc(C2=CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CC=C(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
4-(4-Trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridine (0.985 g, 4.05 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.839 g, 3.86 mmol) were added to DMF (15 ml), and the solution was stirred at 60° C. for 8 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic phases was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford as oil. The oil was dissolved in DMF (20 ml), and sodium hydride (94 mg, 2.35 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (0.192 g, yield 23%) as a light yellow solid.