Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)=C.[Cl-].[NH4+].CON=[C:10]([CH3:23])[CH2:11][CH2:12][CH2:13][C@@H:14]1[O:19][C:18]([CH:21]=[CH2:22])([OH:20])[CH2:17][CH2:16][CH2:15]1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[O:29]1CCCC1>CCOCC.CO>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:22][CH2:21][C@:18]1([OH:20])[CH2:17][CH2:16][CH2:15][C@H:14]([CH2:13][CH2:12][CH2:11][C:10](=[O:29])[CH3:23])[O:19]1)[CH3:25]
Reactant: C=CC1(O)CCC[C@H](CCCC(C)=NOC)O1
Reactant: C1CCOC1
Reactant: CCNCC
Agent: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCN(CC)CC[C@]1(O)CCC[C@H](CCCC(C)=O)O1
Temperature: -57.5 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 9-methoxyimino-5-(S)-hydroxydecanoic acid lactone (144.4 g.) in tetrahydrofuran (850 ml; dry) was cooled under nitrogen in a dry ice-acetone bath to -60°C. A 2.24 molar vinyl magnesium-chloride in tetrahydrofuran solution (159 ml; 70% excess) was added at such a rate that the temperature remained at -50° to -55°C. during 10 min. The reaction mixture was then stirred for an additional 20 min. at -55 to -60°C. after which it was cooled to -70°C. and at this temperature carefully hydrolyzed with methanol (24 ml). The resulting mixture was poured into a mixture of saturated ammonium chloride solution (250 ml), ether (700 ml) and ice (100 g.). The aqueous phase was extracted several times with ether. The ethers were washed with brine and then dried over anhydrous sodium sulfate to give a solution containing 6(S)--(4-methoxyiminopentyl)-2-vinyl-tetrahydropyran-2-ol and its tautomer. Diethylamine (85 ml) was added to this ether solution and the mixture was allowed to stand at room temperature for 1 hr. Filtration and solvent removal affored crude 2(S)-diethylaminoethyl6(S)-(4-methoxyiminopentyl)-tetrohydropyran-2-ol (62.5 g.). This material was dissolved in acetone (850 ml) and treated with 2N sulfuric acid (610 ml) at 0°C. After the reaction mixture was allowed to stand at room temperature for 25 hr, it was concentrated to a volume of 650 ml at 30°C. in vacuo and then extracted with ether. The ether was washed with brine. The aqueous phase was treated with 10N sodium hydroxide solution (155 ml) at 0°C. The resulting mixture was extracted with ether, the ether was washed with brine and then dried over anhydrous sodium sulfate. Filtration and solvent removal afforded pure 2(S)-diethylaminoethyl-6(S)-(4-oxopentyl)-tetrahydropyran-2-ol as a yellow oil (45.5 g.). A sample was chromatographed on aluminum oxide (grade III). Elution with benzene-ether 9:1, 4:1 and 2:1 afforded an analytically pure sample of product as a colorless oil; [α]D 25 -39.91° (C=1.3832 in benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17].C(N(CC)C(C)C)(C)C.[F:27][CH:28]([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([N:14]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:40])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17]
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCN2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N(c2ccccc2Cl)CCC12CCCN2S(=O)(=O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(2-Chlorophenyl)-1,7-diazaspiro[4.4]nonan-6-one (20 mg, 0.00008 mol) was dissolved in DCM. To this solution was added N,N-diisopropylethylamine (DIPEA) (42 μL, 0.00024 mol) and 4-(difluoromethoxy)benzenesulfonyl chloride (21 mg, 0.000088 mol) at 0° C. The solution was allowed to gradually warm to RT while stirring for 18 h. LC-MS: 457.1 (M+1H)+.
Reaction SMILES: C[O-].[Na+].CO.[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8].O[N:17]=[C:18](Cl)[C:19]1[C:20]([CH3:26])=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>C1COCC1>[CH3:26][C:20]1[C:19]([C:18]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:6]([CH:7]([CH3:9])[CH3:8])[O:10][N:17]=2)=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: Cc1ccnc(C)c1C(Cl)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2c(C)ccnc2C)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A 0.5 N solution of sodium methoxide in methanol (2.8 mL, 1.4 mmol) was added to a solution of methyl isobutyrylacetate (0.19 mL, 1.34 mmol) in THF (0.24 mL) at 0° C. A solution of the crude N-hydroxy-2,4-dimethyl-3-pyridinecarboximidoyl chloride (0.22 g, 1.2 mmol) in THF (2.2 mL) was added and the resulting mixture was allowed to warm to room temperature and stir overnight. The solution was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was chromatographed (silica gel, hexane to 3:2 ethyl acetate:hexane) to provide methyl 3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (0.17 g, 52%). ESI-LCMS m/z 275 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.O.[CH2:28]1[O:30][CH2:29]1.C1C[O:34][CH2:33][CH2:32]1>>[OH:34][CH2:33][CH2:32][N:1]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH2:29][CH2:28][OH:30]
Reactant: C1CCOC1
Reactant: C1CO1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Solvent: O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN(CCO)CCO)cc3)cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (step 40.5, 0.5 g, 1.46 mmol) is dissolved in THF (7.5 ml) and water (0.75 ml) and cooled to −10° C. A stream of ethylene oxide is then passed through the solution for about 40 min (amount of ethylene oxide absorbed 5 to 6 g). The flask is sealed and the mixture stirred at 0° C. for 30 min and then at 50° C. for 16 h. The clear yellow solution is cooled and the solvents evaporated. The residue is purified by flash chromatography on 34 g of silica gel. The column is eluted using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:1.25 and ending with 100:2.5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:2.5:0.125 and ending with 100:10:0.5. Fractions containing the title compound were pooled and concentrated on a rotary evaporator. The residue is taken up in a small amount of dichloromethane and the resulting solid collected by filtration; m.p. 194-197° C.; Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.21; MS-ES+: (M+H)+=432.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])#[N:2].[CH3:13]OC(OC)N(C)C>C(Cl)Cl>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1ccccc1C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccccc1CC#N
Reaction time: 38 h

Procedure:
With gentle heating, 175 g (1.08 mol) of 2-cyanomethyl-benzoic acid (for preparation see: Org. Synthesis, Coll, Vol. 3,174) are dissolved in 1.7 liters of CH2Cl2; 242 ml (=90%, 1.6 mol) of dimethylformamide dimethylacetal are added dropwise at room temperature, and stirring is carried out for 38 hours to complete the reaction. The reaction mixture is washed with 2×1.2 liters of saturated NaHCO3 solution and brine. The aqueous phases are extracted using 2 portions of CH2Cl2, and the organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; ethyl acetate/hexane 1:4, applied in ethyl acetate/hexane/CH2Cl2) yields the title compound: m.p. 49-50° C.; 1H NMR (DMSO-d6) 7.96 (d, 1H), 7.66 (t, 1H), 7.57 (d, 1H), 7.51 (t, 1H), 4.26 (s, 2H), 3.86 (s, 3H); Anal. calc. (C10H9NO2) C 68.56%, H 5.18%, N 8.00%; found C 68.5%, H 5.1%, N 7.9%.
Reaction SMILES: O.[C:2]([O:6][C:7]([N:9]1[CH2:14]CC(=O)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CI.[CH3:18]C(C)([O-])C.[Na+].[O:24]1[CH2:28][CH2:27][CH2:26]C1>>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][C:28](=[O:24])[C:27]([CH3:26])([CH3:18])[CH2:14]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a dry, 2 L 2-neck, round-bottom flask equipped with a magnetic stirrer, a condenser, and a large 10° C. water bath was added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (125 g, 628 mmol) and anhydrous tetrahydrofuran (1 L). To the resulting yellow solution was added methyl iodide (85 mL, 1365 mmol). Sodium t-butoxide (150 g, 1560 mmol) was then added portionwise over 30 minutes. An exotherm was detected, especially at the beginning of the addition. The reaction mixture did warm to a gentle reflux, the rate was controlled by the speed of addition of base. The mixture was stirred an additional 30 minutes. The solvent was removed in vacuo. The oily residue was treated with NH4Cl/water (500 mL), and extracted with ether (3×200 mL). The combined organics were washed with brine, dried over Na2SO4, and filtered through a short plug of silica gel. The solvent was removed in vacuo, and the resulting yellow oil had started to ccrystallize. It was left under high vacuum overnight. The mixture was slurried in hexane (50-100 mL) and sonicated for one minute. The yellow solid was collected by filtration and washed with hexane (100 mL). The first crop of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester yielded a yellow solid. (See, preparation of (37) in Vice, S. et al., J. Org. Chem., 66:2487-2492 (2001).)
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1cnc2ccc(C3(O)CCC(=O)CC3)cc21
Product: Cn1cnc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-methyl-3H-benzoimidazol-5-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Li]CCCC.[CH2:12]([O:14][CH2:15][C:16](OCC)=[O:17])[CH3:13]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:16]([CH2:15][O:14][CH2:12][CH3:13])=[O:17])=[N:5][N:6]=1
Reactant: Cc1nnco1
Reactant: CCOCC(=O)OCC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOCC(=O)c1nnc(C)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-methyl-1,3,4-oxadiazole (5.0 g, 59.5 mmol) in THF (100 mL) was added dropwise n-BuLi (23.79 mL, 59.5 mmol) in toluene under N2 at −78° C. After 1 h, ethyl ethoxyacetate (10.22 g, 77 mmol) was added. The reaction mixture was then allowed to warm to −40° C. and stirred for 2 h. The reaction mixture was then quenched with 65 mL of LON HCl and extracted with EtOAc. The organic layer was washed with water and then brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified on a flash chromatography column (Biotage™-40M) using a gradient of 0-100% of n-hexane/Et2O to give the desired product. 1H NMR (500 MHz, CD3OD): δ 1.27 (t, 3H), 2.64 (s, 3H), 3.69 (q, 2H), 4.88 (s, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37].O>CN(C=O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(CCCCl)Cc1ccccc1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN(C)Cc3ccccc3)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry DMF (100 ml) and N-(3-chloropropyl)-N-methylbenzylamine hydrochloride (4.1 g, 16 mmol) added. The temperature was raised to 90° and the mixture stirred for 2 hours, then poured into water and extracted with ethyl acetate. Drying, evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-benzyl-N-methylamino)propoxy)quinoline (0.7 g, 15%), m.p. 100°-102°.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]([NH:14][C:15](=[O:52])[C@H:16]([CH:49]([CH3:51])[CH3:50])[CH2:17][C@H:18]([OH:48])[C@@H:19]([NH:40]C(OC(C)(C)C)=O)[CH2:20][C@@H:21]([CH:37]([CH3:39])[CH3:38])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:24]=1)([CH3:13])[CH3:12])(=[O:10])[NH2:9].[OH-].[Na+].[Cl:55]CCl>>[ClH:55].[C:8]([C:11]([NH:14][C:15](=[O:52])[C@H:16]([CH:49]([CH3:51])[CH3:50])[CH2:17][C@H:18]([OH:48])[C@@H:19]([NH2:40])[CH2:20][C@@H:21]([CH:37]([CH3:39])[CH3:38])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:24]=1)([CH3:13])[CH3:12])(=[O:10])[NH2:9]
Reactant: ClCCl
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.5 ml of trifluoroacetic acid are added to 56 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-(1-carbamoyl-1-methyl-ethyl)]-amide in 1.5 ml of dichloromethane at 0° C. The mixture is stirred for a further 30 minutes at 0° C. The reaction mixture is poured onto cooled 1N sodium hydroxide and the product is extracted repeatedly with dichloromethane. The organic phases are dried, and ethereal hydrochloric acid is added. Concentration by evaporation yields the title compound: Rf (dichloromethane/methanol=8:2)=0.30; HPLC Rf =11.25; FAB-MS (M+H)+ =538.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6]1)=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C(OCC)(=O)CC>O.CO>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]2[C:4](=[O:5])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:6])[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: O=C1OCc2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Sodium methoxide solution (27% in methanol, 400 g, 2 mol) was added over 40 minutes at 20–30° C. to a stirred mixture of phthalide (67 g, 0.5 mol), 3-nitrobenzaldehyde (75.5 g, 0.5 mol), ethyl propionate (250 ml) and methanol (150 ml). The mixture was stirred at ambient temperature for 15 minutes then it was heated under reflux for 2.5 hours, cooled to ambient temperature and poured into water (2300 ml). The aqueous mixture was washed with ether (5×500 ml) then acetic acid (60 ml) was added. The resulting solid was collected by filtration, washed with water (200 ml) and dried in vacuo to give 2-(3-nitrophenyl)indan-1,3-dione (87.92 g) as a dark red-brown solid, m.pt. 216–226° C., which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCN([C:24]2[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][CH:28]=2)CC1.C(OC1C=CC(NN)=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)(=O)C.C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:24]3[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][C:28]=3[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C=C1CCC=C1N1CCOCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C1CCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, and a nitrogen inlet was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 mole equiv.), ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (22.02 kg, 1.104 mole equiv.), ethanol (51.2 kg, 2.429 mass equiv.), and acetic acid (36.8 kg, 1.746 mass eq.). After the reactor contents are allowed to stand for 10 minutes, agitation and then heating to 60° C. to 65° C. (60° C. target) was started. While stirring at that temperature, samples of the reaction mixture were taken over intervals of approximately 30 minutes and analyzed by HPLC for (4-(benzyloxy)phenyl)hydrazine, ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When (4-(benzyloxy)phenyl)hydrazine HPLC % area was <1, TFA (11.6 kg, 101.7 mol, 1.200 mole equiv., 0.550 mass equiv.) was charged over approximately 1 hour while the stirred reaction mixture was maintained at 60° C.±5° C. with reactor jacket cooling. As stirring at 60° C. to 65° C. was continued, the hydrazone and imine content of the reaction mixture was monitored by HPLC. After stirring at 60° C. to 65° C. for at least 12 hours the imine content of the reaction mixture was <5% area by HPLC, and the stirred reaction mixture was cooled to 20° C. to 25° C. over approximately 3 hours. Stirring was maintained at that temperature to allow isomerization of the Z isomer to the desired E isomer. The E isomer crystallizes from the reaction mixture. The Z isomer and E isomer % area content of the reaction mixture was monitored by HPLC during this period of stirring at 20° C. to 25° C., which was continued until the Z-isomer content of the reaction mixture was <15% area by HPLC.
Reaction SMILES: [ClH:1].COC1C=C2C(=CC=1OC)C([CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])C2.COC1C=C2C(=CC=1OC)C(CNC)C2.[CH3:51][O:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][C:61]=1[O:62][CH3:63])[CH2:58][CH:57]([CH2:64]CNC)[CH2:56]2>>[ClH:1].[CH3:63][O:62][C:61]1[CH:60]=[C:59]2[C:55](=[CH:54][C:53]=1[O:52][CH3:51])[CH2:56][CH:57]([CH2:64][CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:58]2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: CNCCC1Cc2cc(OC)c(OC)cc2C1
Agent: CNCC1Cc2cc(OC)c(OC)cc21
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CCC1Cc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by [2-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)ethyl]methylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:19].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:19]
Reactant: COC(=O)CCCCCSc1ccc(Cl)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCS(=O)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexanoic acid methyl ester (2.5 g, 9.2 mmol) in methanol (100 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (2.6 g, 12 mmol) in distilled water (30 mL). The mixture was heated at 60° C. for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:1 to 8:2 ethyl acetate:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (2.0 g, 76%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1(C)C=CC=CC=1.CCCCCC>[I:36][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: II
Reactant: CC(C)CCCC(C)CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCI
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a stirring solution of 43 (5 g, 32 mmol), imidazole (2.59 g, 38 mmol, 1.2 eq) and triphenylphosphine (9.11 g, 35 mmol, 1.1 eq) in toluene (100 ml) under nitrogen was added iodine (10.44 g, 41 mmol, 1.3 eq). The reaction mixture was stirred for 18 hours then filtered. The filtrate was washed with 5% sodium thiosulfate solution (3×100 ml) then dried (Na2SO4) and concentrated in vacuo to give a white solid. This solid was taken up in hexane (20 ml), cooled and filtered. The filtrate was then concentrated in vacuo to give 45 (6 g, 71%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:17]1=[O:36])[CH2:13][CH2:14][CH3:15]>CS(C)=O>[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:4]([C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[O:6][N:34]=2)[C:17]1=[O:36])[CH2:13][CH2:14][CH3:15]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)c1c(F)cccc1Cl
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3c(F)cccc3Cl)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 5.2 %

Procedure:
2-Chloro-6-fluorobenzoic acid (44 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (6.4 mg, 5%).