Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]([O:22]CC)=[O:21])[O:11][C:10]1([CH3:26])[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[C:1]([N:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]([OH:22])=[O:21])[O:11][C:10]1([CH3:26])[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H](C(=O)O)[C@H](c2ccccc2)N1C(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
(4S-trans)-3-Benzoyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid, ethyl ester (1.56 g) was dissolved in THF (10 ml) at room temperature and LiOH (4.63 ml, 1M in H2O) was added dropwise. Initially, a bi-phasic mixture was observed, but after the addition of the last quantity of LiOH and stirring for 5 minutes the solution became homogeneous. After further stirring for ½ hour, the reaction mixture was quenched with aqueous 1N HCl (4.63 ml), and diluted with EtOAc and saturated NaCl. The H2O layer (pH=3) was twice extracted with EtOAc, and the combined organic phase dried with MgSO4. The solvent was removed in vacuo to give 1.39 g of the title product acid (97%) which was homogeneous by TLC and 1H NMR.
Reaction SMILES: O=[C:2]1[CH2:13][O:12]CC(=O)[NH:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:12]1[NH:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3][CH2:2][CH2:13]1
Reactant: O=C1COCC(=O)NCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCNOCCN1
Temperature: 25 °C

Procedure:
A suspension of 5.0 g. of the diamide obtained in Example 44 in 100 ml. hot anhydrous tetrahydrofuran and 4.8 g. LiAlH4 while stirring over a period of one hour. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for eighteen hours. After cooling to room temperature the excess reagent is destroyed by adding a mixture (15 ml.) of water and THF (1.2) followed by 5 ml. NaOH 15% and 15 ml. water. The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and after recrystallization from hot benzene/heptane the desired product is obtained.
Reaction SMILES: Cl.N1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[NH2:30].COC(OC)(OC)CCC>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[N:30]=[C:3]1[CH2:4][CH2:5][CH3:6]
Reactant: c1ccncc1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCCl
Yield: 219.3 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (4.2 g, 36.4 mmol) was added in small amounts to a solution of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine (32.4 g, 97.0 mmol) in toluene (500 mL). Trimethylorthobutyrate (17 mL, 107 mmol) was then added, and the reaction was heated at reflux for two hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL). The solution was washed with water (3×80 mL) and brine (1×40 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an oil, which was dissolved in hexanes (20 mL) and concentrated under reduced pressure to provide an off-white solid. The crude solid was purified by column chromatography on silica gel (eluting with 2:1 hexane:ethyl acetate) to provide 30.8 g of 1-(5-chloropentyl)-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine as white crystals.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16]C(C)(C)C)(=[O:15])[CH3:14].[CH:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[NH4+].[F-]>CCCCCC.C(OCC)C>[OH:26][C@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][C:13]([OH:16])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)CC=O
Agent: [F-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](O)CC(=O)O
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
4.4 ml of 1.6M butyllithium in hexane are added under argon and at -25° C. to a solution of 1.12 ml of diisopropylamine in 15 ml of anhydrous diethyl ether (ether). After 25 minutes at -20° C., the mixture is cooled to -78° C. and 805 μl of tert-butyl acetate are added dropwise in the course of 10 minutes by means of a syringe. After stirring for 45 minutes at -78° C., a freshly prepared solution, precooled to -78° C., of 4.9 g of [(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-bis-(diphenylmethoxy)]-cyclopentadienyltitanium chloride (according to Example 2a) in approx. 100 ml of ether is added via a cannula in the course of 15 minutes. The mixture is stirred for 30 minutes at -78° C. and for 3 hours at -30° C. and cooled to -78° C. and 650 μl of isovaleraldehyde are added by means of a syringe in the course of 5 minutes. After 2 hours at -78° C., 20 ml of 45% NH4F solution are added and the mixture is warmed to room temperature. After stirring for 17 hours it is filtered, 10 ml of saturated sodium chloride solution are added to the filtrate and the mixture is extracted with three times 100 ml of ether. The organic phases are washed with saturated NaCl solution and 1N Hcl, dried (MgSO4) and evaporated. The residue (5.1 g) is stirred in 6 ml of 2N sodium hydroxide solution and 12 ml of methanol for 2 hours at 50° C. After the methanol has been removed by evaporation in vacuo, the residue is extracted with three times 50 ml of ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with three times 100 ml of ethyl acetate. The ethyl acetate phases are washed with twice 50 ml of saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue, 835 mg of 1-(R)-3-hydroxy-5-methylhexanoic acid of 78% optical purity, is recrystallized twice from cyclohexane (60 ml and 150 ml). Yield: 595 mg of product of 96% optical purity, melting point 86° C.; [α]D =-14.7° (c=1, CHCl3). (+)-(R)-Ipsenol can be prepared from this by the instructions in EP-A 0,254,685 (Example 41d to 41g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:24])[C:14]=1B1OC(C)(C)C(C)(C)O1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][C:27]=1[F:36].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:24][C:13]1[CH:12]=[C:4]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][O:8][CH2:7]2)[CH:3]=[C:2]([F:1])[C:14]=1[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][C:27]=1[F:36]
Reactant: CC1(C)OB(c2c(F)cc(OC3CCCOC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Temperature: 120 °C

Procedure:
A mixture of 3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]tetrahydro-2H-pyran (0.436 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL) and water (0.3 mL) was purged with nitrogen and then bis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added. The reaction mixture was sealed and heated at 120° C. for 40 min., then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]([C:30]2[CH:35]=[CH:34][C:33](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:32]([N+:47]([O-:49])=[O:48])[CH:31]=2)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[CH3:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>C(OCCCC)(=O)C>[N+:47]([C:32]1[CH:31]=[C:30]([C:21]([C:6]2[CH:7]=[CH:8][C:9]([N:51]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH3:50])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:29])[F:27])[CH:35]=[CH:34][C:33]=1[N:51]([CH3:50])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O-:49])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(c3ccc(OS(=O)(=O)c4ccc(C)cc4)c([N+](=O)[O-])c3)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])cc1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: CCCCOC(C)=O
Product: CN(Cc1ccccc1)c1ccc(C(c2ccc(N(C)Cc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
3 g (4.08 mmol) of 2,2-bis-(3-nitro-4-tosyloxyphenyl)hexafluoropropane was dissolved in 70 ml of butyl acetate, followed by moderately heating and refluxing. Then 5.26 ml (40.8 mmol) of n-methylbenzylamine was added dropwise into the solution, and after heating and refluxing were continued for 12 hours, the solution was cooled to room temperature. After 20 ml of dilute hydrochloric acid was added and extraction with ethyl acetate was carried out two times, an organic layer was washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and saturated brine. After the washed organic layer was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained liquid product was separated by silica gel chromatography (hexane/ethyl acetate=4/1, hexane/dichloromethane=1/1) to obtain 2.1 g (yield: 81%) of 2,2-bis-[3-nitro-4(N-methyl-N-benzylamino)phenyl]hexafluoropropane in the form of yellow solid.
Reaction SMILES: [NH2:1][C:2](=[N:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[C:7]1([S:4]([CH2:3][C:2]2[N:1]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[NH:14][N:13]=2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccc(F)cc1F
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2ccc(F)cc2F)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
8.0 g (0.023 mol) 2,4-Difluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide were heated at 210° C. for 20 minutes. The molten mass was then cooled, dissolved in 30 ml hot ethanol and stirred overnight at room temperature. The precipitated crystals were filtered off and dried to yield 5.35 g (71%) 3-benzenesulfonylmethyl-5-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole as white solid, MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)C.[N+:15]([CH3:18])([O-:17])=[O:16]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[N+:15]([O-:17])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1/C=C/[N+](=O)[O-]
Temperature: 140 °C
Yield: 64.9 %

Procedure:
Under an atmosphere of nitrogen was added to a solution of 4-chloro-2-methylbenzaldehyde (10.0 g, 64.9 g) in acetic acid (70 mL) ammonium acetate (11.5 g, 149 mmol) and nitromethane (10.0 ml, 185 mmol). The solution was stirred at reflux (oil bath 140° C.) for 2 h. After cooling to ambient temperature water (70 mL) was added and extracted twice with ethyl acetate (70 mL). The organic layers were washed with water (70 mL) and brine (70 mL) and were dried over sodium sulfate. The filtrated was concentrated and the resulting solid was suspended in methanol (30 mL), at 0° C. filtered off and was washed with cold methanol (10 mL) affording the title compound (8.30 g, 65%) as a yellow solid. MS m/e: 197.0 [M]+.
Reaction SMILES: [C-:1]1([C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].P(Cl)(Cl)[Cl:19]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]([CH3:11])([CH3:10])[C:7]([Cl:19])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17]
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C(=O)O)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C(=O)Cl)[c-]1cccc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 2-ferrocenyl-2-methylpropionic acid (7.55 g) and pyridine (15 drops) in 500 cm3 of dry benzene was slowly added 25 cm3 of phosphorous trichloride. The resulting mixture was stirred for 3 h at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The red-brown viscous residue obtained was twice more evaporated from dry benzene to give 6.91 g (85%) of 2-ferrocenyl-2-methylpropanoyl chloride, a red brown solid, which was recrystallised from light petroleum (40° to 60° C.). The ferrocenyl acid chloride (6.91 g) was dissolved in 10 cm3 of dichloromethane and added to a mixture of 6-aminopencillanic acid (5.18 g) and triethylamine (4.85 g) in 100 cm3 of dichloroethane at 2° C. The resulting mixture was stirred for 1 hour at 15° C., filtered and filtrate evaporated cold `in vacuo`. The residue was dissolved in a mixture of water and ethyl acetate and the aqueous phase adjusted to pH 2.5 with 2M HCl. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts of ethyl acetate were washed several times with water, dried and filtered. To the dry ethyl acetate solution was added 10 cm3 of a 40% solution of sodium 2-ethylhexanoate in 4-methylpentan-2-one. The mixture was concentrated under vacuum and then poured into 600 cm3 of dry ether. The product, which separated as a pale yellow solid, was collected by filtration and dried to yield 8.43 g (72%) of the penicillin. The i.r. spectrum showed a strong β-lactam carbonyl absorption at 1760 cm-1. A thin layer silica gel chromatogram (chloroform/acetone/acetic acid) showed a single substance.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC([NH:26][C:27]1[N:42]=[CH:41][C:30]2[N:31]([CH:38]([CH3:40])[CH3:39])[C:32]3[C:37]([C:29]=2[C:28]=1[CH2:43][CH3:44])=[CH:36][CH:35]=[CH:34][CH:33]=3)=O>>[NH2:26][C:27]1[N:42]=[CH:41][C:30]2[N:31]([CH:38]([CH3:40])[CH3:39])[C:32]3[C:37]([C:29]=2[C:28]=1[CH2:43][CH3:44])=[CH:36][CH:35]=[CH:34][CH:33]=3
Reactant: CCc1c(NC(=O)OCC[Si](C)(C)C)ncc2c1c1ccccc1n2C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCc1c(N)ncc2c1c1ccccc1n2C(C)C
Temperature: 50 °C
Yield: 67.1 %

Procedure:
Tetrabutylammonium flouride (1M in THF, 5 ml, 5 mmol) was added to 3-[2-(trimethylsilyl)ethoxycarbonylamino]-4-ethyl-9-isopropyl-9H-pyrido[3,4-b]indole (Method 4; 80 mg, 0.2 mmol) and the mixture was heated to 50° C. for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with water. The organic phase was separated, dried and evaporated in vacuo. The crude product was purified by flash eluting over a gradient of 0-2.5% MeOH in DCM. The product was obtained as a light brown solid (34 mg) after evaporation of the appropriate fractions. NMR (300 MHz, CDCl3) 8.40 (s, 1H), 8.16 (d, 1H), 7.48 (m, 2H), 7.18 (t, 1H), 4.91 (m, 1H), 3.13 (q, 2H), 1.69 (d, 6H), 1.40 (t, 3H); m/z 255.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10].S(=O)(=O)(O)O>>[C:9]([OH:12])(=[O:11])[CH3:10].[C:9]([OH:12])(=[O:11])[CH3:10].[SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(S)cc1
Product: CC(=O)O
Temperature: 100 °C

Procedure:
126.17 grams (1 mole) of p-mercaptophenol is added into 714.6 grams of acetic anhydride with 5 cc. of sulfuric acid. After the resulting mixture is heated at 100° C. for 2 hours, it is allowed to cool and is poured into 3 l. of water in order to precipitate the product. The solid is filtered, recrystallized from 3.5 l. of hexane and dried overnight at 100° C. to yield 198.5 grams of 4-mercaptophenol diacetate which has a melting range of 73-75° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:15]=[C:14]2[C:8]([CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=32)=[CH:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[C:8](=[CH:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[CH:15]=3)[CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[CH:19]=1
Reactant: N
Reactant: CCOC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Product: NC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 2.3 g (6.5 mmole) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca 20% v/v) was heated in an autoclave on a steambath overnight. The solvent was removed at reduced pressure to give a light yellow solid. Recrystallization from ethanol-hexane gave a white solid, mp 236°-237°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Li+].[OH-]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)[CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(=O)c1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Hydrolysis of ethyl 2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate with LiOH as per general procedure H afforded after a standard aqueous workup the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N+:11]([O-:24])[C:12](Cl)=[C:13]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH2:34]([O:41][C:12]1[C:13]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:25][CH:26]([CH3:28])[CH3:27])[N+:11]=1[O-:24])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)Cc1c(OCc2ccccc2)nc(COC2CCCCO2)c(Cl)[n+]1[O-]
Reactant: OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Cc1c(OCc2ccccc2)nc(COC2CCCCO2)c(OCc2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
There was stirred, for 40 minutes at room temperature, a mixture of 170 mg of 3-benzyloxy-6-chloro-2-isobutyl-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide, 72 mg of tetrabutylammonium bromide, 1.5 ml of dry dimethylformamide, 230 μl of benzyl alcohol and 42.5 mg of 60% sodium hydride. The reaction mixture was stirred at room temperature for 40 minutes, diluted with diethyl ether, then the mixture was washed with water several times and dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by a silica gel thin layer chromatography (developing solvent: 10% by volume of ethyl acetatebenzene) to obtain 136 mg of 2,5-dibenzyloxy-6-isobutyl-3-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide (Compound B-14) as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:24])/[CH2:16][O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1>C(OCC)(=O)C.C(N(CC)CC)C>[C:28]([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17][CH2:16]/[C:15](/[CH3:24])=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)COCC(C)(C)CO
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 60.9 %

Procedure:
In 50 ml of ethyl acetate was dissolved 9.2 g of 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropanol, and one drop of triethylamine was added to the resulting solution. To the solution was added dropwise a mixture of 3.1 g of diketene and 9.2 ml of ethyl acetate under reflux over one hour, and the resulting mixture was then subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Merck Silica Gel, 70-230 mesh, eluant: toluene:ethyl acetate (4:1 by volume)] to obtain 7.05 g (yield 60.8%) of oily 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl acetoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[CH3:11].CS[C:16]1[N:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:19][N:20]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:24][O:23][C:21]([N:17]1[CH2:18][CH2:19][NH:20][C:16]1=[N:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[NH:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11])=[O:22]
Reactant: Cc1c(N)cc(C#N)c2nc[nH]c12
Reactant: COC(=O)N1CCN=C1SC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)N1CCNC1=Nc1cc(C#N)c2[nH]cnc2c1C
Temperature: 85 °C
Yield: 75 %

Procedure:
A mixture of 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile (10) (22.3 g, 0.13 mol), 4,5-dihydro-2-(methylthio)-1H-imidazole-1-carboxylic acid, methyl ester (29) (27.1 g, 0.155 mol) and glacial acetic acid (223 mL) is heated to about 85° C. for about 3 hours. The reaction mixture is allowed to cool to ambient temperature and is then concentrated in vacuo. At ambient temperature, water (223 mL) is then added to the oily residue obtained, and the pH of the resultant solution is adjusted to about 8.1 with 6N aqueous NaOH. The solids that formed are filtered, washed with water (75 mL), and dried to provide 2-(7-Cyano-4-methyl-1H-benzimidazol-5-yl-imino)-imidazolidine-1-carboxylic Acid Methyl Ester (30) (29.1 g, 75% Yield), as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[N:21]OC)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1>[Pd].CO>[F:20][C:17]([F:18])([F:19])[CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:13][N:12]=1)[NH2:21]
Reactant: CON=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Pd]
Solvent: CO
Product: NC(CCC(F)(F)F)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a hydrogen atmosphere, a mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-N-methoxybutan-1-imine (169.5 mg), palladium on carbon (263 mg) and methanol (1.648 mL) was stirred at room temperature overnight. The insoluble material was filtered off through celite, the filtrate was washed with 1M aqueous sodium hydroxide solution and saturated brine, and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step F without further purification.