Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl-:17].[Cl-].IC1C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[Cl:17]
Reactant: [Cl-]
Reactant: CC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Product: CC(=O)c1ccc(N)c(Cl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
A mixture of p-aminoacetophenone (20 g), pyridine (11.7 g), and iodobenzene dichloride (40 g) in tetrahydrofuran (300 ml) was stirred for 5 hours at 0° C. The insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from ethanol to give colorless crystals of 4'-amino-3'-chloroacetophenone (20.1 g).
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25]C(C(O)=O)=[CH:20][N:19]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25][C:6]([C:7]([Cl:9])=[O:8])=[CH:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reaction time: 0.25 h

Procedure:
N,N-Dimethylformamide (1 mL) was slowly added to a solution of oxalyl chloride (0.13 g, 1 mmol) in chloroform (5 mL). 6-Morpholinonicotinic acid (0.21 g, 1 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was concentrated under vacuum, diluted with toluene and then concentrated under vacuum to provide 6-morpholinonicotinoyl chloride. This material was kept under vacuum at ambient temperature overnight and then used in the next step.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH4:13]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:13]2[O:4][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]2[OH:10])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C
Product: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
Forty parts by weight of "PINE-DEX #4", a reducing partial starch hydrolysate having an average dextrose equivalent (DE) of 19±1 and an average DP of about 5, prepared by hydrolysing starch, purifying and pulverizing the resultant, available from Matsutani Chemical Ind., Co., Ltd., Kyoto, Japan, was dissolved by heating in 60 parts by weight of water, and the resultant solution was heated to 45° C., adjusted to pH 6.5, mixed with one unit/g reducing partial starch hydrolysate of a non-reducing saccharide-forming enzyme prepared by the method in Experiment 1-1, and incubated for 96 hours, followed by heating the resultant mixture at 100° C. for 10 min to inactivate the remaining enzyme. The solution thus obtained was diluted to give a concentration of about 20%, d.s.b., mixed with 10 units/g reducing partial starch hydrolysate of "GLUCOZYME", a glucoamylase specimen commercialized by Nagase Biochemicals, Ltd., Kyoto, Japan, and incubated for 40 hours, followed by heating the resultant mixture to inactivate the remaining enzyme. The solution thus obtained was in usual manner decolored with activated charcoal, desalted with ion-exchange resins, and concentrated into an about 60% solution containing 29.5% trehalose, d.s.b. The concentrated solution was fed to a jacketed-stainless steel column packed with "CG 6000, Na-form", a strong acidic cation exchange resin commercialized by Japan Organo, Co., Ltd., Tokyo, Japan, and fractionated at 60° C. and SV (space velocity) 0.4, followed by recovering a high trehalose content fraction containing about 90% trehalose, d.s.b. The fraction was concentrated into an about 75% w/w % solution, which was then transferred to a crystallizer, mixed with an about 2% hydrous crystalline trehalose as seed crystal, heated to 50° C., gradually cooled to 25° C. under gentle stirring conditions, and separated by a basket-type centrifuge. The resultant crystals were washed by spraying with a small amount of water to obtain a high-purity hydrous crystalline trehalose with a purity of 99% or higher, d.s.b.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:1])[CH:17]=1)=[O:12]
Reactant: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium carbonate (140 mg, 0.98 mmol) and methyl iodide (0.06 mL, 0.98 mmol) were added under ice cooling to 2-bromo-3-(1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.33 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (5 mL), and the whole was stirred for 2 hours. The reaction mixture was warmed to room temperature, added with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 2-bromo-3-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (99 mg, 95.1%) as red solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: Clc1ccc(Br)cc1Cc1ccc(OC2CCCC2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 40.0 g 4-(5-bromo-2-chloro-benzyl)-phenol and 71.0 g cesium carbonate in 300 mL ethanol are added 23 mL iodocyclopentane. The mixture is stirred at 60° C. over night and then cooled to ambient temperature. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1→10:1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:28][OH:29]>C(O)C>[OH:29][NH:28][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)[CH2:24][CH2:23]1)=[NH:26]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=N)NO)CC3)cc2)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarbonitrile (60 mg, 0.16 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol) in ethanol (5 mL) was heated at 80° C. for 2 h, then cooled to ambient temperature overnight. The mixture was concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 60 mg (93%) of N-hydroxy-4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboximidamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (m, 2H), 7.87 (m, 2H), 7.69 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 3.91 (d, 2H, J=6.0 Hz), 3.84-3.74 (m, 2H), 3.22 (s, 3H), 3.02-2.96 (m, 2H), 2.05 (bs, 2H), 1.86-1.76 (m, 2H), 1.36-1.22 (m, 2H); LRMS (ESI), m/z 404 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[N:42]1([CH2:48][CH2:49][CH2:50][C:51](O)=[O:52])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[ClH:41].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
5.0 g. (14.6 mmoles) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran, 3.14 g. (15.2 mmoles) of dicyclohexylcarbodiimide and 3.15 g. (15.2 mmoles) of γ-piperidinobutyric acid hydrochloride (m.p. 190°-192°), Cruickshank & Sheehan J. Am. Chem. Soc. 83, 2891 (1961), were combined with 250 ml. of methylene chloride and stirred for a total of 40 hours at room temperature. The insoluble by-product of dicyclohexylurea was separated by filtration and the methylene chloride was removed using a rotary evaporator. The brown residue was treated with approximately 75 ml. of benzene, and filtered to remove a small amount of insoluble material. The benzene was evaporated and the brown, viscous residue was triturated with about 200 ml. of ether to give 4.3 g. of crude product as a light brown solid, m.p. 174°-176°C. Recrystallization from benzene gave a total of 3.5 g. (45%) of product as colorless crystals, m.p. 174°-176°C. The infrared and nuclear magnetic resonance spectra were in agreement with the proposed structure.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=O)[CH3:10].[O-:12][C:13]#[N:14].[Na+].Cl[O-].[Na+]>C(O)(=O)C.O>[CH3:9][C:10]1[NH:14][C:13](=[O:12])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CC=O
Reactant: NNc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
In a 50 gallon reactor, a stirred solution of 12 pounds (0.111 lb mole) of phenylhydrazine in 115 pounds of glacial acetic acid was cooled to about 5° to 10° C., and a solution of 5.2 pounds (0.087 lb mole) of acetaldehyde in 6.1 pounds of acetic acid was added at a rate that maintained the reaction mixture temperature at about 12° to 15° C. The complete addition required about five minutes. Immediately upon completion of addition, a cold solution (about 15° C.) of 7.6 pounds (0.117 lb mole) of sodium cyanate in 72 pounds of water was added at a rate that maintained the reaction mixture temperature at about 8° to 12° C. The complete addition required about 30 minutes. Upon completion of addition, the reaction mixture was stirred for 20 minutes and then was warmed to about 20° C. A solution of 13.3 pounds (0.179 lb mole) of sodium hypochlorite in 119.7 pounds of water was then added at a rate that maintained the reaction mixture temperature at 25° to 40° C. The complete addition required about one hour. Upon completion of addition, the reaction mixture was stirred for about one hour, and then about 220 pounds (approximately 72%) of the acetic acid/water solvent was removed by distillation under vacuum (50 mm Hg). Water, 82 pounds, was added, and the resultant slurry was cooled to 25° C. The product was isolated by centrifugation and washed on the centrifuge with water. The product was dried at 70° C. under vacuum, yielding 14.8 pounds of 84.4% pure 4,5-dihydro-3-methyl-1-phenyl-1,2,4-triazol-5(1H)-one (64.2% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([F:38])[CH:17]=1.CCCCCC>C(#N)C.C(OCC)C>[F:38][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:37]=[CH:36][C:19]=1[O:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH:22]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCOCC3)ncn2)c(F)c1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCOCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
2-Phenylacetyl chloride (0.064 ml) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (94.8 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then a solution of morpholine-4-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl}amide (65.0 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:4). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (3 ml)-hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (54.4 mg, 54.6%) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[H-].[Na+].[C:14](OCC)(=O)[CH2:15][CH2:16][CH3:17].Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:14]([CH2:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCCC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(=O)c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2'-hydroxy-5'-fluoroacetophenone (2 gm) in tetrahydrofuran (10 mL) was added dropwise to sodium hydride (600 mg), then ethyl butyrate (10 mL) was added. After 30 minutes, aqueous 1N HCl (50 mL) was added, and the mixture extracted with ethyl acetate, and the extracts washed with H2O, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (7 mL) added, and after stirring overnight at room temperature, dichloromethane and saturated aqueous NaHCO3 were added, and the layers separated. The organic layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 6-fluoro-2-propyl-4H-1-benzopyran-4-one (2.4 gm, Rf=0.4 1:1 diethyl ether/hexanes). This compound (9 gm) was dissolved in ethanol (250 mL) and sodium borohydride (1.6 gm) added, and the mixture heated under reflux. After 3.5 hours additional sodium borohydride (1.6 gm) added, and after 7 hours a further addition of sodium borohydride (1.6 gm) was made. After 10 hours more sodium borohydride (0.8 gm) was added and after 23 hours total reaction time the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 4-hydroxy-2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one (Rf=0.4 1:1 diethyl ether/hexanes). This material (10.8 gm) was dissolved in acetic acid (45 mL) and a solution of chromium trioxide (7.8 gm) in acetic acid (45 mL)/H2O (10 mL) was added dropwise. After one hour, the mixture was poured into ice/H2O (1 L) and extracted with ethyl acetate. The extracts were washed with H2O, saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield the title compound (7.4 g, Rf=0.7, 1:1 diethyl ether/hexanes).
Reaction SMILES: [Cl-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]([CH3:5])=[O:4].[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3[CH:40]=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3/[CH:40]=[CH:2]/[C:3](=[O:4])[CH3:5])[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.3 g (29 mmol) of acetonyltriphenylphosphonium chloride are suspended in 100 ml of tetrahydrofuran under argon. 3.3 g (29.4 mmol) of potassium tert.-butylate was added thereto and the mixture was thereafter stirred at room temperature for a further 30 minutes. After cooling to 10° 4.0 g (14.5 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde was added thereto and the mixture was stirred at 20° for 1 hour and under reflux for 6 hours. The reaction mixture was evaporated, the residue was partitioned between methylene chloride and water, the organic phase was washed with water and subsequently dried over magnesium sulphate, filtered and evaporated. After chromatography of the residue on silica gel with methylene chloride/ethyl acetate (8:2, 7:3 and 1:1) and subsequent recrystallization of the combined pure fractions from ethyl acetate/hexane there was obtained 7-chloro-4,5-dihydro-3-[(E)-3-oxo-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals of melting point 235°-237°.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12]C)=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].[BH4-].[Na+]>CO>[CH2:17]([NH:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Reactant: CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCNCc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (0.65 g, 2.93 mmol) in anyhdrous methanol (12 mL) under nitrogen was added n-butylamine (0.3 mL, 3.07 mmol) and the resultant mixture stirred for 18 h at room temperature, prior to portion wise addition of sodium borohydride (0.144 g, 3.8 mmol). After 30 minutes stirring at room temperature the reaction was quenched by cautious addition of sat. sodium bicarbonate aq. and then extracted into ethyl acetate (2×40 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow oil (0.65 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:45][S:46]([O:15][C@@H:14]1[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:10][C@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of di-tert-butyl (4-{(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (500 mg, 0.957 mmol) in DCM (4.5 mL), triethylamine (0.227 mL, 1.63 mmol) was added followed by methanesulfonyl chloride (0.096 mL, 1.24 mmol). The capped solution was stirred at room temperature for 1 h. The reaction mixture was quenched with aq. NaHCO3, extracted with EtOAc. The organic layer was washed with brine, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a light yellow powder (574 mg, 100%). LCMS calc. for C27H45N4O9S (M+H)+: m/z=601.3. Found: 601.2.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])[C:15]=2[CH:33]=1.CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=4[O:31][CH3:32])[C:15]=3[CH:33]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CN2CCOc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Cyclopentyl chloroformate (0.5 g.) was added in a single portion to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (1.0 g.) and N-methylmorpholine (0.314 g.) in dichloromethane (30 ml.), under an atmosphere of nitrogen. After one hour, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w/v sodium bicarbonate solution, and saturated brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with dichloromethane to give the title compound (0.7 g, 52%) as an oil; NMR (80 MHz, CDCl3): 1.69[m,8H, (CH2)4 ], 3.39(t,2H, OCH2CH2N), 3.90(s,3H, OCH3), 3.91 (s,3H, OCH3), 4.23(t,2H, OCH2CH2N), 4.45(s,2H, CH2.Ar), 5.10(m,1H, --CHO--), 6.2(br s,1H, NHCO), 6.59-7.62(m,6H).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH2:18]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21].[Si](C#N)(C)(C)C.[N:37]1([C:42](N2C=CN=C2)=[O:43])C=CN=[CH:38]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:27]([C:26]4[CH:29]=[CH:30][C:23]([O:22][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=4)[CH2:38][NH:37][C:42]3=[O:43])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: CCCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-butoxybenzaldehyde (0.691 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.03 mL, 7.4 mmol), di-(imidazol-1-yl)methanone (0.658, 4.06 mmol) as described in method 2. The product was purified by means of preparative HPLC.