Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(Cl)Cl>[C:16]([O:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C1CC(O)C(=O)O1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(=O)OC1=O
Temperature: 0 °C

Procedure:
After equipping a thoroughly dried 200 ml-volume three-necked flask with a dropping funnel, a calcium chloride tube and a nitrogen inlet tube, the system atmosphere was charged with nitrogen gas. A stirrer bar coated with Teflon™ was then added into the flask together with 50 ml of dry methylene chloride, 5.0 g (43.1 millimoles) of 2-hydroxysuccinic anhydride and 4.79 g (47.4 millimoles) of dry triethylamine, and the mixture was stirred at 0° C. under the nitrogen atmosphere. To this solution there was added, dropwise and over the period of an hour, 4.50 g (43.1 millimoles) of methacryloyl chloride that had been already placed in the dropping funnel, and then the mixture was stirred at room temperature for 2 hours. After confirming consumption of the starting materials by thin-layer chromatography, the reaction solution was transferred to a 300 ml separatory funnel and washed with 100 ml of water and saturated saline in that order. The aqueous phase was then extracted 3 times with methylene chloride. The organic layer was collected and dried over sodium sulfate anhydride. The dried organic layer was filtered with filter paper and the solvent in the filtrate was distilled off under reduced pressure. This yielded a brown oil. The oil was purified by silica gel chromatography to obtain methacryloxysuccinic anhydride as a colorless transparent oil. The yield was 6.75 g (85%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH:12]1([N:18]=[C:19]=NC2CCCCC2)CCCCC1.C(=S)=[S:28]>N1C=CC=CC=1>[CH3:12][NH:18][C:19]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[S:28]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: S=C=S
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CNC(=S)NCCSCc1nc[nH]c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-((5-methyl-4-imidazolyl)methylthio)ethylamine (3.42 g 0.02 mol) in dry pyridine (15 ml) was slowly added under dry nitrogen to a stirred solution of N,N'-dicyclohexylcarbodiimide (4.12 g 0.02 mol) and carbon disulphide (20 ml) in dry pyridine (10 ml) at -10°. The mixture was stirred for 4 hours at -10° and 18 hours at room temperature and was filtered. The filtrate was evaporated to dryness and the residue was dissolved in warm acetonitrile and the solution was cooled, filtered and the filtrate was evaporated to dryness. The residue was boiled for five minutes with an excess of aqueous methylamine. The solid which crystallised on cooling was recrystallised from water to give N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.C([O:15][C:16](=O)[C:17](OCC)=[O:18])C>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:16](=[O:15])[C:17](=[O:18])[NH:11]2)=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 23 °C

Procedure:
A mixture of methyl-3,4-diaminobenzoate (4.5 g) in diethyloxalate (50 mL) was heated at reflux for three hrs. After cooling to 23° C., the solid was isolated by filtration, affording 2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid methyl ester as a light yellow solid. MS (M−H)−=219.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[CH:11]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([CH3:10])[CH:4]=[C:3]2[C:2]=1[O:1][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]2)=[O:9]
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Temperature: 80 °C
Yield: 23 %

Procedure:
A mixture of 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehyde (5.0 g, 30.46 mmole), K2CO3 (8.41 g, 60.92 mmole) and ethyl 4,4,4-trifluorocrotonate (7.68 g, 45.69 mmole) in anhydrous DMF (40.0 mL) was heated to 80° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 1.2 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark red oil which was subject to flash chromatography (silica gel) and eluted with 50% CH2Cl2/hexane to give a light yellow solid (2.2 g, 23%): GCMS m/z 314.0 (M+). 1H NMR (CDCl3/400 MHz) 10.42 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.26 (s, 1H), 5.80 (q, 1H, J=7.0 Hz), 4.33 (m, 2H), 2.32 (s, 3H), 1.35 (m, 3H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24](O)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:4].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24]([Cl:7])=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccncc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccncc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 72 h
Yield: 126 %

Procedure:
1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH2Cl2. The solution was cooled at −10° C and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([OH:20])=O)[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2].[Li].Cl.[NH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:26]1.O.[OH:42]N1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([NH:24][C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=5)[CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:42])=[O:20])[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2]
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)O
Reactant: N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {5-[1-(4-cyano-3-fluorophenyl)-1-hydroxyethyl]imidazol-1-yl}acetic acid, lithium salt, as described above in Step E, (40 mg, 0.136 mmol), (R)-3-amino-1-[7-hydroxynaphthalen-1-yl]pyrrolidine hydrochloride, as described in Example 29, Step J, (42 mg, 0.151 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.17 mmol), EDC (33 mg, 0.17 mmol), and N,N-diisopropylethylamine (40 mg, 0.31 mmol) in dry, degassed DMF (1 mL) was stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (1 mL) and CHCl3 (3 mL). The aqueous layer was extracted further with CHCl3 (2×2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography, eluting with a gradient of CH2Cl2—6% MeOH—0.6% NH4OH to give the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1cccnc1)N(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 3.5 g. portion of 3-[1-(4-chlorophenylamino)ethyl]pyridine was dissolved in dichloromethane, and 2.7 g. of potassium carbonate and 2.55 ml. of benzenesulfonyl chloride were added. The mixture was stirred at ambient temperature for 1 day, and was then diluted with 10 ml. of dichloromethane and extracted with 20 ml. of aqueous sodium bicarbonate and 20 ml. of water. The organic layer was dried over magnesium sulfate and evaporated under vacuum to an oil. The oil was dissolved in diethyl ether, and the insolubles were separated. The solvent was then evaporated away under vacuum, and the resulting oil was taken up in chloroform and chromatographed over a silica gel column, eluting with chloroform. The product-containing fractions were evaporated to obtain 3.1 g. of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:28])([F:27])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].[C:29](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:29][N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([O:24][C:25]([F:27])([F:28])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.30 g), potassium carbonate (1.05 g) and N,N-dimethylformamide (50 mL) was stirred at 0° C. for 30 min. Methyl iodide (1.08 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (9:1-3:1, volume ratio) to give the title compound (2.26 g, yield 66%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 149-150° C.
Reaction SMILES: CCN(CCNC(C1C=CC(N)=C(Cl)C=1)=O)CC.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][C:21]=1[Cl:31].C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)=O>C1COCC1.CO.C(Cl)Cl>[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[Cl:31]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Agent: CCN(CC)CCNC(=O)c1ccc(N)c(Cl)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 35 °C
Reaction time: 1 h

Procedure:
3-chloro-procainamide, free base, [N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide, free base] (1b). The acid (2), 10 g (0.058 moles) was dissolved in 800 mL of anhydrous THF. Carbonyl diimidazole, 11.1 g (0.067 moles), was added in one portion and the mixture was warmed to 35° C. CO2 began to slowly evolve and then increased rapidly. After one hour, all evolution of gas ceased and the mixture was warmed to 45° C. for fifteen minutes to insure that all of the acid had reacted. N,N′-diethylenediamine, 7.5 g (0.65 moles) was added dropwise over five minutes and then the reaction mixture was warmed to 55° C. After 30 minutes, a TLC of the mixture (CH2Cl2:MeOH, 3:1) showed that the reaction was complete, producing the desired product (Rf 0.4) along with a minor nonpolar impurity (Rf 0.8) and polar impurities (Rf 0.1). The TCL did not change after stirring overnight at 55° C. The solvent was removed on a rotary evaporator at 50° C. and then 100 mL of water was added to destroy any unreacted carbonyl diimidazole, producing a biphasic mixture. The free base was extracted into CH2Cl2 (3×100 mL), and dried over anhydrous K2CO3, and evaporated to give 20 g (>100%) of a brown oil. Attempts to prepare a crystalline salt (sulfate, succinate, tosylate, and adipate) failed. Simple chromatography on 25 g of silica, eluting with hexane:EtOAc (2:1) gave 14.3 g (91%) of 1b as clear tan oil, homogeneous by TLC. The structure of the free base (1b) is shown in FIG. 5. 1H NMR (CDCL3) d 7.75 (d, J=0.8 Hz, 1H, ArH), 7.52-7.48 (dd, J=0.8 Hz, 1H, ArH), 6.84 (bs, 1H, NH), 6.77-6.74 (d, J=2.8 Hz, 1H, ArH), 3.49-3.43 (q, 2H, J=1.8 Hz, CH2NHCO), 2.66-2.54 (m, 6H, (CH2)3N, 1.07-1.02 (t, J=2.4 Hz, 6H, N(CH2CH3)2). IR (KBr) cm−1, 3475, 3320 (NH2, m), 1620, 1600 (C═O, s). MS (El) m/e 269 (M+), 271 (M+2), 240 (M=−Et), 197 (M+−NEt2), 154 (M+−NCH2CH2NEt2), 86 (base peak, M+−CH2NEt2) Anal. Calc'd for C13H20N3—OCl: C, 57.88; H, 7.47; N, 15.58. Fd. C, 58.05; H, 7.56; N, 15.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=C(C)O[N:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:35]([OH:38])(=[O:37])[CH3:36]>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH2:33])=[NH:30])=[CH:25][CH:24]=3)=[O:22])[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2.[C:35]([O-:38])(=[O:37])[CH3:36]
Reactant: CC(=O)O
Reactant: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1
Agent: [Ni]
Solvent: CO
Product: CC(=O)[O-]
Product: N=C(N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1

Procedure:
A solution of 100 mg of [4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl][4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]methanone in 5 ml of methanol is admixed with 100 mg of Raney nickel and a drop of acetic acid and hydrogenated to completion at atmospheric pressure and room temperature. Catalyst and solvent are removed, giving 4-[4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-carbonyl]benzamidine, acetate, FAB 457.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])[CH3:17]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of acetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic; acid (1.14 mL), ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mL) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2S04). After filtering, the extract was concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether, affording an oil that solidified on standing at room temperature.
Reaction SMILES: [Cl-].[C:2]1([N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([N+]2C=CC=CC=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][O:30][C:31]([NH:33][CH2:34][CH2:35][C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([OH:47])=[O:46])[CH:43]=3)[NH:38][CH:37]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O>[C:2]1([N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([O:46][C:45]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[C:36]3[CH2:35][CH2:34][NH:33][C:31](=[O:32])[O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:47])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc12)OCc1ccccc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 1-[(diphenylamino)carbonyl]pyridinium chloride (1.1 g) in water (10 ml) was added rapidly to a stirred solution of 3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid (1 g) and triethylamine (0.6 ml) in water (15 ml). After 0.5 hour, an amorphous yellow solid (1.7 g) was filtered off. A sample (0.5 g) was crystallised from a mixture of ethyl acetate and cyclohexane to give the title compound (0.3 g) as a cream crystalline solid m.p. 137°-138.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH:40]=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:53]>CO>[ClH:53].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[C:39]([O:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[CH:38]=[CH:37]3)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cc(OCCN4CCOCC4)ccc3c2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(COCCCOc2ccc(C3CCNCC3OCc3ccc4cc(OCCN5CCOCC5)ccc4c3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[6-(2-morpholin-4-yl-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 4-[2-[6-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl]-naphthalen-2-yloxy]-ethyl]-morpholine hydrochloride (1:2) in the form of colourless crystals; M: 611 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CCO>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Yield: 74.9 %

Procedure:
To a solution of 2-chloro-3-nitropyridine (25.3 g) in EtOH (300 mL) were added ethyl 2-aminoacetate hydrochloride (28.7 g) and triethylamine (28.9 ml) at room temperature, and the mixture was refluxed for 1 day. The mixture was concentrated under reduced pressure. The residual crystals were removed by filtration and washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-70% AcOEt in hexane). The residual crystals were removed by filtration and washed with IPE. The filtrate was concentrated under reduced pressure to give the title compound (26.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]CC(C)C)=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O-:23].[Na+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(C)c([O-])c1
Reactant: CC(C)COC(=O)C(C)(C)CCCCl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1
Yield: 80 %

Procedure:
subsequently reacting said 2-methylpropyl 5-chloro-2,2-dimethylpentanoate with sodium 2,5-dimethylphenolate under reflux in a solvent comprising a mixture of from 10 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide to 5 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide, hydrolyzing the resulting ester, and thereafter acidifying the mixture and isolating 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Cl:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[Cl-:31].[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([O:10][CH2:11][CH2:12][N+:13]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:15])[CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCOC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)OCC[N+](C)(C)Cc2ccccc2)cc(C(C)(C)C)c1O
Product: [Cl-]
Yield: 85.3 %

Procedure:
A solution of 32.15 g (100 mmol) of 2-dimethylaminoethyl 3,5-di-tert-butyl-4-hydroxybenzoate prepared as described above and 12.66 g (100 mmol) of benzyl chloride in 140 ml of acetonitrile was heated at reflux for 1 hour and then concentrated after filtering off a small amount of insolubles. The viscous residue was treated with boiling heptane and then with ligroine. The resultant amorphous solid was allowed to stand in ether which induced crystallization. This solid was collected and dried giving 38.2 g of N-[2-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)ethyl]-N,N-dimethylbenzylammonium chloride (85.26% of theory); mp=215° C. dec.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1)(=O)C.[OH-].[Na+].O>CO.O1CCCC1>[OH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:24][N:23]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(O)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 3-({[4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazin-1-yl]carbonyl}amino)phenyl acetate (635 mg, 1.50 mmol) in methanol/tetrahydrofuran (2:1) (60 ml) was added an aqueous 1 N sodium hydroxide solution (1.5 ml), and the mixture was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 360 mg (62.9%) of the desired product as a solid.