Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].[C:20](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:17][CH:13]([F:18])[O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH2:1][CH2:20][NH:8]2
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cccc2c1CCN2
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A solution of 10 g of 2-methyl-3-nitrophenol in 20 ml of N,N-dimethylformamide is added to a mixture of 23.4 g of sodium chlorodifluoroacetate and 22 g of potassium carbonate in 30 ml of N,N-dimethylformamide and 6 ml of water. The reaction mixture is then heated at 110° C. for 3 hours and left to stand for 16 hours, and then treated with a mixture of water and ethyl acetate. The organic phase is washed with 1N sodium hydroxide, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give the expected product in the form of a brown oil, used as it is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5]CCCC(NC1C(CC)=C(C=CC=1[N+]([O-])=O)C([O-])=O)=O.[C:29]([NH:34][C:35]1[C:36](CC)=[C:37]([CH:41]=[CH:42][C:43]=1[N+:44]([O-])=O)[C:38]([O-:40])=[O:39])(=O)[CH2:30][CH2:31][CH3:32].Cl[C:50]1C=C(C=C[CH:57]=1)CBr>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:34]1[C:35]2[CH:36]=[C:37]([C:38]([O:40][CH2:50][CH3:57])=[O:39])[CH:41]=[CH:42][C:43]=2[N:44]=[C:29]1[CH2:30][CH2:31][CH3:32]
Reactant: Clc1cccc(CBr)c1
Reactant: CCc1c(C(=O)[O-])ccc([N+](=O)[O-])c1NC(=O)CCCCc1cccc(Cl)c1
Reactant: CCCC(=O)Nc1c([N+](=O)[O-])ccc(C(=O)[O-])c1CC
Product: CCCc1nc2ccc(C(=O)OCC)cc2n1Cc1cccc(Cl)c1

Procedure:
By using the method of example 47, part A, a preliminarily purified material of 3-[N-(3-chlorobenzyl)butyrylamino]-4-nitro-ethylbenzoate isobtained from 3-butyrylamino-4-nitro-ethylbenzoate (1.86 g) and 3-chlorobenzyl bromide (1.64 g). Without purification, this material is changed to 1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (0.57 g) by using the method of example 47, parts B and C. 1H-NMR CDCl3, δ): 1.02 (3H, t, J=7.4 Hz), 1.39 (3H, t, J=7.1 Hz), 1.85-1.92 (2H, m), 2.80 (2H, t, J=7.5 Hz), 4.38 (2H, q, J=7.1 Hz), 5.37 (2H, s), 6.86 (1H, d, J=7.4 Hz), 7.04 (1H, s), 7.21-7.29 (2H, m), 7.77 (1H, d, J=8.4 Hz), 7.96 (1H, d, J=1.2 Hz), 7.99 (1H, dd, J=8.5 and 1.5 Hz).
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[O:5]=[C:6]([N:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:7][CH3:8].[C:27](=[O:30])([O-:29])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[C:16]([OH:18])(=[O:17])[C:27]([OH:29])=[O:30].[O:5]=[C:6]([N:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][N:13]([CH2:4][CH:3]=[CH2:2])[CH2:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: CCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCNCC1
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: C=CCN1CCC(C(=O)OCC)(N(C(=O)CC)c2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2.06 parts of 3-bromo-1-propene, 4.6 parts of ethyl 4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylate, 2,4 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 5 hours. After cooling to room temperature, the reaction mixture is poured onto water. The organic phase is separated, washed with water, dried, filtered and evapoarated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaorated. The oily residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from 8 parts of 2-propanol. The product is filtered off and dried, yielding 3.8 parts of ethyl 4-[(1-oxopropyl)phenylamino]-1-(2-propenyl)-4-piperidinecarboxylate ethanedioate; mp. 152.9° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:16]2[CH2:17][CH:18]([CH2:20]O)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].S(Cl)([Cl:25])=O.O>C1C=CC=CC=1>[C:7]([C:11]1[C:16]2[CH2:17][CH:18]([CH2:20][Cl:25])[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1c(O)ccc2c1CC(CO)O2
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1c(O)ccc2c1CC(CCl)O2
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Pyridine (180 mg, 2.2 mmol) was added to a solution of 4-tert-butyl-5-hydroxy-2-hydroxymethyl-2,3-dihydrobenzofuran (430 mg, 1.9 mmol) in benzene (15 ml) and, subsequently, thionyl chloride (310 mg, 2.6 mmol) was added dropwise under ice cooling. After being allowed to warm to room temperature, the mixture was heated under reflux for 24 h. After cooling, water was added and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (chloroform) to afford 4-tert-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran [280 mg (yield, 61%)] as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([Cl:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(Br)cc1Cl
Reactant: OB(O)c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccncc2)cc1Cl

Procedure:
The title compound was prepared from N-[4-bromo-2-chlorophenyl]acetamide and pyridin-4-ylboronic acid using a similar procedure to Description 3.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([NH:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22](O)([CH3:24])[CH3:23])[CH3:18])(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:9]([NH:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])([CH3:23])[CH3:24])[CH3:18])(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)NC(C)CCCC(C)(C)O
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCC(=O)NC(C)CCCC(C)(C)c1ccc(O)cc1O
Reaction time: 0.5 h

Procedure:
11.0 Parts of resorcinol, 12.2 parts of 2-hexanoylamino-6-hydroxy-6-methyl-heptane and 0.5 parts of p-toluene sulphonic acid are sealed for 4 days in a glass Carius tube. The reaction mixture is then poured into 500 parts of water and stirred for 30 minutes on a steam-bath. After removing the water by decantation, the above washing procedure is repeated twice again before taking up the residual oil in ether. The ether solution is then dried and stripped down under reduced pressure (16 mb) on a rotary evaporator at 100° C. to give 2-hexanoylamino-6-(2,4-dihydroxyphenyl)-6-methylheptane as an amber oil with the following percentage composition by weight
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[CH:10]=O.[N+:17]([CH3:20])([O-:19])=[O:18]>C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9](/[CH:10]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([F:16])[C:14]=1[F:15]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(F)c(F)c(F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (7.3 g) was added to a solution of 3,4,5-trifluorobenzaldehyde (12.6 g) and nitromethane (17.1 mL) in acetic acid (50 mL), and the reaction solution was stirred at 100° C. for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=9:1) to obtain 10.5 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(N1CCC(CO)CC1)(OC(C)(C)C)=O.OC1C=C(C(OC)=O)ON=1.[N].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([NH:43][C:44](=[N:47]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O>>[C:44]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[NH:43])[NH2:47]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: COC(=O)c1cc(O)no1
Agent: [N]
Product: N=C(N)N1CCCCC1

Procedure:
Scheme XIXb outlines the synthesis of the analogous compounds where R1 is 4-(1-amidinopiperidinyl) instead of 4-amidinophenyl. After initial condensation of N-BOC-4-piperidinylcarbinol with methyl 3-hydroxyisoxazole-5-carboxylate under Mitsunobu conditions, the intermediate ester is saponified and condensed with a 1,3-diaminpropionate using conditions described above. The piperidine nitrogen is deprotected and treated with N,N'-diCBz-S-methylisothiourea to give a protected amidinopiperdine. Hydrogenation gives the amidinopiperidine compounds as the methyl esters. ##STR76##
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([CH2:14][CH:15]=[O:16])[CH2:11][CH:12]=O.[CH2:17]([C:24](O)=O)[C:18](CC(O)=O)=O.C([O-])(=O)C.[Na+]>Cl.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH:10]3[CH2:11][CH2:12][CH2:24][CH:17]2[CH2:18][C:15](=[O:16])[CH2:14]3)=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: O=CCCCC=O
Reactant: Cc1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CN2C3CCCC2CC(=O)C3)cc1

Procedure:
A solution of 4-methylbenzylamine (12 g) in dilute hydrochloric acid (5N, 20 ml) was added to glutaric dialdehyde (50%, 24 ml) in water (100 ml) with stirring. A solution of 1,3-acetonedicarboxylic acid (14.6 g) and sodium acetate (8.2 g) in water (100 ml) was then added and the mixture stirred for 24 hours at room temperature. A further quantity of dilute hydrochloric acid (5 ml) was then added and the mixture stirred for a further 48 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]4[O:23][CH2:22]4)=[CH:16][CH:17]=3)[C:12](=[O:24])[C:11](C)(C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:27][NH2:28]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][CH3:27])=[CH:16][CH:17]=3)[C:12](=[O:24])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(OCC3CO3)cc2C1=O
Reactant: CN
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)C(=O)CCC2c1ccc(Cl)c(Cl)c1
Product: Cl
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-(3,4-dichlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone (3.2 g) in ethanol (30 ml) was added a solution of methylamine (10 ml) in ethanol (10 ml) and the mixture left to stand overnight. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated, basified, extracted with ether and the extract dried (MgSO4). Evaporation gave the product as the free base, which was converted to the hydrochloride salt. Recrystallisation from petrol/ether gave 4-(3,4-dichlorophenyl)-7-(2-hydroxy-3-methylaminopropoxy)-1-tetralone hydrochloride as white crystals (2.5 g, 72%) m.p. 105°-10°(dec).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:19])[C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.O>[CH3:12][O:13][C:14](=[O:19])[C:15]([NH:18][CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)N
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.0 g, 31.7 mmol) and 2-amino-2-methyl-propionic acid methyl ester (5.80 g, 49.5 mmol) in DMF (220 mL) was treated with triethylamine (9.0 mL, 18.5 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (3.87 g, 40%) as a light yellow solid: MS (ESI) m/e 302 (M+H)+.
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1Br.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:8]1[C:7]2=[N:6][S:5][N:4]=[C:3]2[C:2]([C:19]2[S:18][CH:17]=[CH:21][CH:20]=2)=[CH:1][N:9]=1
Reactant: Brc1cnc(Br)c2nsnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1csc(-c2cnc(-c3cccs3)c3nsnc23)c1
Temperature: 140 °C
Reaction time: 0.6 h

Procedure:
A 5 mL microwave tube was charged with 4,7-dibromo-pyridal[2,1,3]thiadiazole (PTBr2, 0.556 g, 1.885 mmol), 2-(tributylstannyl)thiophene (Bu3Sn—Th, 1.477 g, 3.957 mmol), Pd(PPh3)4 (0.020 g, 0.018 mmol), toluene (3 mL), and sealed with a teflon cap. The reaction mixture was heated to 120° C. for 3 minutes, 140° C. for 3 minutes, and 170° C. for 36 minutes, using a Biotage microwave reactor. Upon cooling, the residue was passed through a short silica plug eluting with methylene chloride (200 mL). All volatiles were removed in vacuo to give the crude product as a red solid. The solid was slurried in MeOH (100 mL), sonicated for 10 minutes, and filtered. The solid was washed with copious amounts of MeOH and then dried under vacuum for 24 hours. The product was collected as a bright red solid. Recovered yield: 535 mg (94%). 1H NMR (CD2Cl2): δ 8.81 (s, 1H, PT-CH), 8.68 (d, 3JH-H=4 Hz, 1H, Th′—CH), 8.11 (d, 3JH-H=4 Hz, 1H, Th—CH), 7.61 (d, 3JH-H=5 Hz, 1H, Th′—CH), 7.51 (d, 3JH-H=5 Hz, 1H, Th—CH), 7.27 (dd, 3JH-H=4 Hz, 3JH-H=4 Hz 1H, Th′—CH), 7.23 (dd, 3JH-H=4 Hz, 3HH-H=4 Hz 1H, Th—CH), 13C{1H} NMR (CD2Cl2): 155.50, 148.62, 146.91, 142.53 (s, quaternary), 141.28 (s, PT-CH), 137.18 (s, quaternary), 131.97 (s, Th′—CH), 131.00 (s, Th′—CH), 129.40 (s, Th—CH), 128.61 (s, Th—CH), 128.38 (s, Th′—CH), 127.88 (s, Th—CH), 121.00 (s, quaternary). Anal. Calcd. for C13H7N3S3: C, 51.80; H, 2.34; N, 13.94. Found: C, 51.8; H, 2.40; N, 13.7%. UV-vis: (o-DCB) λmax=302, 470 nm, λonset=550 nm, ε=22150 cm−1M−1. PL: (o-DCB) λmax=607 nm. HRMS (EI) m/z, calcd for C13H7N3S3 (M+): 300.98; found: 301.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1>>[Br:22][C:23]1[CH:24]=[N:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Brc1cn[nH]c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.98 g, 3.0 mmol) and commercially available 4-bromo-pyrazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.83 g, 59%). MS (ISP) 437.0 [(M+H)+]; mp 175.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]1)[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH2:1]([O:8][C:9]1([CH:24]=[CH:25][CH:26]=[CH:27][CH2:28]1)[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN(CC2(OCc3ccccc3)C=CC=CC2)C1c1ccccc1
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: C1=CCC(CN2CCNCC2c2ccccc2)(OCc2ccccc2)C=C1

Procedure:
1-Benzyloxy benzyl-2-phenyl-3-keto piperazine prepared according to Example 12, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-benzyloxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of white crystals melting at 140-141° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])[CH:8]=[CH:7][N:6]=1.N1C=CC=CC=1.N(S(O)(=O)=O)O>CO>[CH3:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]2[N:2]=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(/N=C\N(C)C)c1
Agent: O=S(=O)(O)NO
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a cooled (0° C.) solution of (Z)-N,N-dimethyl-N′-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formamidine (1.00 g, 3.33 mmol) in methanol (5 mL) was added pyridine (0.54 mL, 6.66 mmol) and hydroxylamine sulfonic acid (0.427 g, 3.66 mmol). After stirring at room temperature for 2 hours, the precipitate was filtered to provide the product (0.442 g, 49%) as white solid.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([O:12]C)=[O:11])[C:7](=[O:14])[CH:6]1[CH2:15][CH3:16])[CH:2]=[CH2:3].[OH-].[K+].ClCCl>C(O)C.O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7](=[O:14])[CH:6]1[CH2:15][CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C=CCSC1C(CC)C(=O)N1CC(=O)O
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
To a stirred solution of 3 g of methyl 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)acetate in 10 ml of absolute ethanol was added dropwise a solution of 0.9 g of potassium hydroxide in a mixture of 12 ml of ethanol and 1 ml of water. After 5 minutes, the mixture was poured into a mixture of 10 ml of dichloromethane and 20 ml of water. After acidification with 13 ml of 2M HCl, the mixture was extracted with further dichloromethane; the dichloromethane extracts were extracted with saturated sodium bicarbonate solution. These aqueous extracts were acidified to pH 1.5 with 5M HCl and then extracted with dichloromethane. These organic extracts were evaporated to dryness to afford the title compound as a white crystalline solid (2.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.ClCCl>[C:35]([O:34][C:33]([N:32]([CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[O:21][CH2:22][CH2:23][O:24][C:25]=2[CH:30]=1)[CH:40]1[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]2=[O:16])[CH2:42][CH2:41]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 0.19 g of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 14 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.19 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate. (2) To 3 mL of a dichloromethane solution containing 0.17 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate, 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 34 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 0.19 g of sodium triacetoxyborohydride was added and stirred for 1 hour. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].[Cl-].ClC1N(C)CC[NH+]1C>C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Cn1c(C(=O)O)cnc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2cnc(Cl)n2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 2-chloro-3-methyl-3H-imidazole-4-carboxylic acid (0.161 g, 1.0 mmol) is dissolved in toluene (5 mL, anhydrous) and DIEA (0.26 mL). N-isopropylpiperazine (0.2 M in toluene; 5.5 mL; 1.1 mmol) is added followed by the slow addition of 2-chloro-1,3-dimethylimidazolinium chloride (0.3 M in acetonitrile; 4.0 mL; 1.2 mmol). The reaction mixture is stirred at rt for 2 hr and is then diluted with EtOAc and washed with NaOH (1 N). The aqueous layer is drained and reextracted with EtOAc and the combined organic extracts are extracted twice with HCl (1 N). The combined acidic aqueous extracts are washed with EtOAc then basified with NaOH (2.5 M). The resulting basic aqueous solution is extracted three times with EtOAc and the combined organic extracts are washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo.