Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH3:8][C:9]1[C:10](=[O:28])[O:11][C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:20]=3[CH:21]=2)=[C:13]([CH3:16])[C:14]=1[OH:15].[C:29](Cl)(=[O:31])[CH3:30].O>C(Cl)Cl.CCOC(C)=O>[C:29]([O:15][C:14]1[C:13]([CH3:16])=[C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:20]=3[CH:21]=2)[O:11][C:10](=[O:28])[C:9]=1[CH3:8])(=[O:31])[CH3:30]
Reactant: Cc1c(-c2cc3cc(C=O)ccc3o2)oc(=O)c(C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(-c2cc3cc(C=O)ccc3o2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding Et3N (1.7 g) to a suspension of 3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (5.0 g) in CH2Cl2 (100 ml), the mixture was cooled on ice, acetyl chloride (1.32 g) was added and the mixture was stirred at room temperature for one hour. Water (100 ml) was added to the reaction solution, extraction was performed with AcOEt, and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:16]([N+:21]([O-])=O)[CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.ClCCl.[Ni](Cl)Cl>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:16]([NH2:21])[CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 89.8 %

Procedure:
Sodium borohydride (29.0 g, 0.767 mol) was added in small portions to a solution of nickel(II)chloride (22.8 g, 0.096 mol) in methanol (1.25 L). A solution of (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine (67.4 g, 0.192 mol) in methanol (300 mL) and dichloromethane (300 mL) was added to the resulting mixture. A precipitate was present and was dissolved by the addition of dichloromethane (500 mL). Additional sodium borohydride (˜10 g) was added in small portions until the (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine was consumed. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 50:50 dichloromethane:methanol. The filtrate was concentrated under reduced pressure, and the black, oily residue was treated with water and dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was treated with activated charcoal, filtered, and concentrated under reduced pressure to yield 55.4 g of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine a brown semi-solid.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH:6]1[CH:12]([OH:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]3[NH:18][C:19](=[O:20])[N:9]([C:10]=23)[CH2:8][CH2:7]1.CO.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:5][C@H:6]1[C@H:12]([OH:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]3[NH:18][C:19](=[O:20])[N:9]([C:10]=23)[CH2:8][CH2:7]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: NC1CCn2c(=O)[nH]c3cccc(c32)C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3 g of sodium cyanoborohydride were added over 15 minutes at 0° to 5° C. to a mixture of 6 g of (6RS, trans) 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one, 60 ml of methanol and 30 ml of acetone and the mixture was stirred at room temperature for 3 hours and was evaporated to dryness under reduced pressure. The residue was added to 60 ml of water and the mixture was extracted with chloroform. The organic phase was dried and evaporated to dryness to obtain 3.6 g of (6RS,trans) 6-isopropylamino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one melting at ≃166° C. The latter was dissolved in 60 ml of ethanol and ethyl acetate saturated with hydrogen chloride was added thereto. The mixture was vacuum filtered to obtain 3.7 g of the corresponding hydrochloride melting at ≃270° C. The product was dissolved in hot methanol and ethyl acetate was added to obtain 3.3 g of the said product melting at ≃270° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5([NH:31]S(C(C)(C)C)=O)[CH2:30][CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1COCC[Si](C)(C)C.Cl.O1CCOCC1>CO>[NH2:31][C:27]1([C:24]2[N:25]=[CH:26][C:21]([C:11]3[C:10](=[O:38])[C:9]4[CH:8]=[CH:7][N:6]5[C:2](=[O:1])[NH:3][N:4]=[C:5]5[C:14]=4[O:13][C:12]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cn2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)[nH]nc45)c3=O)cn2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methyl-propane-2-sulfinic acid (1-{5-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-pyridin-2-yl}-cyclobutyl)-amide (40 mg, 0.061 mmol) in MeOH (3 mL) was added a solution of HCl in dioxane (4 M, 0.3 mL, 1.2 mmol) at RT. After 1 h, the reaction mixture was evaporated to dryness. The residue was dissolved in DCM (2 mL), cooled in an ice bath, and TFA (2 mL) was added. The mixture was stirred at RT for 2 h before evaporating to dryness. The residue was dissolved in MeOH and loaded on to a 5 g SCX-2 cartridge. The cartridge was washed with MeOH before eluting with 2 M NH3 in MeOH solution. The eluent was collected and evaporated. The resulting residue was dissolved in a mixture of MeOH (1.5 mL), water (8.5 mL) and 1 M HCl (0.2 mL) and then chromatographed on a 5 g C18 cartridge {gradient 15 to 45% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)}. The purified hydrochloride salt was dissolved in MeOH and loaded on to a 5 g SCX-2 cartridge. The cartridge was washed with MeOH before eluting with 2 M NH3 in MeOH solution. The eluent was collected and evaporated to dryness to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.28 (d, J=1.9 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.63 (dd, J=8.2 and 2.2 Hz, 1H), 7.57 (dd, J=8.0 and 1.0 Hz, 1H), 7.49-7.39 (m, 5H), 6.96 (d, J=7.1 Hz, 1H), 6.10 (br s, 3H), 2.53-2.45 (m, 2H), 2.08-1.93 (m, 3H), 1.77-1.68 (m, 1H). LCMS (Method E): RT=2.49 min, [M+H]+=426.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)(Cl)Cl>[N:30]1([CH2:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: C1CCNC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CN2CCCC2)nc1

Procedure:
A solution of methyl 6-methyl-3-pyridinecarboxylate (0.43 g) N-bromosuccinimide (0.59 g) and benzoylperoxide (50 mg) in dry carbon tetrachloride (10 ml) was stirred at 22° and irradiated with a 200 w light bulb for 2 days. Pyrrolidine (2.4 ml) was added and after 15 min the solution was partitioned between dichloromethane (20 ml) and 2N sodium carbonate solution (20 ml). The organic phase was washed with water, saturated brine, dried and evaporated to leave an oil (0.68 g). The oil was purified by flash chromatography eluting with a mixture of dichloromethane, ethanol and ammonia (300:8:1) to give the title compound as an oil (0.22 g). T.l.c. silica (Dichloromethane:methanol: 0.88 ammonia 300:8:1) Rf 0.5.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=CC=1>C1COCC1>[CH:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: ClC1CCCCC1
Solvent: c1cnccn1
Solvent: C1CCOC1
Product: c1ccc(C2CCCCC2)cc1
Yield: 85 %

Procedure:
Chlorocyclohexane (59.5 mg, 0.5 mmol) and a THF solution (0.77 mL, 0.97 M, 0.75 mmol) of phenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of phenylmagnesium bromide was added dropwise at 40° C. over 2 hours. 1H-NMR analysis was conducted using pyrazine (19.4 mg, 0.24 mmol) as an internal standard (yield 85%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10]C(OC(C)(C)C)=O)[CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[S:6][C:5]=1[C:7]([NH2:9])=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
5-Bromo-3-(t-butyloxycarbonyl)aminothiophene-2-carboxamide (0.76 g) was stirred in dichloromethane (30 ml). Trifluoroacetic acid (51 ml) was added, the solution was stirred at room temperature for 1 h, poured into saturated aqueous sodium hydrogen carbonate solution (200 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were washed with brine (150 ml), dried (magnesium sulphate), filtered and evaporated to give a yellow solid (0.511 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.N>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 9.7 g. (37 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 40 ml. methylene chloride and 6.3 g. (80 mmole) anhydrous pyridine is added dropwise at 0° C., in the course of 40 minutes, a solution of 7.0 g. (37 mmole) 4-chlorophenylacetyl chloride in 20 ml. methylene chloride, a cheesy precipitate being formed. After stirring at 20° C. for 4 hours, the reaction mixture is poured into 250 ml. ice water, rendered alkaline with ammonia and extracted several times with methylene chloride. The methylene chloride solution is washed twice with water, dried with anhydrous sodium sulphate and evaporated. After the addition of ligroin, crystallisation occurs. The product is recrystallised from diethyl ether to give 51% of theory of the desired product; m.p. 88°-89° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[C:16]([Cl:22])[CH:15]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][NH2:13])=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:56]1([C:59](O)=[O:60])[CH2:58][CH2:57]1>C(Cl)Cl.O>[F:24][C:2]([F:1])([F:23])[CH:3]([C:14]1[CH:15]=[C:16]([Cl:22])[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][NH:13][C:59]([CH:56]2[CH2:58][CH2:57]2)=[O:60])=[CH:8][CH:7]=1
Reactant: NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Cl2 (5 mL) was added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIPEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with CHCl3 (35 mL) The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1)[C:32](=[O:33])[CH2:31][Cl:30]
Reactant: CN(C)CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)CCl
Product: CN(C)CCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 22, 1-[4-(2-dimethylaminoethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 54b) is reacted with chloroacetyl chloride, yielding 1-{4-[N-(2-dimethylaminoethyl)-N-chloroacetylamino]benzoyl}-4-[2(4-chlorophenyl)ethyl]piperazine. The hydrochloride thereof melts at 215°-216° (decomposition).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH:6]=[CH:5]2.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][N:11]=[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[CH:3]=2)[N:8]=1
Reactant: Clc1cc2ccc(-c3ccccc3Cl)nc2cn1
Reactant: NC(=O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(-c3ccccc3Cl)nc2cn1)C1CC1
Temperature: 90 °C
Yield: 23.2 %

Procedure:
A mixture of 6-chloro-2-(2-chlorophenyl)-1,7-naphthyridine (50 mg, 0.2 mmol), cyclopropanecarboxamide (27 mg, 0.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol), palladium acetate (4 mg, 0.02 mmol), and cesium carbonate (118 mg, 0.36 mmol) in 1,4-dioxane (1 mL) was heated at 90° C. for 3 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.71 (m, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 1.64 (m, 1H), 1.21-1.14 (m, 2H), 1.01-0.91 (m, 2H). LCMS (Method E): RT=4.970 min, M+H+=324.1.
Reaction SMILES: [I-].Cl[C:3]1[CH:8]=[CH:7]C=C[N+:4]=1C.C(N(CC)CC)C.C(N)CC.[C:21]([NH:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[CH:29]=[C:28]1[C:38]([OH:40])=O)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[CH:29]=[C:28]1[C:38]([NH:4][CH2:3][CH2:8][CH3:7])=[O:40])(=[O:23])[CH3:22]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCN
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.18 g of 2-chloro-1-methylpyridinium iodide, 0.25 ml of triethylamine and 0.06 ml of propylamine in dichloromethane to a solution of 0.20 g of the compound obtained in Step C of Example 1 in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]C(=O)C(C)(C)C>Cl>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH:3]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[NH:2][CH3:1]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1cccs1
Agent: Cl
Product: CNC(Cc1ccccc1N)c1cccs1
Yield: 72 %

Procedure:
A stirred suspension of 11.28 g of N-[2-[2-methylamino-2-(2-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide in 100 ml of 6N hydrochloric acid was refluxed under nitrogen for 8 hours. The mixture was cooled, decanted over crushed ice and water (200 ml), basified by the addition of 50% sodium hydroxide solution, and extracted with dichloromethane (3×150 ml). The combined extract was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by means of HPLC on a Water's Model 500A High Pressure Liquid Chromatograph (silica gel) utilizing methanol as the eluent. Concentration of the appropriate fractions yielded 5.96 g of 2-amino-N-methyl-α-(2-thienyl)benzeneethanamine. A sample of the product (2 g) in methanol (5 ml) was treated with ethereal hydrogen chloride and a solid was precipitated by further dilution with anhydrous ether. Recrystallization from absolute ethanol gave 2.12 g of 2-amino-N-methyl-α-(2-thienyl)benzeneethanamine dihydrochloride hemihydrate, mp 210°-215° C. (dec.).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:44])[C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([C@H:32]([NH:35]C(OC(C)(C)C)=O)[CH2:33][CH3:34])[C:25]=2[F:43])=[CH:19][N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C@@H:32]([C:26]1[C:25]([F:43])=[C:24]([C:23]([C:20]2[CH:19]=[N:18][C:17]([NH2:7])=[CH:22][CH:21]=2)=[O:44])[C:29]([O:30][CH3:31])=[CH:28][CH:27]=1)[CH2:33][CH3:34]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2ccc(N(Cc3ccc(OC)cc3)C(=O)OC(C)(C)C)nc2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)c1ccc(OC)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 70 °C
Yield: 59.3 %

Procedure:
Step 3 {5-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-2-fluoro-6-methoxy-benzoyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (0.063 g, 0.1 mmol) treated with TFA (2 ml) in DCM (3 ml) over 48 hours, still PMB group present heated at 70° C. for 3 hours. Reaction evaporated to dryness then triturated with diethyl ether to give [3-((R)-1-Amino-propyl)-2-fluoro-6-methoxy-phenyl]-(6-amino-pyridin-3-yl)-methanone (0.018 g). [M-NH2]+287
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].CS[C:15]1[S:19][CH:18]=[CH:17][S+:16]=1>>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[S:16]1[CH:17]=[CH:18][S:19][C:15]1=[N+:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CN1CC[N+](=c2sccs2)CC1

Procedure:
1.2 ml of N-methylpiperazine and 1.0 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 0.9 g (yield: 74.8%) of 1-(1,3-dithiol-2-ylidene)-4-methylpiperazinium perchlorate (Compound No. 31) was obtained as crystals having a melting point of 192° C.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.[CH2:21]([C:23]1([CH3:43])[CH:28]([CH3:29])[CH:27]([NH-:30])[CH2:26][C:25]([CH2:32][CH3:33])([CH3:31])[N:24]1[O:34][CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36])[CH3:22]>>[CH2:21]([C:23]1([CH3:43])[CH:28]([CH3:29])[CH:27]([NH:30][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:26][C:25]([CH2:32][CH3:33])([CH3:31])[N:24]1[O:34][CH:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:22]
Reactant: CCC1(C)CC([NH-])C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCC(=O)NC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C

Procedure:
Octadecanoic acid[2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl-amide;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH:16]=[CH:17][C:18]=1[N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)#[N:21]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Product: N#Cc1cc(NC(=O)c2ccc3ccccc3c2)ccc1N1CCC(O)CC1
Yield: 67.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using naphthalene-2-carboxylic acid (0.44 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (0.5 g), the title compound (0.58 g) was obtained. melting point: 183-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH:6]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[CH3:24])=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41]C([O-])=O)[CH3:38].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:11]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH3:24])[CH2:7]1)=[O:12])[CH3:38]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)cc1C
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
1-(Methoxycarbonyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (7.79 g, 22.56 mmol) (reference compound 31) was dissolved in THF (60 mL) and then di(1H-imidazol-1-yl)methanone (5.49 g, 33.84 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (7.68 g, 45.12 mmol) and anhydrous magnesium chloride (4.30 g, 45.12 mmol) were suspended in THF (60.0 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The content of flask 1 was added to flask 2 and stirred under nitrogen for 48 h. The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phases were evaporated and purified by column chromatography on silica (100 g Biotage column with heptane/EtOAc 88/12-33/67 over 9 column volumes) to give cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 67%). 1H NMR (400 MHz, cdcl3) δ 1.23-1.33 (m, 3H), 1.68-1.97 (m, 2H), 2.08-2.21 (m, 2H), 2.44 (s, 3H), 2.87-2.98 (m, 1H), 3.46 (s, 2H), 3.44-3.66 (m, 1H), 3.58 (s, 3H), 4.15-4.29 (m, 3H), 4.91-5.01 (m, 1H), 7.24-7.32 (m, 1H), 7.36-7.43 (m, 2H). MS m/z 416 (M+H)+