Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: CCCCO
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 93 μL of 1-ethylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 422.0 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH:47][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 16.8 %

Procedure:
(8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.2 g, 3.06 ml, prepared according to Example 9) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.36 g, 8.48 mmol) were combined in toluene (4 ml) and heated to 105° C. for 12 hours. The resulting paste was diluted with toluene, filtered, washed with toluene and partitioned between diethyl ether and 1 N citric acid. The mixture was filtered, and the solid was washed with water and diethyl ether. The solid then was dissolved in chloroform, dried over anhydrous magnesium sulfate, filtered, and the filtrate diluted with diethyl ether, giving a solid precipitate. This solid was collected by filtration and dried in vacuo to give 4-[6-(6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.311 g, 17%). MS (APCI) M++1; Calc'd, 607.3. Found, 607.2.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 29.2 g (216 mmol) of 2,4,6-trimethylaniline, 50.0 g (144 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 22.0 g (159 mmol) of K2CO3 in 1100 cm3 of DMF was stirred at 80° C. for 12 h. The resulting mixture was poured into 2000 cm3 of water. The product was extracted with 3×400 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane). Yield 45.0 g (78%). Anal. Calc. For C26H32BNO2: C, 77.81; H, 8.04; N, 3.49. Found: C, 77.99; H, 8.24; N, 3.26. 1H NMR (CDCl3): 8.27 (m, 1H, 8-H in naphthyl), 7.84 (m, 1H, 5-H in naphthyl), 7.81 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.54 (m, 1H, 7-H in naphthyl), 7.48 (m, 1H, 6-H in naphthyl), 7.37 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 6.87 (s, 2H, 3,5-H in mesityl), 4.39 (s, 2H, CH2N), 3.68 (br. s, 1H, NH), 2.31 (s, 6H, 2,6-Me in mesityl), 2.30 (s, 3H, 4-H in mesityl), 1.49 (s, 12H, CMe2CMe2).
Reaction SMILES: C1C=CC=CC=1.II.[C:9]1([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22][CH2:21]3)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH:30](C)[C:31]([O:33][CH2:34]C)=[O:32]>O.[Zn]>[CH3:34][O:33][C:31](=[O:32])[CH2:30][C:24]1([OH:28])[C:25]2[C:20](=[CH:19][C:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CCOC(=O)C(C)Br
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal (0.505 g, 7.72 mmol), I2 (0.01 g) and 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10 minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g, 7.07 mmol) was added and the reaction mixture was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mL of water and extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester. MS: 375 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
(2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (11.3 g, 0.06 mol) and triethylamine (18.2 g, 0.18 mol) in DMSO (180 mL) at 25° C. was treated with a solution of pyridine-sulfurtrioxide complex (28.6 g, 0.18 mol) in DMSO (150 mL). The resulting mixture was stirred for 0.5 h, poured into H2O (100 mL) and extracted with ether (3×100 mL). The organics were washed with 10% citric acid(aq) (250 mL), saturated NaHCO3 (250 mL) and then with brine (2×250 mL). The organics were dried and concentrated to an off-white solid which was recrystallized from hexanes to afford the desired material (8.0 g, 71%) as white needles: 13C NMR (DMSO-d6, 100 MHz) δ 202.07, 155.58, 78.95, 58.64, 28.42, 21.58.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:41][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[NH:37][C:36]2=[O:46])[CH2:31][CH2:30]1.C1C[O:50][CH2:49]C1>CN(C=O)C>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1][C:49]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]2[CH2:41][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[NH:37][C:36]2=[O:46])[CH2:33][CH2:34]1)=[O:50])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: C1CCOC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CN(C)C=O
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 0 °C

Procedure:
1.70 g (4.39 mmol) of (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-propan-1-one, dissolved in 25 mL of THF, was slowly added dropwise to the ice-cooled mixture of 75 mL of THF and 0.80 g (4.63 mmol) of CDT. Then the mixture was stirred for 30 min in the ice bath and for a further 45 min at RT before the solution of 1.1 g (4.48 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 20 mL of DMF was added and refluxed for 4 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with 50 mL of 15% K2CO3 solution and exhaustively extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, evaporated down and purified through silica gel. The crystallisation was from acetone. The desired product was obtained in the form of a crystalline solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][CH:14]([OH:15])[CH3:16]
Reactant: CC1CO1
Reactant: Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2c1ccn2CC(C)O
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 4-methylindole at 0° as and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of (RS)-1-(4-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [Br:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](Cl)(=O)[C:11](Cl)=O.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(Br)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Br)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (a few drops) was added to a mixture of 1-bromocyclopentane-carboxylic acid (23.9 g, 124 mmol) and oxalyl chloride (11.6 mL, 130 mmol) in 250 mL of CH2Cl2. The mixture was stirred at ambient temperature for 2 h. After removing the low-boiling solvents in vacuo, ethanol (50 mL) was added to the residue followed by the addition of N,N-diisopropylethylamine (22.7 mL, 130 mmol). The mixture was stirred at ambient temperature for 20 min. After removing the low-boiling solvents in vacuo, the residue was partitioned between diethyl ether and water. The organic portion was washed with water and brine, and conc. in vacuo. The crude product was filtered through a plug of silica gel using 0 to 10% EtOAc in hexanes as the eluant. The title compound was obtained as a pale oil.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[CH2:4][N:5]=[C:6]([NH2:22])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:21])=[NH:20])[N:9]=1.[C:25](OCC)(=[O:30])[CH2:26][C:27]([CH3:29])=O.[H-].[Na+]>CO>[OH:30][C:25]1[CH:26]=[C:27]([CH3:29])[N:21]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[N:9]=[C:8]([NH:7][C:6]([NH2:22])=[N:5][CH2:4][C:3]([F:2])([F:23])[F:24])[CH:13]=[CH:12][N:11]=2)[N:20]=1
Reactant: N=C(N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)nc(CCCCOc2nccc(NC(N)=NCC(F)(F)F)n2)n1

Procedure:
5-(4-[2-(2,2,2-Trifluoroethyl)guanidino]pyrimid-2-yloxy)valeramidine hydrochloride (0.5 g.) was added to a solution of ethyl acetoacetate (0.352 g.) and sodium hydride (0.07 g.) in MeOH (6 ml.). The resulting solution was heated under reflux for 18 hours. The solvent was evaporated and the residue taken up in aqueous HOAc and extracted with EtOAc. The aqueous layer was basified with potassium carbonate and extracted with EtOAc. Work up gave a sticky solid which was crystallised from acetonitrile to give 4-hydroxy-6-methyl-2-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)butyl]pyrimidine as white crystals (0.22 g.), m.p. 191°-193°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.C(N(CC)CC)C.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Yield: 98.1 %

Procedure:
Dissolve 4-bromo-2-fluoro-benzoyl chloride (1 g, 4.21 mmol) in DCM and cool the solution in an ice bath. Add triethylamine (0.87 mL, 6.32 mmol) and cyclohexylamine (502 mg, 5.1 mmol) and stir the mixture at ambient temperature for 2 h. Partition the reaction mixture between brine and DCM. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to give the desired intermediate as a white solid (1.24 g, 98%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[SH:25].[OH-].[Na+]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:25][C:17]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: COCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 101.3 %

Procedure:
2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazole thiol (15.0 g (100 mmol)) and sodium hydroxide (13.4 g (335 mmol)) were added together and reacted for about 2 hours at 50° C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure, toluene (30 ml) and water (168 ml) were added thereto. After stirring and still standing the water layer was separated. The organic layer was washed with 10% aqueous sodium hydroxide solution (50 ml) and water (2×50 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (34.8 g) (HPLC purity 98.7%, yield 101%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(Br)s1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 371 mg (19%) of the expected methyl ester, with a melting point of 84°-85° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([OH:13])[CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Yield: 92.3 %

Procedure:
A mixture of 1.7 g (8.6 mmol) of 3-hydroxy-5-nitrobenzoic acid methyl ester [prepared as described by D. J. Abraham, D. M. Gazze, P. E. Kennedy and M.Mokotoff, J. Med. Chem. 27, 1549 (1984)], 3.2 g (9.5 mmol) of 1-bromooctadecane and 1.8 g (12.9 mmol) of potassium carbonate in 35 ml ofanhydrous DMF was stirred and heated at 75° for 25 hours. After cooling, 150 ml of methylene chloride was added and the insoluble salts were removed by filtration. The filtrate was concentrated at reduced pressure to a solid which was purified by HPLC using 30% methylene chloride-hexane to give 3.57 g (92% yield, mp 64°-66°) of 3-nitro-5-(octadecyloxy) benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of trans-1-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester (83.7 g) in dry dimethylformamide (80 ml), imidazole (36.76 g) and t-butyldimethylsilyl chloride (54.26 g) were added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid and water and dried over magnesium sulfate. Removal of the solvent gave trans-1-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-L-proline methyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[F:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1F
Temperature: 148.5 °C
Reaction time: 0.67 h
Yield: 81.7 %

Procedure:
5.10 g of diethyl (3-fluoro-2-pyridyl)malonate and 25 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.29 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 145 to 152° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 2.99 g of ethyl (3-fluoro-2-pyridyl)acetate.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:14]3[CH:24]=[CH:25][S:26][C:13]=23)[CH2:8][CH2:7]1)=O)C.[CH2:27]([NH2:29])[CH3:28].[Na]>CO>[CH2:27]([NH:29][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:14]3[CH:24]=[CH:25][S:26][C:13]=23)[CH2:10][CH2:11]1)=[O:3])[CH3:28]
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccsc23)CC1
Reactant: CCN
Agent: [Na]
Solvent: CO
Product: CCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccsc23)CC1
Yield: 39 %

Procedure:
A solution of 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethyl ester (50 mg, 0.14 mmole), ethylamine (2 mL), and a catalytic amount of sodium cynide in MeOH (10 mL) is heated in a sealed tube at 70° C. oil bath for 48 hours. The solvent is removed on rotary-evaporator. The resulting residue is purified on a preparative tlc plate to give N-Ethyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide (20 mg, 39% yield) as a colorless oil. This material is dissolved in ethyl acetate (1 mL), diluted with HCl saturated ethyl acetate (2 mL), and concentrated to afford N-ethyl 1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide hydrochloride (compound 1, 26 mg ) as greasy oil. The salt is solidified with ether, collected by filtration, washed with ether, and dried in vacuo. m.p.>270° C. (dec).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([CH:7]=O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.Cl.[CH2:16]([NH:23][C:24]([N:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]=[C:2]1[CH2:3][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([CH2:7][N:33]2[CH2:32][CH2:31][CH:30]([N:26]([C:24]([NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:25])[CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:6]1
Reactant: CCCN(C(=O)NCc1ccccc1)C1CCNCC1
Reactant: C=C1C[C@@H](C=O)[C@H](c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C1CC(CN2CCC(N(CCC)C(=O)NCc3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (+−)-trans-4-methylene-2-phenylcyclopentanecarboxaldehyde from Step C (880 mg, 4.7 mmol) in 1,2-dichloroethane (50 mL) was added 4-(N-(benzylaminocarbonyl)-(N-prop-1-yl)amino)piperidine hydrochloride (1.62 g, 5.2 mmol) and DIPEA (1.0 mL, 5.7 mmol). After 15 min, sodium triacetoxyborohydride (2.0 g, 9.5 mmol) was added and the reaction was stirred at rt for 4 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC eluting with 60% ethyl acetate in hexanes to give the title product (1.8 g) as the free amine. MS (NH3/ESI): m/z 448 (M +1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:18]([CH2:19][O:20][CH3:21])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.ClOC(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCc2[nH]c3cccc(OCc4ccccc4)c3c2C1COC
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
10 mmol of 5-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ethyl ester is dissolved in 45 ml of methylene chloride. The solution is cooled to -15° C. and 4.6 ml of triethylamine is added Then a solution of 3.6 ml of tert-butyl hypochlorite in 45 ml of methylene chloride is added within about 10 minutes and stirred for 5 minutes more. After further addition of 3.8 ml of triethylamine, heating to ambient temperature and stirring at this temperature for 4 hours takes place. The solvent is distilled off in vacuum (bath temperature +30° C.) and condensed to dryness at +60° C. bath temperature. The residue is taken up in methylene chloride, filtered over silica gel, rewashed with methylene chloride, the product is eluted with ethyl acetate, the eluate is condensed and washed with ice water. The precipitate is filtered off and wahsed with ice-cold ethyl acetate. 2.93 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester (80.5% of theory) with melting point 190.0° C. is obtained.