Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[C:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][NH2:30])[CH2:24][CH2:23]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[O:39]1CCC[CH2:40]1>>[C:1]([NH:5][C:40]([NH:30][CH2:29][C:28]([N:25]1[CH2:24][CH2:23][C:22](=[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=3[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]2=3)[CH2:27][CH2:26]1)=[O:31])=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: C1CCOC1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 1 h

Procedure:
A solution of 36.6 mg (0.50 mmol) of t-butylamine in 1 ml of tetrahydrofuran was slowly added to the resultant solution at 0° C. in argon stream. After stirring for 1 hour, a solution of 110.7 mg (0.30 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride and 30.3 mg (0.30 mmol) of triethylamine in 1 ml of tetrahydrofuran was slowly added thereto. After stirring for 2 hours, the solvent was evaporated and the product was purified by the silica gel chromatography (hexane:ethyl acetate=85:15 to 3:2) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH3:35])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2([CH3:35])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC1(CBr)COC1
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OC
Temperature: 80 °C
Yield: 29.3 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and 3-(bromomethyl)-3-methyloxetane (132 mg, 0.798 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 29%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (70 g, crude, 0.1 mol) and DMAP (1.83 g, 15 mmol, 0.15 eq) in dry CH2Cl2 (150 mL), Et3N (12.1 g, 15.8 mL, 120 mmol) was added. The resulting mixture was cooled to 0˜5° C. using a ice-water bath, a solution of methyl chloroformate (11.28 g, 120 mmol, 1.2 eq) in dry CH2Cl2 (100 mL) was added drop wise. After addition, the reaction mixture was stirred for 3 h at 0˜5° C. TLC showed the starting material had disappeared. Water (80 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers were washed with 10% citric acid (2×150 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)-methyl)piperidine-1-carboxylate (10.7 g, the total yield for three steps is 25%). 1H NMR (400 MHz, CDCl3):1.12-1.40 (m, 4H), 1.43 (s, 9H), 1.64 (m, 2H), 2.82 (m, 2H), 3.25 (m, 2H), 3.61 (s, 3H), 3.74 (m, 1H), 4.05 (m, 1H), 4.16 (m, 1H), 7.22 (m, 1H), 7.32 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[I-:12].[K+].C(OCC)(=O)C>C(O)(=O)C>[Cl:8][C:7]1[C:2]([I:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(I)c(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 2,3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100° C. for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 mL) added. The organic phase was separated and washed with water (2×100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[O:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:15][CH:16]=1)[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(CCNCc2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of 4-benzoxybenzaldehyde (2.5 g, 12.6 mmol), 3-methoxyphenethyl amine (1.9 g, 12.6 mmol), a catalytic amount of p-toluenesulfonic acid monohydrate in absolute ethanol (12 mL) was stirred at 80° C. for 1.5 hours. After cooling to room temperature, NaBH4 (0.49 g, 13.0 mmol) was added in portions. The reaction mixture was stirred at 80° C. for 1 hour, then cooled to room temperature, and the ethanol was removed in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined extracts were washed with saturated NaCl, dried over MgSO4, filtered, and solvent removed in vacuo to afford a colorless oil which was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane saturated with NH3 to afford the title compound (3.2 g, 76%) as a colorless oil. MS (DCl/NH3) m/e 334 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.82 (t, 2H), 2.92 (t, 2H), 3.77 (s, 2H), 3.80 (s, 3H), 6.80 (m, 3H), 6.98 (m, 3H), 6.08 (t, 1H), 7.22 (m, 3H), 7.32 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C[O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH:34]=O)[CH:28]=1.[OH-].[K+].Cl>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:13]=[CH:34][C:29]4[C:30](=[CH:31][CH:32]=[C:27]([C:26]([OH:25])=[O:36])[CH:28]=4)[N:33]=3)=[CH:10][C:9]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])=[CH:8][CH:7]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a mixture of Compound 259a (0.388 g, 1.184 mmol) and Compound 7 (0.223 g, 1.243 mmol) was added a solution of KOH (0.234 g, 3.55 mmol) in EtOH (18 mL). The reaction mixture was stirred under Ar at 75° C. for 16 h. EtOH (10 mL) was added to make a clean solution, which was neutralized by adding 4 N HCl in dioxane (about 1 mL) to pH 3. After evaporation of solvent, H2O (15 mL) was added and the precipitates were collected by filtration, washed with water and dried. Yield 0.125 g, 89%. MS: 457.12, 458.13 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[CH3:22]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) in dichloromethane (10 mL) at 0° C. was added ethyl chloroformate (0.9 mL, 9.16 mmol) dropwise. The ice bath was removed and the solution was allowed to warm to room temperature and stirred for an additional 16 hours. Afterwards dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil (1.65 g, 100%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([N:20]([CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:26]
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: NCC1CCCCC1
Product: O=C(NCCCl)N(CC1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 61.8 %

Procedure:
3.6 g of D-galactose, 4.5 g of cyclohexylmethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 4.7 g of 1-(2-chloroethyl)-3-cyclohexylmethyl-3-(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:34])[NH:11][N:12]1[CH2:18][CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=2[CH2:14][CH2:13]1)[CH3:8].S(OC)(OC)(=O)=O.O>O1CCCC1>[CH2:7]([O:9][C:10](=[O:34])[N:11]([CH3:1])[N:12]1[CH2:18][CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=2)[C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=2[CH2:14][CH2:13]1)[CH3:8]
Reactant: CCOC(=O)NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CCOC(=O)N(C)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Potassium-t-butoxide (3 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)3-benzazepin-3-yl]carbamic acid ethyl ester (8 g) in 100 ml tetrahydrofuran. After thirty minutes, a solution of dimethyl sulfate (3.1 g) in 25 ml tetrahydrofuran was slowly added. After one hour, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated. The residue was triturated with ether to yield 6 g solid, mp 204°-205°. A 2 gram sample was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 218°-219°.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.N#C[Br:16].CCOC(C)=O>C(#N)C>[Br:16][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccnc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 107 (100 mg, 0.50 mmol) in acetonitrile (1 mL) at room temperature was added cyanogen bromide (107 mg, 1.0 mmol) and the mixture was allowed to stir at room temperature for 3 h, concentrated to dryness and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (eluents EtOAc/hexane 25:75, then EtOAc), to afford the title compound 108 (45 mg, 32% yield) as a colorless oil. MS (m/z) 277.0/279.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:11]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[C:3]1=O.Cl.O>C1COCC1>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2[N:11]3[C:10]4[C:9]([C:13]=2[CH2:14]1)=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]([CH3:23])[CH2:3][C:2]3([CH3:1])[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)C(=O)N4C)C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (240 mg, 0.7 mmol) in THF (20 mL) at 25° C. was added BH3/THF complex (0.7 mL, 0.7 mmol). The mixture was stirred at 80° C. for 5 hours then cooled to rt and added 6N HCl (10 mL) with stirred for another 1 hr. About 30 mL of H2O was added and then was extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil (152 mg, 66%). MS [M+H]+327. 1H NMR (CDCl3, 300 MHz) δ 7.01 (t, 1H, J=7.7 Hz), 6:97 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.7 Hz), 4.68 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 3.11 (m, 2H), 2.99 (s, 3H), 1.54 (s, 6H), 1.27 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(OCC)(=O)C.O>N1C=CC=CC=1>[C:20]([O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCC[C@@H](O)C(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC[C@@H](OC(C)=O)C(=O)O
Reaction time: 12 h

Procedure:
To (R)-(+)-2-hydroxyhexadecanoic acid (0.5 g; prepared according to the method described in Agric. Biol. Chem., 54(12), 3337-3338, 1990) dissolved in pyridine (15 ml) was added acetic anhydride (0.23 ml) at 0° C., and the mixture was stirred 12 hours. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried and concentrated to give (R)-(-)-2-acetoxyhexadecanoic acid (0.52 g). The acetoxy derivative was dissolved in DMF (20 ml), and N-hydroxysuccinimide (191 mg) and N,N'-dicyclohexylcarbodiimide (342 mg) were added to the solution at 0° C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered, and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (0.65 g) and triethylamine (1.1 ml) were added to the filtrate. The mixture was stirred for 12 hours. After the reaction mixture was concentrated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK198 in the yield of 119 mg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:23])([CH3:22])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9][CH:10](O)[CH2:11][C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13].O>CO>[CH3:2][O:3][C:4]([CH3:22])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9]/[CH:10]=[CH:11]/[C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13]
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(C)(C)CCCC(C)C/C=C/C(=O)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
1 ml of methanol saturated with hydrochloric acid is added to a solution of 2.1 g (0.007 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 15 ml of dry methanol, and the mixture is allowed to stand at room temperature for 12 hours. 2 ml of water are added to the mixture, and the mixture is stirred at room temperature for 5 hours. The solvent is distilled off in vacuo, the residue is taken up in ether, the etheral solution is washed with water, dried, and the solvent is distilled off. The residue is purified by chromatography (adsorbent: Kieselgel 60, solvent: a 10:0.1 mixture of benzene and methanol). 1.4 g (70%) of the aimed compound are obtained; Rf =0.75 (developed with a 10:0.1 mixture of benzene and methanol).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C1COCC1.C(OC(=O)C)C>[CH:5]1([CH2:4][N:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: BrCC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCN(CC2CC2)CC1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Add bromomethylcyclopropane (2.025 g, 15 mmol) to a solution of 4-hydroxypiperidine (3.035 g, 30 mmol) in THF (10 mL) and stir the mixture overnight. Dilute the mixture with ethylacetate, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 8% 2M NH3-methanol in CH2Cl2) provides 1.087 g (47%) of the title compound: mass spectrum (ion spray): m/z=156.2 (M+1); 1H NMR (CDCl3, ppm): 3.60 (m, 1H), 2.81 (m, 2H), 2.16 (d, 1H), 2.10 (m, 3H), 1.84 (m, 2H), 1.53 (m, 3H), 0.79 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:50]=[CH:49][C:20]([C:21]([N:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]4[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42][CH2:41]4)=[O:39])[CH3:24])=[O:22])=[CH:19][C:18]=3[O:51][CH3:52])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:53]=O.[C:55]([BH3-])#[N:56].[Na+].[ClH:59]>CO.C(O)(=O)C.C(O)C>[ClH:59].[ClH:59].[CH3:53][N:56]([CH3:55])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:50]=[CH:49][C:20]([C:21]([N:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]4[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42][CH2:41]4)=[O:39])[CH3:24])=[O:22])=[CH:19][C:18]=3[O:51][CH3:52])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1-c1ccc(N)cc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1-c1ccc(N(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(4′-aminobiphenyl-2-carboxamido)-3-methoxy-N-[2-[5-(4-dimethylaminopiperidin-1-ylcarbonyl)pent-1-yloxy]-4-methylphenyl]-N-methylbenzamide (180 mg) and 37% formalin (3 ml) in methanol (20 ml) and acetic acid (0.5 ml) was added sodium cyanoborohydride (80 mg) at ambient temperature. The mixture was stirred at same temperature for 3 hours and quenched with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate, brine and dried over sodium sulfate. The solvent was removed by evaporation and the crude product was purified by preparative thin layer chromatography (10% methanol in chloroform) to give free product. To a solution of this product (120 mg) in ethanol (10 ml) was added 1N hydrochloric acid (0.33 ml) and stirred at ambient temperature for 10 minutes. The solvent was removed to give 4-(4′-dimethylaminobiphenyl-2-carboxamido)-3-methoxy-N-[2-[5-(4-dimethylaminopiperidin-1-ylcarbonyl)pent-1-yloxy]-4-methylphenyl]-N-methylbenzamide dihydrochloride (130 mg) as amorphous.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:27][C:28]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:6][CH2:7]1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: Cc1ccccc1
Product: O=C(NC(=S)NC1CCN(Cc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042m) and benzoylisothiocyanate (0.69 g, 0.0042 m) in toluene (120 cm3) was stirred at room temperature for 6 hours. The solvent was evaporated and the gum dissolved in isopropyl alcohol and acidified with ethanolic HCl. The solvent was evaporated and the residue dissolved in ethyl acetate. The title compound crystallised and was filtered and dried as the monohydrochloride quarterhydrate salt, m.p. 212°-214° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:7])[CH3:2].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1.[OH-].[K+]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:7])[CH3:2]
Reactant: ClCc1ccncn1
Reactant: CCOC(=O)CC(=O)Nc1ccc(I)cc1F
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
N-(2-Fluoro-4-iodo-phenyl)-malonamic acid ethyl ester (20.5 g, 58.4 mmol), 4-chloromethyl-pyrimidine (5.0 g, 38.9 mmol) and potassium hydroxide (3.28 g, 58.4 mmol) were dissolved in IMS (200 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10-40% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (6.9 g, 39%). LCMS (Method B): RT=3.29 min, M+H+=444.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=1.O>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]=[C:11]([Cl:16])[N:10]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCC2CC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
109 mg of cyclopropylcarbinol was dissolved in 2 ml of dimethylformamide, and 60 mg of 60% sodium hydride was added thereto under ice water cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 400 mg of 2,4,6-trichloropyridine, and stirred at room temperature for 30 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the objective compound as colorless oil.