Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:10]=1[CH2:11][NH:12][C:13](=[O:25])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[C:16]([O:23][CH3:24])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40]C)=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:37][C:38]([OH:40])=[O:39])[C:9]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:10]=1[CH2:11][NH:12][C:13](=[O:25])[C:14]1[CH:15]=[C:16]([O:23][CH3:24])[C:17]([CH3:22])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCc2ccccc2)cc(OC)c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(CC(=O)O)Cc2ccccc2)cc(OC)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Compound 23a (163 mg, 0.35 mmol), methyl bromoacetate (0.166 mL, 1.75 mmol), and potassium carbonate (145 mg, 1.05 mmol) in DMF (2 mL) was sealed in a pressure tube and heated at 80° C. overnight. The reaction mixture was filtered through a silica gel pad in ethyl acetate and concentrated on a rotary evaporator. The residue was dissolved in a mixture of THF (3 mL) and MeOH (1 mL) and 10% LiOH (2 mL) was added. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated on a rotary evaporator, dissolved in water (50 mL), and acidified with conc. HCl. The white precipitate was filtered and dried invacuo to give compound 23b (155 mg, 83%). ESI-MS m/e 531.3 (M+1).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[CH3:10][CH2:11][C:12](=[O:15])[CH2:13][CH3:14]>O1CCCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH2:4][CH2:3][C:12]([CH2:13][CH3:14])([OH:15])[CH2:11][CH3:10]
Reactant: FC(F)(F)CCCBr
Reactant: CCC(=O)CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCC(F)(F)F
Reaction time: 1 h
Yield: 76.1 %

Procedure:
1.3 g of magnesium, 10.0 g of 1-bromo-4,4,4-trifluorobutane and 20 g of tetrahydrofuran were added to a four-necked flask equipped with a nitrogen feeding pipe, a reflux condenser, a dropping funnel and a thermometer, and a Grignard reagent was prepared by a conventional method. Then, a mixture containing 5.0 g of 3-pentanone and 4 g of tetrahydrofuran was dropwise added to the obtained Grignard reagent at a temperature of 25 to 35° C. over 30 minutes, followed by stirring at the same temperature for 1 hour. The reaction mixture was treated by a conventional method, and the resulting organic phase was washed with water, followed by drying with anhydrous magnesium sulfate. Thereafter, the resultant was concentrated under reduced pressure, thereby obtaining 7.9 g of 7,7,7-trifluoro-3-ethyl-3-heptanol in the form of a pale yellow oily matter.
Reaction SMILES: Cl.[C:2]([NH:10][NH2:11])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-:12][C:13]#[N:14].[K+]>O>[C:2]([NH:10][NH:11][C:13]([NH2:14])=[O:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNC(=O)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A four neck flask (1000 ml) equipped with a thermometer and a stirrer was charged with 78.2 g (0.75 mol) of 35% hydrochloric acid and 700 ml of deionized water. Added thereto was 68.0 g (0.5 mol) of benzohydrazide at room temperature (20° C.) while stirring, and then 60.7 g (0.75 mol) of potassium cyanate was gradually added in 30 minutes. Stirring was continued at 30° C. for one hour, and then crystal was filtered off and washed with 200 ml of deionized water. This was dried under reduced pressure to obtain white crystal.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([Cl:26])[CH:18]=1>ClCCl.CCCCCC>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[C:19]([Cl:26])[CH:18]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (700 mg, 3.31 mmol) in dry dichloromethane (15 mL) was added 4-bromo-2-chloro-1-isocyanatobenzene (770 mg, 3.31 mmol). The reaction was stirred overnight, diluted with hexane (15 mL), and the precipitate collected and washed with hexane to provide the title compound (1.3 g, 2.93 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.85 (br. s, 1H), 8.82 (br. s, 1H), 8.50-8.23 (m, 1H), 8.05 (dd, J=5.3, 8.8 Hz, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 3.81 (dd, J=7.6, 9.9 Hz, 0.5H), 3.77-3.39 (m, 2H), 3.31-3.13 (m, 1H), 2.94 (d, J=19.5 Hz, 0.5H), 2.64-2.54 (m, 0.5H), 2.47-2.39 (m, 0.5H), 2.28 (dd, J=7.3, 16.7 Hz, 2H), 2.17-1.88 (m, 1H), 1.80-1.47 (m, 2H), 0.81-0.61 (m, 4H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]1>CN(C)C=O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:37][CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][C:20]2[N:19]([CH2:18][C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)[CH2:30][CH2:31]1)=[O:11]
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred mixture of 4.9 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 45 parts of N,N-dimethylformamide were added dropwise 10.15 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 45 parts of C at 50° C. Upon completion, stirring was continued for 4 hours at 70° C. After cooling, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 10 parts (73%) of 2-amino-N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]benzamide; mp. 125.7° C. (466).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14.0 g of 4-nitrophenol in 250 ml of dimethylformamide is treated with 6.0 g of sodium methoxide. After 15 minutes, 28.2 g of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione is added, and the mixture then stirred at room temperature for 16 hours. The reaction mixture is diluted with 1500 ml of cold water, the precipitated solid collected, washed with water, and dried. Recrystallization from ethanol gives the desired compound, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:7][CH:6]=1)=[O:4].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Temperature: 20 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 12.3 mL, 12.3 mmol) slowly at 20° C. After stirring 0.5h, iodomethane (0.96 mL, 15.4 mmol) was added and the mixture was stirred for 3 h at 20° C. After quenching with water, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried (anhyd Na2SO4) and concentrated under reduced pressure to yield 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester as an oil (2.8 g, 92%), which was used in the next step without purification. MS (ES): 298 (MH+). To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]#[N:25])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([N:30]([CH3:40])[C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].[N-:43]=[N+:44]=[N-:45].[Na+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]3[NH:45][N:44]=[N:43][N:25]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([N:30]([CH3:40])[C:31]([NH:33][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccc(Cl)cc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccc(Cl)cc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-methyl-amino)-benzimidazol-1-yl)-methyl]-4-chloro-2-cyano-biphenyl and ammonium chloride/sodium azide.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][C:9]21[CH2:12][O:11][CH2:10]2)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[OH-].[OH-].[Pd+2]>[CH2:10]1[C:9]2([CH2:13][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][NH:8]2)[CH2:12][O:11]1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C2(COC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1CNC2(COC2)C1
Yield: 105.3 %

Procedure:
A solution of ethyl 5-benzyl-2-oxa-5-azaspiro[3.4]octane-7-carboxylate (550 mg, 2.00 mmol) in 30 mL of EtOH was stirred with 10% Pd(OH)2/C(105 mg) in the presence of TFA (20 μL) at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in 20 mL of DCM and washed with saturated Na2CO3 (20 mL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to afford ethyl 2-oxa-5-azaspiro[3.4]octane-7-carboxylate (390 mg, yield: 100%) as viscous oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27]Br)=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1.C(=O)(O)[O-].[K+]>O1CCCC1>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27][N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(CN3CCN(Cc4ccccc4)CC3)cc(=O)oc2c1

Procedure:
0.03 mol of 1-benzylpiperazine, 0.03 mol of 7-methoxy-2-oxo-4-bromomethyl-3-chromene and 0.03 mol of potassium bicarbonate are introduced into an Erlenmeyer flask containing 150 ml of tetrahydrofuran. The mixture is brought to reflux for 24 hours. The reaction is brought to an end and, after cooling, the solution is filtered and evaporated under reduced pressure. The residue is then purified by chromatography on a column of silica gel, methylene chloride generally being used as eluent. The final product is thus obtained in the base form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH2:15]3)[CH2:9]1)[CH2:11]2)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(O)(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
5.6 g (21 mmole) of tert-butyl(3-hydroxy-1-adamantyl)carbamate are dissolved in 80 ml of dichloromethane, 4.4 ml (31.5 mmole) of triethylamine are added to it. The mixture is cooled to 0° C. and 1.82 ml (23.5 mmole) of methanesulphonyl chloride is added to it dropwise. The reaction mixture is stirred at that temperature for 45 minutes, then washed consecutively with water and saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, evaporated, the residue is purified by column chromatography (n-hexane—ethyl acetate—chloroform 2:1:1) and crystallised from n-hexane, to obtain 2.9 g (40%) of product: Mp.: 100-102° C. 1H-NMR (DMSO-d6): 1.37 (s, 9H), 1.48 (s, 2H), 1.77 (q, 4H), 2.05 (t, 4H), 2.17 (d, 2H), 3.10 (s, 3H), 6.66 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
Following the procedure of Example 5, 2.5 g of 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.11 ml of isovaleryl chloride is transformed to 1.03 g of title product with melting point 93°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11]>C(OCC)(=O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: COc1cc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)ccc1OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)ccc1OS(C)(=O)=O
Yield: 7.3 %

Procedure:
1.5 g (33.4 mmole) 5-(4-[2-(3-methoxy-4-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated on Pd/C (10%) in 150 ml ethyl acetate and 5 ml acetic acid at atmospheric pressure over night. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was crystallized in ethanol to give 1.1 g (yield 73%) of the desired product.
Reaction SMILES: C[C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:28]([NH:32][C:12]([C:9]1[C:8](=[O:15])[N:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1cnc2ccccn2c1=O
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
A mixture containing i6.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 15 minutes. After stirring for 5 minutes, 6.43 g (0.088 mol) of butylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -15° C. during 50 minutes. The reaction mixture is stirred for 1 hour at the same temperature and then let to stand under cooling by ice. For working up, the mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 14.9 g (71.8%) of the named product as yellow crystals, m.p.: 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][O:12][CH3:13])=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(Cl)c(CO)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-dichloro-3-(methoxymethoxy)benzyl alcohol (1.1 g) and triethylamine (563 mg) in dichloromethane was added a solution of methanesulfonyl chloride (585 mg) in dichloromethane at <20° C. over 5 minutes under nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes and under ice-cooling for 30 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1,3-dichloro-2-methanesulfonyloxymethyl-4-(methoxymethoxy)benzene.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10])(C)(C)C.[Cl:44]CCCl>Cl.O1CCOCC1>[ClH:44].[NH2:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10]
Reactant: ClCCCl
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
[2-[2-Ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 40, is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 1 hour, then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1.1 g (99% yield) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CCOC(C)=O.O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=2)=[CH:15][CH:14]=1
Reactant: OCCc1cccc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNc2cccc(CCO)n2)cc1

Procedure:
Chloropyridine 30-2 (150 mg, 0.95 mmol) and 4-methoxybenzylamine (4 mL, 31 mmol) were combined neat and heated in a sealed tube at 160° for 4 days. After diluting with EtOAc and water the pH was adjusted to 7 phases separated and the organic phase was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (twice on silica, 50% and 40% EtOAc/hexane) provided 30-3 as a yellow semi-solid.
Reaction SMILES: C(OCC)C.O=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[C-:20]#[N:21].[Na+].C(=O)([O-])O.[Na+]>O>[C:20]([C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)#[N:21]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC=C(C#N)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Diethyl ether (15 ml) and 8 ml of water were added to 790 mg of tert-butyl 4-oxopiperidine-1-carboxylate, 216 mg of sodium cyanide and 672 mg of sodium hydrogen carbonate and the solution was stirred at room temperature for 1.5 hours. The resulting product was extracted with ether, washed with water and a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, 10 ml of chloroform, 0.84 ml of triethylamine and 0.34 ml of methanesulfonyl chloride were added to the resulting residue followed by stirring at room temperature for 20 minutes. The reaction was stopped by water, the product was extracted with chloroform and the organic layer was washed with a saturated sodium hydrogen carbonate and a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo, 10 ml of pyridine was added to the resulting residue and the mixture was stirred for one night under heating to reflux. After cooling to room temperature, the solvent was evaporated in vacuo followed by adding ethyl acetate and water. The organic layer washed with a saturated saline solution and dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=6/1) to give 650 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH2:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C)C=O>[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH:51][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 72 h
Yield: 95 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95 g) were added to a solution of (±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.00 g) in N,N-dimethylformamide (10 ml) at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and dichloromethane (30 ml), a saturated aqueous solution (150 ml) of sodium hydrogencarbonate and water (150 ml) were added to the residue. After collecting colorless precipitate formed was collected by filtration and dried to obtain the title compound (5.21 g) as a colorless solid.