Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].C(Cl)Cl.[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:3]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:1][CH3:2])=[O:36])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1ccccc1C(=O)c1ccccc1)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1

Procedure:
Twenty-four grams of trans N-(2-ETHYLAMINOCYCLOHEXYL)-p-TOLUENESULFONAMIDE from Example III,200 ml of methylenechloride, 24ml of triethylamine and 20 grams of ψ-acid chloride of o-benzoylbenzoic acid were mixed together and refluxed 4 hours. The mixture was extracted successively with water, 15% hydrochloric acid, and saturated sodium carbonate solution. The methylenechloride solution was dried over magnesium sulfate, then evaporated to dryness. The residue was slurried with ethyl acetate and filtered. Recrystallization from ethyl acetate afforded trans-2-BENZOYL-N-[2-(p-TOLUENESULFONAMIDO)CYCLOHEXYL]-N-ETHYL BENZAMIDE, mp. 201.5°-204°C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[CH:21][CH:20]=1>CCO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=3)[N:25]=2)[N:24]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CS(=O)(=O)Nc1cc(C#N)cc(C(=O)CBr)c1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(C#N)cc(-c2cn3nc(Cl)ccc3n2)c1
Yield: 50 %

Procedure:
A mixture of N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide (0.8 mmol) and 6-chloropyridazin-3-amine (0.8 mmol) in EtOH (8 mL) was refluxed for 4 hours. After cooling, the resulting mixture was filtrated to give N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide in 50% yield. 10% Pd/C (20 mg) was added to the solution of N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide (0.3 mmol) in THF (25 mL. Then it was stirred at room temperature for 4 hours. After filtration, it was concentrated to give N-(3-cyano-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide in 95% yield.
Reaction SMILES: COC.[CH3:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[C:13]([O:17][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH3:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: COCCCCCCO
Reactant: C=CC(=O)O
Agent: COC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OCCCCCCOC

Procedure:
803.6 grams of the monomethyl ether described in Part (A) above were azeotropically esterified with 629.8 grams acrylic acid in 254.6 grams toluene in the presence of 24 grams p-toluenesulfonic acid and inhibitors until no more water was collected. Conditions were 95°-98° C., nitrogen sparge in vacuo. On completion, the product was washed and neutralized with sodium carbonate. 900 ppm p-methoxyphenol (MEHQ) was added and the solvent removed at 80° C. with maximum vacuum in the presence of an air sparge. Filter aid was added and the product filtered at 60° C. to give a clear, yellow liquid having a viscosity of 6.5 cps and a Gardener color 3. Equipment used was a 2 liter flask, thermometer, Dean-Stark condenser and sparge tube.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[F:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(F)c1F
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1F
Yield: 21.1 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 840 mg of 2,3-difluoroaniline in place of the 2-fluoroaniline. 83 mg of N-(2,3-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1]C(OCC)=O.[CH3:7][O:8][N:9]=[C:10]([C:15]#[C:16][CH2:17]N1CCOCC1)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[Cl:1][CH2:17][C:16]#[C:15][C:10](=[N:9][O:8][CH3:7])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CON=C(C#CCN1CCOCC1)C(=O)OC
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CON=C(C#CCCl)C(=O)OC

Procedure:
1.4 ml of ethyl chloroformate are added to a solution of 12.1 g of methyl 2-methoxyimino-5-morpholin-4-ylpent-3-ynoate in 25 ml of THF. The mixture is now heated for 20 hours at 70°. After evaporation, the residue is chromatographed on silica gel (ether/hexane 1:2). This gives 8.2 g of colourless crystals of the title compound of melting point 64-67°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].COC(=O)C1C=C([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)C=C([N+]([O-])=O)C=1N>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Product: COC(=O)c1cc(-c2ccncc2)cc2[nH]c(N)nc12
Yield: 50 %

Procedure:
0.25 g (50% overall yield) of 2-amino-6-pyridin-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized according to procedures described for the synthesis of 2-Amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) starting from 0.5 g (1.8 mmol) of above synthesized 2-Amino-3-nitro-5-pyridin-4-yl-benzoic acid methyl ester. LCMS: 269 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:8]=2[S:7][C:6]=1[CH2:21][C:22]1[C:23]([CH3:28])=[N:24][NH:25][C:26]=1[CH3:27])=[O:4].[OH-].[Na+:30]>C1COCC1.O.CO>[Na+:30].[CH3:27][C:26]1[C:22]([CH2:21][C:6]2[S:7][C:8]3[N:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=3[C:5]=2[C:3]([O-:4])=[O:2])=[C:23]([CH3:28])[NH:24][N:25]=1
Reactant: COC(=O)c1c(Cc2c(C)n[nH]c2C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)[O-])c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Prepared from a solution of the product of step e) (19.0 g) and sodium hydroxide (2.52 g) in THF (400 ml), water (35 ml) and methanol (60 ml). After stirring at ambient temperature for 24 hours the precipitate was filtered off and washed with cold THF to give the sub-title compound as a white solid (17.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][N:9]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:8]2)[CH:2]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2cccnc2)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(pyridin-3-yl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+]=[N-].[Na+].O.CCOCC>CN1CCCC1=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([NH2:31])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(N)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 52 %

Procedure:
To a solution of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine (100 mg, 0.24 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added sodium azide (200 mg, 3.1 mmol). The resulting suspension was heated at 80° C. until the reaction was judged complete by thin layer chromatography. The mixture was cooled to room temperature and water and ether were added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (2:1 to 1:1 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (50 mg, 52%) as a yellow powder. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.87 (d, 1 H), 7.62 (d, 2 H), 7.27 (m, 1 H), 7.01 (d, 2 H), 6.37 (d, 1 H), 6.17 (d, 1 H), 5.39 (s, 2 H), 5.19 (d, 1 H), 4.39 (m, 1 H), 3.90 (s, 3 H), 2.10 (m, 2 H), 1.82–1.54 (m, 6 H); MS m/z 401(M+1).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:35]3[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1cccnc1)c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cccnc3)c3ccc(Cl)c(Cl)c3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (78.6 mg, 0.183 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (3,4-dichlorophenyl)(pyridin-3-yl)methanone (50.2 mg, 0.199 mmol, Intermediate 90: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 20 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (d, J=2.0 Hz, 1H), 8.32 (dd, J=4.8, 1.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.5, 0.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 2H), 7.53-7.48 (m, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.17 (dd, J=7.8, 4.7 Hz, 1H), 7.06 (dd, J=8.4, 2.2 Hz, 1H), 6.39 (dd, J=2.4, 1.9 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 3H); MS m/e 601.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:39])[CH2:26][CH2:27][C:28]3([C:33]([O:35]CC=C)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1CCOCC1>CN(C=O)C.C([Pd](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:39])[CH2:26][CH2:27][C:28]3([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)C1(CCC(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)[Pd](C(c2ccccc2)(c2ccccc2)c2ccccc2)(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(CCC1(C(=O)O)CCCC1)NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
Allyl 1-(3-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylamino)-3-oxopropyl)cyclopentanecarboxylate (360 mg, 0.676 mmol) was dissolved in DMF (15 mL) and cooled to 0° C. under nitrogen. Tetratritylpalladium (122 mg, 0.113 mmol) and morpholine (941 mg, 10.8 mmol) were added and the mixture stirred for 2 h. Solvent was removed under reduced pressure and material was purified by reverse-phase chromatography. Recovered 1-(3-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylamino)-3-oxopropyl)cyclopentanecarboxylic acid (54.4 mg, 0.110 mmol, 16.34% yield).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH:20]=[CH:19]1.O>O1CCCC1>[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]=[CH:19]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C1C=CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.2 g, 55 mmol) in tetrahydrofuran (100 ml) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (11.2 g, 50 mmol) over 30 min, and the mixture was stirred at room temperature for 1 h. To this was added 4,4-dimethyl-2-cyclohexene-1-one over 20 min and the reaction mixture was stirred for a further 1 h. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (9.7 g, 100%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCCc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.56 g (5.14 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]thiazolidine-2,4-dione and 0.46 ml (5.14 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.37 g (74.6%, light yellow oily substance) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: O=C(NC1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Agent: O=[Pt]
Product: Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
1-[2-(p-Nitrophenyl)ethyl]-4-benzamidopiperidine (3.0 g.) was hydrogenated in absolute alcohol (400 ml.) at 50 p.s.i. and 20° C. for 3 hours in the presence of 300 mg. of platinum oxide as catalyst. The catalyst was filtered off and the solution evaporated to give the crude product as a foam. Crystallisation from a mixture of benzene and n-hexane gave the title compound, m.p. 193°-195° C. (Found: C, 74.4; H, 7.9; N, 12.9. C20H25N3O requires C, 74.3; H, 7.8; N, 13.0%).
Reaction SMILES: [ClH:1].[C:2]([NH:6][CH2:7][C:8]#N)([CH3:5])([CH3:4])[CH3:3].[CH2:10]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[OH:26])=[O:16])[CH2:11][CH2:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[N+](C1C=CC=CC=1)([O-])=[O:33]>>[ClH:1].[CH2:10]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([C:8](=[O:33])[CH2:7][NH:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH:22]=[CH:21][C:20]=2[OH:26])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(=O)c1cc2cccc(O)c2[nH]1
Reactant: CC(C)(C)NCC#N
Reactant: O=[N+]([O-])c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCOC(=O)c1cc2c(C(=O)CNC(C)(C)C)ccc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under ice cooling and agitation, 818 mg of tert-butylaminoacetonitrile hydrochloride and 1.2 g of 7-hydroxyindole-2-carboxylic acid n-butyl ester are added to a solution of 2.7 g of aluminum chloride in 20 ml of nitrobenzene. Then gaseous hydrogen chloride is introduced into the mixture at 0° to 3° C. for 7 hours, the reaction mixture is stirred for 16 hours at 0°-3° C., and then poured into ice water. The mixture is agitated for 10 minutes and then the precipitate is vacuum-filtered. The precipitate is recrystallized from isopropanol, thus obtaining 765 mg of 4-tert-butylaminoacetyl-7-hydroxyindole-2-carboxylic acid n-butyl ester hydrochloride, decomposition point 203°-208° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]2[N:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[N:11]=[C:12]([CH3:13])[C:3]=12.[CH3:23][C:24]1C=C[C:27](S(O)(=O)=O)=[CH:28][CH:29]=1.C([NH:36]CCC)C>CS(C)=O.[Cu](Br)Br>[CH2:24]([CH:29]([NH:36][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]2[N:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[N:11]=[C:12]([CH3:13])[C:3]=12)[CH2:28][CH3:27])[CH3:23]
Reactant: CCCNCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)c(C)c(C)nc32)c(C)c1
Agent: Br[Cu]Br
Solvent: CS(C)=O
Product: CCC(CC)Nc1c(C)c(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of 4-chloro-3,5,6-trimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin (227 mg, 0.72 mmol), p-TsOH (124 mg) and ethylpropylamine (0.5 ml) in 1 ml of dimethylsulfoxide (DMSO) was heated at reflux for 4 hours (thin layer chromatography showed no reaction). Copper bromide (40 mg) was added and the reaction was heated for an additional 15 hours at reflux. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (EtOAc). The organic layer was washed with brine, dried and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using chloroform (CHCl3) and hexane in a ratio of 8:3 as eluent to give the title compound as a colorless oil. 1H NMR (CDCl3) 6.92 (s, 2H), 3.97 (d, 1H, NH), 3.56 (brs, 1H, OH), 2.70 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 1.89 (s, 6H), 1.4˜1.7 (m, 4H), 0.94 (t, 6H) ppm. The compound was prepared as the corresponding HCl salt as an off-white crystals after recrystallization from a solvent mixture of ethyl ether and ethyl acetate, mp 201-205° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[NH:11][C:12]([NH:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[C:13]2[C:17]([N:18]=1)=[N:16][CH:15]=[N:14]2>C(Cl)Cl.CO>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[NH:11][C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)=[C:13]3[C:17]([N:18]=2)=[N:16][CH:15]=[N:14]3)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Nc2[nH]c(N[C@H]3CC[C@H](N)CC3)nc3ncnc2-3)cc1
Product: Cl

Procedure:
970 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.), 269 mg of the product obtained in stage 1 above are added and the medium is then heated at 140–145° C. for 4 hours. The medium is allowed to return to room temperature and it is taken up in 50 ml of a CH2Cl2-methanol: 80-20 mixture. The medium is washed twice with 20 ml of H2O and once with 20 ml of sodium chloride as a saturated aqueous solution. The medium is dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]2[O:9][N:10]=[C:11]([OH:12])[C:6]2=[CH:5][CH:4]=1.[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:16]=[O:17]>C1COCC1>[CH2:18]([NH:15][C:16]([N:10]1[C:11](=[O:12])[C:6]2[C:7](=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)[O:9]1)=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Oc1noc2nc(C(F)(F)F)ccc12
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1oc2nc(C(F)(F)F)ccc2c1=O

Procedure:
In analogy to example 1c, 47 mg (0.23 mmol) of 6-trifluoromethylisoxazolo-[5,4-b]pyridin-3-ol were reacted with 34.9 mg (0.27 mmol) of 1-isocyanatohexan in THF. Yield: 15 mg (20%), M+H+: 332.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccncc3)c(Cl)cc21
Yield: 103.9 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (250 mg), 4-aminopyridine (68.4 mg) and 2-chloro-1-methylpyridinium iodide (222 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-chloro-N-(4-pyridyl)thiochromane-7-carboxamide (317 mg) was obtained as a colorless amorphous solid.