Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=[O:21])[C:16]([C:17](O)=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]3[C:20](=[O:21])[O:22][C:17](=[O:18])[C:16]3=[C:11]2[N:10]=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)C(=O)OC3=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
A mixture of the 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylic acid (4.40 g, 14.2 mmol) and acetic anhydride is stirred for 5 hours at reflux temperature, cooled to 0° C. and filtered to give the title product as a pale yellow solid (3.78 g, 91.1%), identified by 1HNMR spectrography.
Reaction SMILES: Cl[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH3:16])[CH:6]=1)[C:3]#[N:4].[NH2:17][C:18]([NH2:20])=[S:19].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[CH:6]=[C:5]([CH:2]2[S:19][C:18](=[NH:20])[NH:17][C:3]2=[NH:4])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[CH3:16]
Reactant: NC(N)=S
Reactant: CCOc1ccc(C(Cl)C#N)cc1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2SC(=N)NC2=N)cc1OCC
Yield: 69.7 %

Procedure:
4.8 g of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile and 2.3 g of thiourea, in 70 ml of ethanol, are stirred under reflux for 1 hour. After cooling, the solution is poured in 200 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The extract is washed with water, dried (MgSO4) and distilled to remove the chloroform. The above procedure provides 3.9 g (69.6%) of 5-(3,4-diethoxyphenyl)-2,4-diiminothiazolidine, m.p. 185°-190° C.
Reaction SMILES: [Na].[CH2:2]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].O>C(O)C>[CH2:2]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[C@H]1CC[C@@H](C(=O)OCC)CC1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 20 °C

Procedure:
Sodium (7.5 g, 0.33 mol) was dissolved in anhydrous ethanol (200 ml) and ethyl cis-4-n-butylcyclohexanecarboxylate (13) was added. The reaction mixture was heated at reflux for 16 hr and was then cooled to 20° C. Water (38 ml) was added and the mixture was re-heated to reflux for a further 24 hr. The resulting mixture was evaporated to a small volume and the residue was dissolved in water (115 ml). The solution was acidified using concentrated hydrochloric acid and the product was then extracted into dichloromethane (4×50 ml). The combined dichloromethane extracts were evaporated to give predominantly trans-4-n-butylcyclohexanecarboxylic acid (11, 45.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.C1C(=O)N([I:24])C(=O)C1>C(Cl)Cl.CO>[I:24][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2cccc(C#N)c2)nc(N)n1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)nc(-c2cccc(C#N)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 3.2 g (12 mmol) 4-methyl-6-(3-cyano-phenyl)-pyrimidin-2-ylamine and 2.8 g (13 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.5 g (78%).
Reaction SMILES: [CH2:1]([C:5]1[C:9](=[NH:10])[S:8][N:7]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1=[CH:6][N:7]([C:11]([CH3:14])([CH3:15])[CH2:12][F:13])[S:8]/[C:9]/1=[N:10]\[C:20](=[O:21])[C:19]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:18]=1[O:17][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Reactant: CCCCc1cn(C(C)(C)CF)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)CF)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.7 %

Procedure:
To a solution of Example 152C (0.46 g, 2.0 mmol) in THF (10 mL) were added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (0.52 g, 2.2 mmol, JRD Fluorochemicals Ltd) and triethylamine (0.84 mL, 6.0 mmol). After stirring at 60° C. for 14 hr, the reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 75 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.22-1.46 (m, 2 H), 1.65 (s, 2 H), 1.65 (s, 6 H), 2.63-2.83 (m, 2 H), 3.89 (s, 3 H), 4.60 (d, J=47.1 Hz, 2 H), 7.31 (d, J=8.8 Hz, 1 H), 7.80 (dd, J=8.6, 2.5 Hz, 1 H), 8.10 (d, J=2.4 Hz, 1 H), 8.63 (s, 1 H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C20H24F4N2O2S: C, 55.54; H, 5.59; N, 6.48. Found: C, 55.75; H, 5.23; N, 6.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)cnc3c2c(C)nn3C)cc1
Yield: 77.6 %

Procedure:
A mixture of 1.34 g (2.7 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylate, 2.97 ml of 1N potassium hydroxide in 7.8 ml of ethanol and 4.83 ml of water was refluxed for 20 hr. Another 0.54 ml of 1N potassium hydroxide was added and the mixture refluxed 4 hrs. The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was dissolved in water (20 ml) and extracted with ethyl acetate. The aqueous layer was acidified with 2 N citric acid and the precipitated solid filtered off and washed with water. The solid was dried under vacuum to give 0.98 g of solid, mp 256-258° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[CH:12]=[CH:11]2)[CH:7]=[C:6]([N:20]=[N+]=[N-])[N:5]=1)=[N+]=[N-].C.[H][H]>CCOC(C)=O>[CH3:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:10]([C:8]1[CH:9]=[C:4]([NH2:1])[N:5]=[C:6]([NH2:20])[CH:7]=1)[CH:11]=[CH:12]2
Reactant: [H][H]
Reactant: Cc1cccc2ccn(-c3cc(N=[N+]=[N-])nc(N=[N+]=[N-])c3)c12
Solvent: CCOC(C)=O
Product: Cc1cccc2ccn(-c3cc(N)nc(N)c3)c12
Reaction time: 24 h

Procedure:
A crude reaction mixture from the preparation of 1-(2,6-diazidopyridin-4-yl)-7-methyl-1H-indole G1 (approx. 340 mg, 1.2 mmol in 2 ml crude mixture) is diluted with EtOAc (10 ml). Under an atmosphere of nitrogen palladium on activated charcoal (10 mg, 10% Pd) is added. At RT the atmosphere is replaced by hydrogen (5 bar) and stirring is continued for 24 h. The mixture is filtered and extracted with an aqueous 0.5 mol/l sodium hydroxide solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 120 mg (43%). HPLC-MS: M+H=239; tR=0.81 min (Method—2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc(C3CCNCC3)co2)cc1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A solution of 4-fluorobenzamide (4.54 g, 32.7 mmol) and t-butyl 4-(bromoacetyl)-piperidine-1-carboxylate (5.0 g, 16.3 mmol) in DMF (40 mL) was heated at 145° C. for 16 h. Upon completion of the reaction, the solution was allowed to cool to rt and concentrated to a dark oil. The oil was purified by reverse phase HPLC to afford the title compound (760 mg). LC/MS: m/e 247.08 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][CH2:8][C:9]([C:22](=[O:24])[CH3:23])([C:19](=[O:21])[CH3:20])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])(C)(C)C.Cl>C(O)(C)(C)C.O>[C:22]([C:9]([C:19](=[O:21])[CH3:20])([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][C:6]([OH:25])=[O:5])(=[O:24])[CH3:23]
Reactant: CC(=O)C(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)C(C)=O
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)C(CCC(=O)O)(CCC(=O)O)C(C)=O
Yield: 69 %

Procedure:
4,4-Diacetyl-heptanedioic acid di-tert-butyl ester was hydrolyzed at 95° C. over 5 hours using a mixture of tert-butanol and water as solvent and 11 weight-% hydrochloric acid. The solvent was removed and the obtained crude product was recrystallized from a mixture of acetone and petroleum ether (1:1) to yield 4,4-diacetyl-heptanedioic acid as white crystals at a yield of 69%. (melting point: 176° C.; purity 94%; colorless).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=1)[C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:19]
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1=C(C)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 93.8 %

Procedure:
N-[5-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.070 g, 0.144 mmol) was dissolved in methanol (4 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane (1:1) to obtain the titled compound (0.060 g, 0.135 mmol, 94%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:28])[NH:26][CH3:27])[CH3:23].[H-].[Na+].Cl.O>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:28])[N:26]([CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1)[CH3:27])[CH3:23]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)NC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
1.00 g (3.2 mmol) of 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) was dissolved in 20 ml of DMF. Then, the reaction mixture was cooled down to 0° C. 0.36 ml=0.366 g (3.52 mmol) of methyl-carbamic acid ethyl ester was added to the stirred solution, followed by 0.14 g (3.2 mmol) of sodium hydride (55%). After 18 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to <3 with HCl/H2O and it was then extracted twice with Et2O. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of EtOAc, n-heptane) to give 0.87 g of the title compound as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[N:17]1([CH2:22][CH2:23][O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:11]1([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:29]4[CH2:30][CH2:31][CH:26]([CH2:25][O:24][CH2:23][CH2:22][N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:27][CH2:28]4)=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: Clc1ncc2c(-c3ccccc3)csc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc(-c2csc3nc(N4CCC(COCCN5CCCC5)CC4)ncc23)cc1
Temperature: 150 °C
Yield: 26 %

Procedure:
2-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (150 mg, 0.61 mmol), 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (293 mg, 0.92 mmol) and potassium carbonate (253 mg, 1.83 mmol) were combined in acetonitrile (2 mL) and heated in the microwave at 150° C. for 30 minutes. The reaction mixture was diluted with DCM (10 mL), washed with water (10 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC to afford 5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (67 mg). LCMS [M+H]+=423.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CCN=C=O
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.02 mL, 0.137 mmol, 3 eq.) and ethyl isocyanate (0.005 mL, 0.068 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 15 mg (65%) of (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03-1.34 (m, 3 H) 1.56-1.96 (m, 4 H) 2.18 (br. s., 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.73-4.42 (m, 3 H) 5.05 (br. s., 1 H) 6.02 (d, J=5.84 Hz, 1 H) 7.09-7.63 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine was reacted with ethyl isocyanate according to the general procedure of Example 2. The crude product was purified by radial chromatography eluting with a gradient of 70% ethyl acetate/30% chloroform to 100% chloroform to give the title compound, 1-[2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-yl]-3-ethylurea, mp 185°-187° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:17])=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH:1]1([N:6]([CH3:18])[C:7]2[C:8]([CH3:17])=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(NC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 85.7 %

Procedure:
To a stirred solution of methyl 3-(cyclopentylamino)-2-methylbenzoate (2.2 g, 9.44 mmol) in acetonitrile (20 mL) was added cesium carbonate (6.13 g, 18.8 mmol) and methyl iodide (6.7 g, 47.2 mmol). The resulting mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered, washing with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford methyl 3-(cyclopentyl(methyl)amino)-2-methylbenzoate (2 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][S:11](=[O:13])(=[O:12])[NH2:14]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1cccc(Cl)c1Cl
Yield: 71.9 %

Procedure:
This compound was prepared according to the procedure of Example 84. Thus, a mixture of 16.3 g (0.10 mole) of 2,3-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene gave 17.4 g (72%) of the title compound as an off-white solid, mp 116°-117° C. (benzene).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)=[O:5].Br.Br[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ccc(NC(=O)CCBr)cc1
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CCBr)Nc1ccc(N2CCNCC2)cc1
Yield: 29.5 %

Procedure:
A mixture of 14.0 g of N-(β-bromopropionyl)-p-aminoaniline, 18 g of bis(β-bromoethyl)amine monohydrobromide and 70 ml of methanol was stirred under reflux for 15 hours. After cooling, the reaction mixture was added 3.06 g of potassium carbonate and stirred under reflux for 8 hours. After cooling, crystals which formed were collected by filtration and washed with methanol to give 5.3 g of N-(β-bromopropionyl)-p-piperazinylaniline. Production of the compound was confirmed by IR and NMR spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CCCCC.[CH2:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:28]([N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCc2ccccc2)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of 10.0 g (37 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 250 ml of anhydrous dimethylformamide was added with stirring to a suspension of 2.8 g (55.5 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 125 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture was heated at 90° for 2 hours, then cooled to 40°, at which time a solution of 14.0 g (74 mmoles) of phenethyl bromide in 20 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. The cooled solution was poured into ice-water and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, eluting with acetone-benzene). The major fraction was identified as N-phenethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1C(=O)C)(=[O:5])=[O:4].Cl[Si](C)(C)C.C([OH:26])C>S(=O)(=O)(O)O>[CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:26])(=[O:5])=[O:4]
Reactant: CCO
Reactant: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Product: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 100 %

Procedure:
A solution of N-methyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (170 mg, 0.55 mmol), 0.5 mL of chlorotrimethylsilane and 3 drops of fuming sulfuric acid in ethanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (160 mg, >100%). EI-MS (m/z) 265.2, 267.2 (M−).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:1][CH2:2][CH:3]2[CH2:6][CH2:5][O:4]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC1CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-N-(2-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (60 mg, 0.119 mmol) and (trans)-cyclohexane-1,4-diamine (136 mg, 1.191 mmol) in NMP (1 mL) was heated at 90° C. for 8 h and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) to obtain the pure product as a white solid, which was used without further purification.