Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17]CC3C=CC(OC)=CC=3)=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 94.6 %

Procedure:
(6)In 45 ml of ethanol was dissolved 9.10 g (20.1 mmol)of 5-(3,5-dichlorophenylthio)-1-methyl-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17b), followed by addition of 90 ml of 6N-hydrochloric acid, and the mixture was refluxed for 1 hour. This reaction mixture was concentrated under reduced pressure to remove ethanol and the residue forming a couple of layers was extracted twice with n-hexane to remove p-methoxybenzyl chloride. The aqueous layer was extracted with methylene chloride and the extract was neutralized with an aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was rinsed with isopropyl ether to provide 6.3 g (yield 95%)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (12=Compound I-8). mp 157-158° C.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[N:3]=1.[NH2:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[N:3]=[C:2]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(-c3cccnc3)no2)n1
Product: COCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3cccnc3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-methoxymethyl-2-[2-{3-(pyrid-3-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 35(a)) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [N:1]1([C:15](=[O:18])[CH2:16][CH3:17])[C@H:10]2[C@@H:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[N+:19]([O-])([OH:21])=[O:20].O.S(=O)(=O)(O)O>[N+](C)([O-])=O>[N+:19]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][C@@H:10]3[C@H:5]([CH2:4][CH2:3][CH2:2][N:1]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][C:7]=2[CH:14]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)N1CCC[C@@H]2Cc3ccccc3C[C@H]21
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(=O)N1CCC[C@@H]2Cc3cc([N+](=O)[O-])ccc3C[C@H]21
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
2.5 g trans-1-(3,4,4a,5,10,10a-Hexahydro-2H-benzo[g]quinolin-1-yl)-propan-1-one (10.27 mmol) were dissolved in 25 ml nitromethane. At −5° C. to −10° C., a mixture of 0.71 ml of nitric acid (10.27 mmol), 1.5 ml of water, and 9.5 ml of sulphuric acid (170 mmol) were added within 30 minutes. Stirring continued for 1.5 h under cooling conditions before the mixture was poured onto crushed ice. The aqueous phase was extracted twice with ethyl acetate, the combined organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 2.7 g of the nitrated product as a mixture of several nitro-isomers, which was used in the subsequent reaction without further separation.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[N:30](C2CCCCO2)[N:29]=1>>[OH:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:31]3[NH:30][N:29]=[C:28]([CH3:27])[CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(Br)c1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 37 using 5-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 37.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 41.1) to afford a white lyophilizate. HPLC (Condition 7) tR=5.50 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 3.59-3.67 (m, 2H) 3.99-4.08 (m, 2H) 4.37-4.45 (m, 1H) 6.21 (s, 1H) 7.35 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, J=9.40 Hz, 2H) 8.11 (d, J=1.96 Hz, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.28 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1.[OH-].[Na+].O>C(O)(=O)C>[OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc(Nc2ccccc2O)[nH]c1=O
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Ethyl 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3 g). M.p. 254°-256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:27][C:25]([CH2:24][N:18]1[C:17](=[O:22])[CH:16]([CH2:15][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10](=[O:14])[N:11]3[CH3:13])[S:20][C:19]1=[O:21])=[O:26]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)SC(Cc2ccc(OC)c3c2ccc(=O)n3C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
350 mg of 5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.156 ml of methyl bromoacetate and 0.25 g of potassium carbonate were added to the solution, followed by stirring at room temperature overnight. Water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography and recrystallized from methanol-acetone, giving 245 mg (57% yield) of 3-methoxycarbonylmethyl-5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as white crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[NH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)CCN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)CCNc1ccc(C(=O)N(CC)CC)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.4 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), ethyl 3-aminopropanoate (0.116 g, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight. After work-up, the crude product was purified by silica gel column chromatography (50% EtOAc/Hexanes to 100% EtOAc) to provide the title compound (0.162 g, 63%). 1H-NMR (CDCl3): δ 8.34 (br t, J=5.6 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.69 (q, J=6.4 Hz, 2H), 3.44 (br s, 4H), 2.72 (t, J=6.4 Hz, 2H), 1.30 (t, J=6.4 Hz, 3H), 1.22 (t, J=6.8 Hz, 6H). MS (ESI) (M+H)+=338.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH:19]([CH3:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH:19]([CH3:28])[C:18]([OH:29])=[O:17])=[CH:26][CH:25]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Product: CC(Cc1ccc(OCc2cccnc2SC2CCCC2)cc1)C(=O)O
Yield: 40 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.056 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 A were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=O)[CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc([N+](=O)[O-])ccn1

Procedure:
6.0 g of 4-nitro-2-pyridinecarboxylic acid were stirred at 60° bath temperature for 4 hours in 300 ml of absolute tetrahydrofuran and 5.9 g of 1,1'-carbonyldiimidazole. Thereafter, 6.0 g of t-butyl (2-aminoethyl)carbamate were added thereto and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and thereafter partitioned between ethyl acetate and water. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate, whereby there was obtained t-butyl [2-(4-nitropyridine-2-carboxamido)ethyl]carbamate as white crystals, m.p. 130°-131°.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.CC(O)C.Cl>O>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-c2cc3nccn3c(Nc3ccc(C#N)cc3)n2)cc1OC
Temperature: 87.5 °C
Reaction time: 8 h

Procedure:
To the suspension of 5-chloro-7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol) and 4-aminobenzonitrile (35.44 mg, 0.3 mmol) in the mixture of 2.5 ml 2-propanol and 1.5 ml H2O was added conc.HCl. Then the mixture was stirred at 85 to 90° C. overnight, and cooled to room temperature. The produced solid was collected by filtration and purified by preparative TLC to give the desired product of 4-[7-(3,4-dimethoxy-phenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-benzonitrile. (38 mg, 51.2%).
Reaction SMILES: [CH:1]1([C:5]([NH:7][NH:8][C:9]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:12]=2)=O)=O)[CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:12]=[C:11]([C:9]3[S:41][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[N:7][N:8]=3)[C:15]=2[CH3:16])=[CH:18][CH:19]=1
Reactant: Cc1c(C(=O)NNC(=O)C2CCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1c(-c2nnc(C3CCC3)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 180 °C
Yield: 55.2 %

Procedure:
N-cyclobutanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.14 g, 0.29 mmol) was added to a microwave reactor containing Lawesson's reagent (0.18 g, 0.44 mmol) in 1,4-dioxane (3 mL). The capped reactor was placed into a microwave reactor and the mixture was heated at 180° C. for 15 min, and the process was repeated one more time. The reaction mixture was then purified by preparative HPLC to provide the title compound (60 mg, 0.16 mmol, 43%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[N+:5]([O-])=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)c[n+]1[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(F)cn1
Reaction time: 0.17 h
Yield: 142.1 %

Procedure:
4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol), from Step 7, was dissolved in 52 mL of glacial acetic acid in a 3-necked flask equipped with a mechanical stirrer, a condenser and a thermometer. Iron powder (6.45 g, 115.5 mmol) was added to the solution at ambient temperature and the reaction mixture was carefully heated to 35°-40° C. After 10 min at 30° C., an exothermic reaction took place which caused the reaction temperature to rise to 120° C. and the reaction mixture became a very dark brown-colored solution. The flask was transferred to a cold water bath and the temperature of the solution brought down to ambient. The reaction mixture was then poured over ice. The resultant aqueous mixture was adjusted to pH 9 with potassium carbonate and steam distilled. The aqueous distillate collected at 92°-96° C. was extracted with three portions of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and distilled to afford 15.91 g (71% yield) of the title compound, b.p. 138°-140° C.; MS GC-MS M/Z:146 (M+H)+ ; 1H NMR (CDCl3) d 2.53 (s, 3H), 7.23 (d, 1H, J=6.0 Hz), 8.37 (s, 1H).
Reaction SMILES: C[C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][O:3]1.[C:12]([O:20]CC=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]([C@H:5]1[CH2:4][O:3][CH:2]([CH2:11][O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1)=[O:8]
Reactant: O=CCOC(=O)c1ccccc1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1COC(COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of methyl-α,β-isopropylidene-D-glycerate (II) (Fluka: registry # 52373-72-5), (9.76 g, 60.9 mmol, 1 eq) and benzoyloxyacetaldehyde I (10 g, 60.9 mmol, 1 eq) in toluene (20 mL) at 80° C., p-toluenesulfonic acid (PTSA) (460 mg, 2.4 mmol, 4 mol %) was added. The reaction flask was kept under vacuum for one hour and a distillate was collected (80-85° C.) during this period of time. The residue was then cooled to room temperature (RT) and purified by column chromatography on silica gel, using hexanes/ethyl acetate as eluent to produce 13.2 g (81%) of the title compound as a mixture of cis and trans isomers in a ratio of 3:1.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[N:11]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3].[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[CH2:1]([O:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[N:11]([CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCNCC1

Procedure:
A solution of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid allyl ester (1.40 g, 3.49 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 302.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: Fc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: Fc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-fluorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 151°-153° C.) and piperazine.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OCC)C>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:9][C:10]=1[C:16]([F:17])([F:18])[F:19])#[N:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60%, 2.0 g, 50 mmol) was added to a stirred solution of 4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile (6.0 g, 25 mmol), and tert-butyl bromoacetate (6.82 g, 35 mmol) in 20 mL of DMF at 0° C. over 20 minutes. The mixture was then stirred at 5-10° C. for 30 minutes. Diethyl ether (200 mL) was added to the mixture and the resulting slurry was extracted with water (3×50 mL). The organic phase was dried (MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified with silica gel chromatography (eluent: hexane-EtOAc; 3:1) to obtain 6.55 g (74%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.8 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.8, 2.7 Hz, 1H), 4.10 (s, 2H), 3.33 (d, J=6.6 Hz, 2H), 1.43 (s, 9H), 1.05 (m, 1H), 0.62 (m, 2H), 0.26 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH3:22])=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:22])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1c(N)sc2c1CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1c(C)[nH]c2ccccc12)CCCC3
Yield: 57.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methyl-1H-indol-3-yl)methanone (0.310 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-70%) in heptane furnished 0.233 g (57%) of the title compound as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:14]([OH:16])=O)[CH3:9].[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][CH:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:14]([NH:28][C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:16])[CH3:7]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (5.72 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at ambient RT for 4 hours. The mixture was evaporated in vacuo to a residue, which was taken up in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo to a residue, which was partitioned between water (50 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 30% ethyl acetate in isohexane, and crystallised from ethyl acetate/isohexane to give the desired compound (5.52 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: C[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reaction time: 66.5 h

Procedure:
To a 500 mL round-bottomed flask were added a stirbar, (S)-2-aminopropan-1-ol (2.151 g, 28.65 mmol), dry DCM (100 mL), and DIPEA (14.0 mL, 81.2 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (6.981 g, 27.32 mmol) and stirred for 66.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (7.31 g, 91%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[CH2:1]([C:4]1[C:5]([O:13][C:21](=[O:23])[CH3:22])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2cn[nH]c12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCc1c(OC(C)=O)ccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from Step B (6.35 g, 37 mmol) in THF (100 mL) containing triethylamine (7.6 ml, 55 mmol) was stirred for 5 minutes at ambient temperature, cooled to 0° C. (ice bath), and acetyl chloride (2.63 mL, 37 mmol) was added. The mixture was stirred at 0° C. for 2 hours, additional acetyl chloride (0.26 mL, 3.7 mmol) was added, and the mixture stirred for 10 min at which point another portion of acetyl chloride (0.26 ml, 3.7 mmol) was added and stirring continued for 15 min. The reaction was quenched with triethyl amine (1 mL) and saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried (MgSO4) and evaporated to an oil (9.27 g) which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a white solid, (3.50 g, 44%): LC/MS (+APCI) m/z 217 (M+H).