Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH:29]([NH:32][CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC(C)NC(C)C
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C(C)C)C(C)C
Temperature: 130 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and diisopropylamine (0.78 ml, 5.58 mmol) in DMF (10 ml) was stirred at 130° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (398 mg, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClCCl.[OH:15]O>C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:15])=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
59.74 g (411 mmol) of 8-hydroxyquinoline, 350 ml (822 mmol) of dichloromethane, 82.2 ml of 35% aqueous hydrogen peroxide solution and 0.52 g (2.5 mmol) of methylrhenium trioxide (MTO) are placed in a 1 l round-bottomed flask. The reaction mixture is stirred at ambient temperature (25° C.) for 24 h and then 80 ml of aqueous hydrogen peroxide solution and 0.32 g of manganese dioxide are successively added. The mixture is stirred for 1 h 30 and then separated by settling. The aqueous phase is extracted with dichloromethane (2×200 ml). The organic phases are combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide 64 g of 8-hydroxyquinoline N-oxide in the form of an organe-colored solid; M.p.=112° C. (Yield: 97%)
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[S:13][C:14]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:15]([CH3:17])[CH:16]=2)=[N:5]S(=O)[N:3]=1.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[CH3:21][N:19]([CH2:18][C:14]1[S:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])=[CH:16][C:15]=1[CH3:17])[CH3:20]
Reactant: Cc1cc(CSCCNC2=NS(=O)N=C2N)sc1CN(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc(CSCCNC(=N)C(=N)N)sc1CN(C)C
Reaction time: 3 h
Yield: 80 %

Procedure:
A stirred solution of 3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (17.9 g, 50.0 mmoles) [prepared according to the general procedure described in published United Kingdom Patent Application No. 2,067,987] in 500 mL of methanol was treated with 33.3 mL of concentrated HCl. After stirring for 3 hours, the reaction mixture was concentrated and excess water was removed by azeotropic concentration with absolute ethanol to give an almost colorless crystalline residue. The residue was triturated with 200 mL of absolute ethanol at 0° C., filtered and dried to give 16.9 g (80%) of the title compound, m.p. 206°-220° C. (dec.). Recrystallization from 50% methanol-ethyl acetate gave a product having m.p. 210°-221° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]1=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH2:11]([NH:18][CH:3]1[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][CH:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CC1CCC(C)(C)CC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(C)(C)CC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude racemic 2,5,5-trimethyl-cyclohexanone (theoretically 31.7 mmol) and benzylamine (3.8 mL, 34.79 mmol) in 50 mL of toluene was stirred for 45 minutes at reflux with continuous removal of H2O. The reaction mixture was cooled to RT and evaporated. The residue was taken into 50 mL of DCM and sodium triacetoxyborohydride (8.1 g, 38.22 mmol) was added, followed by acetic acid (2 mL, 34.94 mmol). The resulting mixture was stirred at RT overnight before being diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified (DCM/(DCM:MeOH:NH4OH 60:10:1] 90% DCM) to give 3.84 g of racemic benzyl-(2,5,5-trimethyl-cyclohexyl)-amine. NMR showed the presence of about 5% of the trans isomer.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20]O)=[C:18]([F:26])[C:17]=1[F:27].[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([OH:36])=[O:35])[C:32]1([CH3:38])[CH3:37]>O1CCCC1>[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([O:36][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:15][O:14][CH3:13])=[C:23]([F:24])[C:22]=2[F:25])=[O:35])[C:32]1([CH3:38])[CH3:37]
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added to a mixture of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid {containing the stereoisomers in a ratio of (1R)-trans form: (1R)-cis form: (1S)-trans form: (1S)-cis form=99:0:1:0} and tetrahydrofuran under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (hereinafter referred to as the present compound 5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4'-chloropropiophenone (39.6 g) and anhydrous aluminum chlorid (0.1 g) were dissolved in 100 ml of chloroform. To the resulting solution was protionwise added bromine (37.6 g) at a temperature of 30° to 35° C. The reaction mixture was stirred at room temperature for 30 minutes. Then nitrogen was blown into the reaction mixture to remove the formed hydrogen bromide therefrom. Thereafter, the solvent was distilled off under reduced pressure to give 2-bromo-4'-chloropropiophenone (58.1 g). mp 77.5°-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.C([O-])(=O)C.[Na+].BrBr>O1CCCC1.CCOCC.O.C(O)(=O)C>[Br:20][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:10]=1[S:15][C:16]([F:17])([F:19])[F:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen purge, a solution of 2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole-3-carbonitrile (0.6 g, 0.002 mol) in tetrahydrofuran is treated with N-bromosuccinimide (0.36 g, 0.002 mol), stirred for 16 hours at room temperature and concentrated in vacuo to obtain a residue. The residue is dissolved in ether and diluted with water. The organic phase is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. High performance liquid chromatography indicates that the solid contains 20% starting material. A solution of the mixture and sodium acetate (0.05 g, 0.006 mol) in acetic acid is treated with bromine (0.03 mL, 0.0006 mol), stirred for 16 hours at 60° C., cooled and concentrated in vacuo to obtain a semi-solid. The semi-solid is partitioned between ethyl acetate and water. The organic phase is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from ethylene dichloride to give the title product as an off-white solid (mp 241°-243° C.) which is identified by 1 HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.C(N(CC)CC)C.[CH2:43]([O:45][CH2:46][CH2:47][NH:48][C:49]1[N:54]=[CH:53][CH:52]=[CH:51][N:50]=1)C>C1(C)C=CC=CC=1.ClCCl>[CH3:43][O:45][CH2:46][CH2:47][N:48]([C:49]1[N:50]=[CH:51][CH:52]=[CH:53][N:54]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: CCOCCNc1ncccn1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ncccn1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 in toluene. Then treatment with triethylamine and (2-ethoxy-ethyl)-pyrimidin-2-yl-amine in dichloromethane.
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=1[CH3:11].[C:12]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=1)#[CH:13]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[CH3:11][C:5]1[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=1[CH:3]=[CH:2][C:13]#[C:12][C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=1
Reactant: CC1=C(C=CI)C(=O)CCC1
Reactant: C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1=C(C=CC#Cc2ccc(C(=O)OCC[Si](C)(C)C)cc2)C(=O)CCC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 1-iodo-2-(2-methyl-6-oxocyclohex-1-enyl)ethene (Compound E, available in accordance with the teachings of U.S. Pat. No. 5,760,276, 0.70 g, 2.67 mmol), (trimethylsilyl)ethyl 4-ethynylbenzoate (Compound C, 0.79 g, 3.21 mmol) and triethylamine (32 ml) was purged with argon for 10 minutes, and then treated with bis(triphenylphosphine)palladium (II) chloride (47 mg, 0.07 mmol) and copper (I) iodide (12.8 mg, 0.07 mmol). The solution was stirred 40° C. for 3 hours, and concentrated under a water aspirator vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (90:10, hexane:ethyl acetate) to give the title compound.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[C:9]([O:13][C:14]([N:16]([CH3:26])[C@H:17]([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([O:13][C:14]([N:16]([CH3:26])[C@:17]([CH3:3])([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNC(=O)[C@](C)(C(=O)OC)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
Iodomethane (1.4 mL) and potassium carbonate (1.6 g) were added to an acetonitrile (5.0 mL) solution of N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, 2.0 g), and the mixture was stirred for 20 hours at room temperature under closed conditions. Iodomethane (2.8 mL) was added, and the mixture was stirred for 3 days at room temperature under closed conditions. Further, iodomethane (2.8 mL) was added, and the mixture was stirred for 1 day at room temperature under closed conditions, and then stirred for 9 hours at 50° C. After the reaction mixture was stirred for 14 hours at room temperature, potassium carbonate was filtered out. Then, the system was washed with ethyl acetate, and the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→100/0) to obtain N2-(t-butoxycarbonyl)-N,N2,O,2-tetramethyl-3-oxoserinamide (Intermediate 8-2, yellow oil) (1.5 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18].[CH3:22][Zn]C.CO.CCOCC>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:22])[CH:5]=[CH:4][C:3]=1[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: C[Zn]C
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc(C)cc1F
Yield: 69.7 %

Procedure:
To a suspension of [1,2-bis(diphenylphospino)ethane]-dichloropalladium(II) [Pd(dppe)Cl2] (14.1 mg and 1.3 mol %) in dry 1,4-dioxane (3 mL), a solution of compound (18) (0.62 g, 1.9 mmol) in dry 1,4-dioxane (3 mL) was added dropwise under argon gas flow. To this suspension, dimethyl zinc (2M-solution in toluene, 9.0 mL, 2.0 mmol) was slowly added dropwise. After completion of the dropwise addition, the suspension was heated to reflux for 4 hours. After cooling, methanol (0.4 mL) was added thereto and the mixture was treated with ether. The organic layer was washed with a 1M aqueous solution (18 mL) of hydrochloric acid and dried (over sodium sulfate), and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 0.26 g (70%) of compound (19) of interest as colorless liquid matter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1>>[CH:16]1([CH:14]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:12][C:11]=2[CH3:13])[OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(F)cc2)cc1C(O)C1CCCCC1
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-fluorophenyl)-2-methyl-3-furaldehyde (2.0 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (15 mL) to give the title compound (2.4 g, 83%) as a white crystal.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:27][C@@:16]2([C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24]Cl)[C:18](=[O:26])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>>[CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:27][C@@:16]2([C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][N:33]3[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]3)[C:18](=[O:26])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OC1CCNCC1
Reactant: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCN3CCC(O)CC3)C2=O)c2cc(F)ccc2O1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95.3 %

Procedure:
A mixture of (2S,4S)-N-butyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Reference Example 4, 17.0 g, 41.4 mmol), 4-hydroxypiperidine (8.36 g, 82.8 mmol), K2CO3 (7.43 g, 53.8 mmol) and N,N-dimethylformamide (68.0 ml, 880 mmol) was stirred for 5 hours at 80° C. After distilling off the solvent, the residue was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1), and evaporated in vacuo to dryness to give amorphous crystals of the desired compound (18.8 g, 95.4%).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C1CCCC(Br)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2CCCC(=O)c3ccccc32)CC1
Yield: 52 %

Procedure:
9-Bromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (590 mg, 2.5 mmol), 1-t-butoxycarbonylpiperazine (500 mg, 2.7 mmol) and potassium carbonate (510 mg, 3.7 mmol) were stirred overnight in DMF. The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 450 mg (1.3 mmol, 53%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: NCc1ccncc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccncc2)nc(N2CCOCC2)n1
Yield: 25.5 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 4-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated under gentle reflux for 5 min, before being cooled and diluted with water. The mixture was extracted with CH2Cl2 and the organic layer was dried with Na2SO4. Chromatography on alumina, eluting with CH2Cl2/EtOAc (9:1), followed by chromatography on silica, eluting with CH2Cl2/EtOAc (3:2) gave 56 mg (26% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 188-190° C.; 1H NMR (CDCl3) (rotamers) δ8.60 (br s, 2H), 8.42 and 8.13 (2d, J=7.4 and 8.0 Hz, 1H), 7.88 (m, 1H), 7.64 (t, JHF=53.6 Hz, 1H), 7.44-7.25 (m, 4H), 5.78 and 5.71 (2 m, exchangeable with D2O, 1H), 4.74 and 4.70 (2 d, J=6.0 and 6.0 Hz, 2H), 3.92-3.69 (m, 8H).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][C:7]#[N:8].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1>O.CN(C)C=O>[CH3:9][C:10]1[N:11]([CH:6]([CH2:5][CH3:4])[C:7]#[N:8])[CH:12]=[CH:13][N:14]=1
Reactant: N#CCCCBr
Reactant: Cc1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#N)n1ccnc1C
Reaction time: 8 h

Procedure:
12.8 g of sodium hydroxide was dissolved in 12 ml of water and diluted with 150 ml of dimethylformamide containing 20.3 g of 2-methylimidazole. A solution of 50.0 g of 4-bromobutyronitrile in 100 ml of dimethylformamide was added slowly maintaining the temperature below 30° C. The resulting mixture was stirred overnight and was concentrated. The residue was taken up in 150 ml of brine and extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. The product was distilled. The early fractions were mostly 2-methylimidazole and were discarded. The main fraction 23.2 g, bp 160°-185° C./2.5 mm, was redistilled to give 14.7 g (31%) of (2-methyl-1H-imidazol-1-yl)-butanitrile, bp 140°-147° C./0.5 mm.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH2:19][CH2:18]2)=[O:16])=[C:12]([CH3:14])[N:13]=1)=O)(C)(C)C>C(O)=O>[NH2:8][C:9]1[S:10][C:11]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH2:21][CH2:22]2)=[O:16])=[C:12]([CH3:14])[N:13]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Solvent: O=CO
Product: Cc1nc(N)sc1C(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
6-[4-(2-tert-Butoxycarbonylamino-4-methylthiazole-5-carbonyl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (1.2 g) was dissolved in formic acid (25 ml) and the solution was stirred for 4 hours at ambient temperature. After the solvent was removed, ethyl acetate (10 ml) and water (10 ml) was added to the residue and the mixture was adjusted to pH 4.5 with 10% aqueous solution of potassium carbonate. The resulting precipitate was collected and recrystallized from methanol-water to give 6-[4-(2-amino-4-methylthiazole-5-carbonyl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (0.9 g).