Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(O)cc2)c(-c2ccncc2)o1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenol (21 mg, 0.083 mmol) in 2.5 mL of dry DMF was added Cs2CO3 (54 mg, 0.17 mmol). After stirring for 0.5 h, 2-(chloromethyl)quinoline (17.8 mg, 0.100 mmol) was added and the mixture was stirred at 85° C. for 12 h. After removal of the DMF under vacuum, the residue was purified by PTLC (1:2 hexane/EtOAc) to give 13 mg (40%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.54 (s, 3H), 5.41 (s, 2H), 7.06 (m, 2H), 7.41 (m, 2H), 7.53 (m, 3H), 7.68 (d, 1H), 7.80 (t, 1H), 7.83 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.53 (m, 2H). MS m/z: 394 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH2:34][CH2:35][CH3:36])[N:33]=[C:29]5[C:28](CC5C=CC(C6C=CC=CC=6C6N(C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)N=NN=6)=CC=5)=[C:27]4[CH2:74][CH3:75])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:88]([C:90]1[CH:97]=[C:96]2[N:92]([N:93]=[C:94]([CH2:135][CH2:136][CH3:137])[N:95]2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[N:91]=1)[CH3:89].C(C1C(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)=C2N(N=C(CCC)N2)N=1)C.C(C1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)N2C(C=1)=NC(CCC)=N2)C>>[CH2:74]([C:27]1[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:82]4[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=4)[C:76]4[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=4)[N:9]=[N:10][N:11]=3)=[CH:24][CH:23]=2)[N:30]2[C:29]([CH:28]=1)=[N:33][C:32]([CH2:34][CH2:35][CH3:36])=[N:31]2)[CH3:75].[CH2:88]([C:90]1[CH:97]=[C:96]2[N:92]([N:93]=[C:94]([CH2:135][CH2:136][CH3:137])[NH:95]2)[N:91]=1)[CH3:89]
Reactant: CCCc1nn2nc(CC)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCCc1nc2cc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCCc1nn2nc(CC)c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c2[nH]1
Product: CCCc1nn2nc(CC)cc2[nH]1

Procedure:
In the same manner as described in Example 38, 0.49 g of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-6-ethyl-2-propyl-5 H-pyrazolo[1,5-b][1,2,4]triazole (compound 47a), 2.30 g of 6-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 47b), 0.18 g of 6-ethyl-2-propyl-7-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 47c) and 2.28 g of 6-ethyl-2-propyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 47d) were obtained from 2.17 g of 6-ethyl-2-propyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](F)[C:19]([CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[Cl:15][C:16]1[C:17]([N+:24]([O-:26])=[O:25])=[CH:18][C:19]([CH3:23])=[C:20]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]2=[O:1])[CH:21]=1
Reactant: Cc1cccnc1O
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1-n1cccc(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.50 g (13.8 mmol) of 2-hydroxy-3-methylpyridine in 70 ml of DMF are admixed at 0° C. with 2.31 g (20.6 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 2.87 g (15.1 mmol) of 2-chloro-4-fluoro-5-methylnitrobenzene are added while continuing to stir at RT. After 17 h, the mixture is admixed with 1000 ml of water and then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and, after filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (2:1 cyclohexane/ethyl acetate). This affords 2.15 g (56% of theory) of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:16]2[C@@H:12]([O:13][C:14](C)([CH3:17])[O:15]2)[O:11][C@@:10]1([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>CC(O)=O.OS(O)(=O)=O>[C:14]([O:13][CH:12]1[C@H:16]([O:35][C:33](=[O:34])[CH3:32])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH:19]([F:20])[F:21])[O:11]1)(=[O:15])[CH3:17]
Reactant: CC1(C)O[C@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound (3aR,5R,6S,6aR)-6-(benzyloxy)-5-(benzyloxymethyl)-5-(difluoromethyl)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole (1.0 g, 6.3 mmol) in Ac2O (2.5 mL) and AcOH (10 mL) was added H2SO4 (3 drops). The mixture was stirred at room temperature for 3 hrs. TLC showed the reaction was complete. The mixture was poured to water, extracted with EtOAc, dried (Na2SO4) and purified by silica gel chromatography [ethyl acetate:petroleum ether (1:3)] to afford compound 5 (1.0 g, crude) as a light-color oil. LC-MS (M+H)+=465.1
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=O)=O.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K].O>CN(C)C=O>[C:26]1(=[O:36])[N:30]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-(3-methanesulfonyloxypropyl)phenoxy]-2-methylpropionate (1.93 g, 5.18 mmol) was dissolved in dimethylformamide (10.0 mL). Subsequently, potassium phthalimide (1.15 g, 6.22 mmol) was added thereto, and the mixture was stirred overnight at 80° C. Water was added thereto, and the resultant mixture was extracted with diethyl ether. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=5/1), thereby the target compound was obtained (1.8 g, 82%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]>C(O)C>[CH3:6][N:4]([CH3:5])[CH:3]=[CH:22][C:21]([C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][C:11]=1[O:10][CH3:9])=[O:23]
Reactant: COc1ccc(NC(C)=O)cc1C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: COc1ccc(NC(C)=O)cc1C(=O)C=CN(C)C
Temperature: 22 °C
Reaction time: 30 h
Yield: 101.4 %

Procedure:
Dimethylformamide dimethyl acetal (693.3 g) was added to a suspension of 2′-methoxy-5′-acetamidoacetophenone (3, 1215.1 g) in ethanol (12.15 L) stirred under nitrogen at 22° C. After the resulting suspension had been stirred and refluxed under nitrogen for 18 hours, all solids had dissolved, and additional dimethylformamide dimethyl acetal (346.2 g) was added to the homogeneous reaction mixture. Stirring and refluxing under nitrogen were continued for an additional 30 hours, after which additional dimethylformamide dimethyl acetal (346.2 g) was added. The reaction mixture was then stirred and refluxed under nitrogen for a final 17.5 hours, after which the reaction mixture was rotary evaporated at <45° C. and <50 mm HgA to a solid residue that was dried further overnight at <45° C. and <1 mm HgA to provide brown solid 4 (1547.9 g, 100.6% yield). LC/MS analyses revealed 98.3% and 100% conversion of 3 to 4 before and after evaporation of solvent, respectively.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C1C=C2C(=CC=1)N(CCC)C(=O)C2=O>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Product: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-methyl-1-propylindoline-2,3-dione. 1H NMR δ 8.13 (dd, 2H), 7.60 (t, 1H), 7.46 (dd, 2H), 7.27 (s, 1H), 7.17 (dd, 1H), 6.80 (d, 1H), 6.19 (s, 1H), 3.74 (m, 2H), 2.33 (s, 3H), 1.80 (m, 2H), 1.04 (t, 3H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>CN(C=O)C>[Cl:33][C:31]1[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][N:28]=[C:27]([NH:15][CH2:14][C:13]2[C:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=3)=[N:9][CH:10]=[N:11][CH:12]=2)[N:32]=1
Reactant: Cc1ccc(Oc2ncncc2CN)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncncc2CNc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: -10 °C
Yield: 27 %

Procedure:
(4-(p-Tolyloxy)pyrimidin-5-yl)methanamine (1.0 equiv.) was placed in a round bottom flask with DIEA (1.0 equiv.), and DMF (0.4 M). The flask was placed in a cooling bath and cooled to −10° C. To the flask was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv.) and stirring continued at −10° C. The reaction mixture was allowed to warm to room temperature over 3 h. The reaction mixture was loaded directly onto a silica gel column (100 g) and purified using 5-27% ethyl acetate in hexanes, followed by 27% ethyl acetate in hexanes. Fractions containing desired product (lower Rf spot by thin layer chromatography) were combined and the solvent was were removed under reduced pressure to give 4-chloro-N-((4-(p-tolyloxy)pyrimidin-5-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine (27.0% yield) as a light yellow solid. MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:11]1([N:7]2[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[CH2:24][CH2:25]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OC(CCCCl)CN1c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC(CCCN2CCN(c3ccccn3)CC2)CN1c1ccccc1
Yield: 56 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(3-chloropropyl)-3-phenyl-2-oxazolidinone (4.5 g, 0.0188 mol), 1-(2-pyridinyl)piperazine (3.07 g, 0.0188 mol), potassium carbonate (7.81 g, 0.0565 mol), and potassium iodide (1.0 g) in n-butanol (200 mL) gave a solid which was recrystallized from isopropanol/isopropyl ether and dried under high vacuum to give 3.86 g (56% yield), mp 123°-125° C.
Reaction SMILES: C(O[Al](OC(C)C)OC(C)C)(C)C.[C:14]([O:18][C:19](=[O:33])[NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](=[O:25])[CH2:23][Cl:24])([CH3:17])([CH3:16])[CH3:15].Cl>C1(C)C=CC=CC=1>[C:14]([O:18][C:19](=[O:33])[NH:20][C@@H:21]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:22]([OH:25])[CH2:23][Cl:24])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triisopropoxyaluminum (200 mg, 0.98 mmol) was diluted with 6 ml of toluene. Thereto was added 285 mg (0.96 mmol) of [1(S)-benzyl-2-oxo-3-chloropropyl]carbamic acid t-butyl ester, and the mixture was stirred at 25° C. for 16 hours. After hydrolysis with 1N hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The solution obtained was analyzed quantitatively by HPLC under the same conditions as used in Example 1 and the yields and selectivity were calculated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[N:30]1([S:36]([C:39]2[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([S:36]([C:39]2[CH:40]=[C:41]([NH:45][C:27]([C:26]3[CH:25]=[N:24][N:17]4[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]([C:6]5[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=5)=[N:15][C:16]=34)=[O:29])[CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 642.2 [(M−H)−]; mp 235° C.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>O1CCCC1>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][N:12]1[C:11]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:10]=2[N:9]=[C:8]1[NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:23]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2cc(CC(=O)O)ccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
A solution of ethyl (2-o-tolylamino-3H-benzimidazol-5-yl)acetate (5 g, Reference Example 8) in tetrahydrofuran (200 mL) was treated with sodium hydride (0.71 g, 60% dispersion in mineral oil) under nitrogen with stirring at room temperature. On completion of the addition the mixture was stirred at room temperature for a further 30 minutes and then treated with (2-trimethylsilylethoxy)methyl chloride (2.95 g). After stirring at room temperature for a further 1 hour the mixture was evaporated to low bulk and the residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ether (3:2, v/v). The material (5.2 g) from chromatography was dissolved in methanol (100 mL) and the solution was treated with aqueous sodium hydroxide solution (30 mL, 1M). After standing at room temperature for 4 hours the mixture was evaporated to low bulk and then diluted with water (50 mL). The mixture was acidified by addition of acetic acid to give a white gum which was decanted from which the aqueous mother liquors. The gum was washed once by decantation with a little water and then triturated with the minimum of ethanol to give the title compound (910 mg) as a white solid. Evaporation of the ethanol solution gave a further quantity of the title compound (3.0 g) as an orange foam.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>C(O)C>[ClH:2].[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: ClCC1=NCCN1
Reactant: Cc1cccc(N)c1C
Agent: Cl
Solvent: CCO
Product: Cc1cccc(NCC2=NCCN2)c1C
Yield: 75.1 %

Procedure:
31 g of 2-chloromethyl-2-imidazoline hydrochloride and 48.4 g of 2,3-dimethylaniline are refluxed for 5 hours in 65 ml of absolute ethanol. After cooling, the crystallised substance is collected by suction and recrystallised from water, affording 36 g (77% yield) of the final product with a melting point of 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].Cl.O1CCOCC1>O.C(OCC)C>[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: N=C(N)Nc1ccccc1
Temperature: 80 °C

Procedure:
Aniline (30 mmol, 1 equiv.), cyanamide (1.3 g, 31 mmol, 1.03 equiv.), and 4N hydrogen chloride in dioxane (8 mL, 32 mmol) was stirred for 10 minutes at room temperature and heated to 80° C. for 18 hours. The mixture was diluted with water (30 mL) and diethyl ether (50 mL). The aqueous layer was washed with ether (30 mL) and the organic layers were discarded. The aqueous layer was neutralized with 6N aqueous HCl (6 mL) and diluted with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) four times. The combined organic layers were concentrated under reduced pressure to afford a solid compound. The solid was washed with diethyl ether (30 mL) to provide pale yellow title compound. The compound was characterized by LC/MS and HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21](OCC)=[O:22])[O:18][N:17]=2)[N:3]=1.C[Al](C)C.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]([NH:38][C:35]3[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[O:22])[O:18][N:17]=2)[N:3]=1
Reactant: COc1ccc(N)cn1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of ethyl 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazole-5-carboxylate (prepared in an analogous manner to Example 73, 0.2 g, 0.58 mmol) in toluene (10 mL) at 0 C was added trimethylaluminium (2M in toluene, 0.88 mL, 1.7 mmol) over a period of 5 min and the mixture was then stirred at room temperature for 2 h. 6-Methoxypyridin-3-amine (0.21 g, 1.7 mmol) was added and the mixture was heated to 60 C for 15 h. The mixture was cooled to room temperature and quenched with ice water. The mixture was extracted with EtOAc (3×20 mL) and the organic layers were concentrated under vacuum. The residue was slurried in acetonitrile for 30 min and the resultant precipitate was filtered off to afford the title compound (0.100 g, 43%).
Reaction SMILES: Cl.ClC1C=C(Cl)C(Cl)=CC=1OCCCONC(N(C(C)C)C(=N)N)=N.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.[Br:34][CH2:35][CH2:36][CH2:37]Br>[OH-].[Na+]>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:37][CH2:36][CH2:35][Br:34])=[CH:29][CH:28]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: CC(C)N(C(=N)N)C(=N)NOCCCOc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Product: Clc1ccc(SCCCBr)cc1

Procedure:
In similar fashion to the synthesis of (XV), 4-chlorothiophenol (28.9 grams, 0.2 mol) was treated with sodium hydroxide (40 mL of 20% aqueous solution) and then combined with 1,3-dibromopropane (160 grams, 0.8 mol) and refluxed for 4 hours. The mixture was cooled, the aqueous layer separated and neutralized with 20% sodium hydroxide solution, and the lower layer washed five times with water and distilled at 1 mm Hg. The main fraction was collected between 120°-130° C. as a colorless oil (47.5 grams, 90%) which crystallized on standing to give 4-chlorothiophenoxy propyl bromide (XIX) is then further reacted with acetohydroxamic acid as described previously in Example 1 and hydrolyzed to give the 3-(4-chlorothiophenoxy)propyloxamine hydrochloride (XX). This in turn is reacted with isopropyl dicyanodiamide as described previously in Example 1 to give the title compound (XXI).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]1C[CH2:18][CH2:17][CH2:16][CH:15]1CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH:8]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:13])=[O:5]
Reactant: CCOC(=O)C1CCCCN1C
Reactant: CN1CCCCC1CO
Agent: CCCC[Sn](=O)CCCC
Product: CN1CCCCC1COC(=O)C1CCCCN1C
Temperature: 130 °C

Procedure:
A mixture of 85.6 g (0.5 mole) of ethyl 1-methylpipecolinate, 64.6 g (0.5 mole) of 1-methyl-2piperidinemethanol and 1.1 g dibutyltin oxide was heated at 130° C. for three hours and then gradually heated to 200° C. When the amount of ethanol collected indicated the reaction was essentially complete the liquid product, N-methyl-(2-piperidyl)methyl N-methylpipecolinate, was distilled at 0.25 mm Hg pressure at about 130° C. The nuclear magnetic resonance and infrared spectra of the product were consistent with the structural assignment.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:32].[CH:33](OCC)(OCC)OCC>Cl.CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:29]=[CH:33][N:20]([CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:18]=4[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:32]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(NCCN3CCOCC3)c2)ccc1F
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2ncccc2-c2ccc3ncn(CCN4CCOCC4)c3c2)ccc1F
Temperature: 65 °C

Procedure:
The above residue containing 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine was added DMA (1 mL), triethyl orthoformate (250 uL) and treated with one drop of concentrated HCl. The homogeneous solution was heated at 65° C. for 15 hours in a sealed vial. The reaction was cooled and the volatiles were removed with a stream of nitrogen gas. The residue was triturated with aq. NaHCO3, resulting solid collected by filtration and purified by HPLC to yield 25 mg of the desired product 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholino ethyl)-1H-benzo[d]imidazole. 1H NMR (DMSO-d6): δ 8.58 (dd, J=4.7, 1.6 Hz, 1H), 8.15 (s, 1H), 7.84 (dd, J=7.8, 1.6 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.43 (dd, J=7.8, 4.7 Hz, 1H), 7.28 (d, J=4.8 Hz, 2H), 7.05 (dd, J=8.3, 1.5 Hz, 1H), 7.03-6.75 (m, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.55-3.36 (m, 4H), 2.44-2.15 (m, 6H), 2.06 (s, 3H). MS (m/e): 417 (MH+).