Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 45 °C
Yield: 88 %

Procedure:
4-Nitrobenzyl bromide 22 (10.57 g, 48.93 mmol) was added to a solution of diethyl malonate 21 (52 mL, 54.86 g, 342.51 mmol) and K2CO3 (14.21 g, 102.8 mmol) in acetone (40 mL). The reaction mixture was heated at 45° C. for 1 hour. The mixture was allowed to cool to room temperature and the resulting yellow slurry was filtered off to remove K2CO3 and washed with acetone (2×20 mL). The solvent was evaporated from the combined filtrate and washings under reduced pressure. The excess of diethylmalonate was removed by horizontal distillation (2 hr, 80-130° C., and 0.005 mbar). The yellow oily residue was dissolved in ethanol (200 mL). The precipitated white solid (dialkylated product) was filtered and washed with ethanol (2×20 mL). The solvent was evaporated from the combined filtrate and washings under reduced pressure to give a solid, which was recrystallized from hexane/Et2O (1:1) to afford white crystalline needles 23 (12.72 g, 88% yield).
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][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C1(C2C=[C:32]([NH:34]C(=O)OC3C=CC=CC=3)[O:31]N=2)CC1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:32](=[O:31])[NH2:34])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(C2CC2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(N)=O)c3)c2cc1OC
Yield: 67 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (90 mg, 0.264 mmol) and phenyl 3-cyclopropylisoxazol-5-ylcarbamate from Example 124A (78 mg, 0.317 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 143-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (68 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 10.21 (brs, 1H), 9.08 (brs, 1H), 8.55 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.78 (m, 2H), 3.30 (s, 3H), 1.90 (m, 1H), 0.94-0.98 (m, 2H), 0.71-0.73 (m, 2H); LC-MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][OH:5].Br[CH2:8][CH2:9][CH2:10][CH3:11]>>[CH2:8]([O:5][CH2:4][CH2:3][CH2:2][OH:6])[CH2:9][CH2:10][CH3:11]
Reactant: OCCCO
Reactant: CCCCBr
Agent: [Na]
Product: CCCCOCCCO
Temperature: 40 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
Sodium metal (2.13 g) was added by small portions to 1,3-propanediol (15.75 g) and 1-bromobutane (10.3 g) by reference to non-patent reference [J. Am. Chem. Soc. 249 (1939)]. After the addition, the mixture was stirred at 40° C. for 1 hr and further stirred at 60° C. for 1 hr. The precipitated inorganic compound was filtered off, and the filtrate was distilled away under reduced pressure to give the title compound (3.15 g) as a colorless oil.
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[N:13]=[C:12](O)[N:11]=1)[CH2:7][CH3:8]>O1CCOCC1>[S:2]([O:5][C:12]1[N:13]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[N:15]=[C:10]([NH:9][CH2:6][CH2:7][CH3:8])[N:11]=1)([OH:1])(=[O:4])=[O:3]
Reactant: CCCNc1nc(O)nc(NCCC)n1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(OS(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
95% H2SO4 (28 μL, 0.52 mmol) was added to the suspension of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII) (110 mg, 0.52 mmol) in 1,4-dioxane (2 mL). The mixture was stirred for 30 min at room temperature. The resultant precipitate were filtered, washed with Et2O and dried to afford 4,6-bis(propylamino)-1,3,5-triazin-2-ol hydrogen sulfate (CLXXIX) in quantitative yield. 400 MHz 1H NMR (CD3OD+CF3COOD, ppm) 3.35-3.45 (3.2H, m), 3.22-3.27 (0.8H, m), 1.58-1.70 (4H, m), 0.91-1.0 (6H, m). ESI-MS (m/z): 212 [M+H]+. Major Fragments (M+H) 170, 128, 86.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([C:32]([CH3:38])([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([C:32]([CH3:38])([CH2:36][CH3:37])[C:33]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:34])[CH3:31]
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(C)(CC)C(=O)Cl
Product: CCC(C)(CC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 74.4 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (2.4 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 1.4 g (9.4 mmol) of 2-ethyl-2-methylbutyryl chloride, to provide 951 mg of the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:5])[C:3]#[CH:4].[CH2:6]([O:8][C:9](=[O:13])[CH:10]=[N+:11]=[N-:12])[CH3:7]>O>[CH2:6]([O:8][C:9]([C:10]1[CH:4]=[C:3]([C:2](=[O:5])[CH3:1])[NH:12][N:11]=1)=[O:13])[CH3:7]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
But-3-yn-2-one (Int 5, 1 eq) and diazo-acetic acid ethyl ester (Int 6, 1.1 eq) are added to a solution of InCl3 (0.2 eq) in water and stirred for 30 min at room temperature. After overnight stirring at room temperature, the mixture is diluted with water and extracted with EtOAc. The resulting organic phase is dried and evaporated to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:24][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3Oc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Yield: 43.2 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-ol (48 mg, 0.149 mmol) in THF (1.0 mL) was added 4-flurophenol (23 mg, 0.2 mmol), Ph3P (58 mg, 0.22 mmol) and DEAD (39 mg, 0.22 mmol). The reaction mixture was stirred over night at 50° C. The reaction mixture cooled, diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as solvent to afford 27 mg of the title product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN1CCN(C)C1=O
Reactant: Nc1ccccc1CN1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C)C1=Nc1ccccc1CN1CCOCC1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4-(2-aminobenzyl)morpholine (3.8 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 20 hours to yield 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)benzyl]morpholine (m.p. 56°-58° C.) which was recrystallised from hexane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:8]=[CH:9][CH:10]=1)=O.[BH4-].[Li+]>>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(e), by reducing tert-butyl (3RS,4RS)-4-(3-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate with lithium borohydride there was obtained tert-butyl 4-(3-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 448 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:14]([OH:16])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:5]([C:14]([NH2:31])=[O:16])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Product: COc1ccc(-c2c(C(N)=O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
4-Cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.035 g, 0.10 mmol), HOBT (0.028 g, 0.18 mmol) and EDCI (38 mg, 0.20 mmol) were suspended in DCM (5 mL). After 50 min the reagents dissolved. To the resulting solution was added concentrated aqueous ammonia (0.2 mL, 5 mmol) and the solution was allowed to stir vigorously at rt for 2 h. The reaction mixture was concentrated and the residue was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4 filtered and concentrated to give 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxamide (66) (0.028 g, 80%). LCMS: (AA) ES+ 344. 1H NMR (400 MHz, d6-DMSO) δ: 7.32-7.35 (m, 2H), 7.06-7.09 (m, 2H), 3.82 (s, 3H), 3.76-3.78 (m, 4H) and 3.52-3.54 (m, 4H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:15]2[CH:14]=[CH:13][C:12]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=3)=[CH:17][CH:16]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(OC(C)=O)c3)cc1)n2C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(O)c3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Ethyl 2-[4-(3-acetoxyphenyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (87 g) obtained in Example 27 was dissolved in methyl alcohol (250 ml) and tetrahydrofuran (250 ml), and potassium carbonate (31 g) was added. The mixture was stirred for 30 min at room temperature. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was neutralized with 2N hydrochloric acid. The precipitated crystals were collected by filtration to give the title compound (78 g, yield 97%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18]Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: ClSc1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2cc(Cl)ccc2Cl)c1

Procedure:
Under a nitrogen atmosphere, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride and cooled with stirring in an ice-water bath. 2,5-Dichlorobenzenesulfenyl chloride (4.24 g., 20 mmoles) was added dropwise. The bath was removed and the reaction stirred for 1 hour at room temperature, at which time thin layer chromatography (silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant) indicated that virtually all of the starting pyrrole ester had been consumed. An equal volume of ether was added, the mixture filtered and the filtrate evaporated in vacuo to a partially crystalline gum (5.2 g.). The latter was recrystallized from methylene chloride/hexane to yield purified methyl 5-(2,5-dichlorophenylthio)pyrrole-3-carboxylate (2.68 g., m.p. 162°-165° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (3), using 1-fluoro-4-nitrobenzene and 4-(trifluoromethyl)-1H-pyrazole. 1H NMR (400 MHz, CDCl3, δ): 8.38 (m, 1H), 8.30 (m, 1H), 7.97 (s, 2H), 7.90 (m, 2H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[NH2:18].O.[Cl-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCCC>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCl
Product: CC(=O)CC(=O)Nc1c(Br)cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of diketene (57.71 mL, 748.2 mmol) was added dropwise over 2 h to a stirred solution of title compound of Step A (34.57 g, 149.6 mmol) and 4-dimethylaminopyridine (914 mg, 7.48 mmol) in dry tetrahydrofuran (450 mL) at room temperature under a nitrogen atmosphere. The reaction was allowed to stir at room temperature overnight. First, water was added to the reaction, and then the reaction mixture was poured into water. The mixture was saturated with sodium chloride and was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give a brown oil. The brown oil was suspended in 1-chlorobutane. The resultant precipitate was filtered from this suspension to afford the title compound of Step B as a brown solid melting at 136°-138° C. (21.67 g, 46%). 1H NMR (CDCl3): δ2.35 (s,3H), 2.41 (s,3H), 3.63 (s,2H), 7.69 (s,2H), 9.6 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([CH2:26]Cl)[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)[CH:22]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Product: Brc1ccc2nc(COc3ccc(CCCn4ccnc4)cc3)cn2c1
Yield: 57 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 6-bromo-2-chloromethylimidazo[1,2-a]pyridine to give 6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridine. The yield was 57%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 103-104° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[N:7][C:8]=2[CH:22]=1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: NC1CC1
Solvent: ClCCl
Product: C[C@H]1O[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Yield: 50.8 %

Procedure:
Following General Procedure V, cyclopropyl amine (Aldrich, 5 mL, 71.28 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave the title compound (120 mg, 0.33 mmol, 52%); MS (El): m/z (rel. intensity) 358 (0.08, M+); 1H NMR (DMSO-d6) δ7.48 (s, 1H, Ar—H), 7.35 (s, 1H, Ar—H), 7.13 (d, 1H, NH, J=2.0 Hz), 5.61 (d,1H, CH, J=6.6 Hz), 5.25 (m, 2H, 2 overlapping OH), 4.36 (m,1H, CH), 3.88 (m, 1H, CH), 3.79 (m, 1H, CH), 2.76 (m, 1H, CH), 1.36 (d, 3H, CH3, J=6.3 Hz), 0.70 (m, 2H, CH2), 0.53 (m, 2H, CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NCc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[4-(4-Cyano-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was suspended in 10 mL of dry EtOH. To this suspension was added NaBH4 (12.8 mg, 0.46 mmol) followed by CoCl2 (60 mg, 0.46 mmol). Reaction mixture was stirred at room temperature for 4 hours. Reaction mixture was filtered and filtrate concentrated under reduced pressure to yield crude product which was then purified using reverse phase HPLC. MS: 433.1 (M+H+); H1 NMR (MeOH-d4): δ(ppm) 8.00 (d, 2H), 7.49 (m, 3H), 7.37 (m, 2H), 7.18 (d, 1H), 7.02 (m, 2H), 5.03 (m, 2H), 4.49 (m, 1H), 4.16 (s, 2H), 3.96 (m, 2H), 3.61 (m, 2H), 2.39 (m, 1H), 1.99 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2].[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(=NO)(C1C=CC=CC=1)C>[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:25]=[CH:24]/[C:23]2[CH:26]=[CH:27][C:20]([O:19][C:16](=[O:18])[CH3:17])=[CH:21][CH:22]=2)[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(=O)Oc1cc(Br)cc(OC(C)=O)c1
Agent: [Pd]
Agent: CC(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A 10 ml Schlenk tube equipped with a magnetic stirrer is charged with 218 mg (0.8 mmol) 3,5-diacetoxybromobenzene, 136 mg (0.84 mmol) 4-acetoxystyrene, 187 mg potassium carbonate (0.9 mmol) and 0.22 mg (0.1 mol %) of the acetophenon-oxim derived palladium catalyst CAS No. 32679-19-9 as used in Example 9. The tube was evacuated and flushed with argon three times and 1 ml de-aerated DMF was added under inert conditions. The reaction was carried out under stirring for 15 hours at 150° C. Work-up was conducted following the procedure of Example 4 and to give (E)-3,4′,5-triacetoxystilbene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][C:37]2=[O:43])[C:34]=1[Cl:35])[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][C:37]2=[O:43])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CN1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C)CC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg, 0.113 mmol), 3-amino-4-chloro-5-(4-methyl-2-oxopiperazin-1-yl)benzonitrile (28 mg, 0.106 mmol), palladium(ii) acetate (12 mg, 0.053 mmol), XANTPIIOS (12 mg, 0.021 nmmol), DPPF (12 mg, 0.022 mmol) and cesium carbonate (90 mg, 0.275 mmol) in Dioxane (1.5 mL) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 3 h. LC-MS showed reaction was complete. The reaction mixture was filtered through a pad of Celite, rinsed with EtOAc and the filtrate was concentrated and purification via flash chromatography (0-70% EtOAc in Hexane, 24 g) gave 2-((2-chloro-5-cyano-3-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (60 mg) as a light oil.